3: Disorders of the Immune System

The function of the immune system is to protect the host from invasion of foreign organisms by distinguishing “self” from “non-self.” Such a system is necessary for survival. A well-functioning immune system not only protects the host from external factors such as microorganisms or toxins but also prevents and repels attacks by endogenous factors such as tumors or autoimmune phenomena. A normal immune response relies on the careful coordination of a complex network of biological factors, specialized cells, tissue, and organs necessary for the recognition of pathogens and subsequent elimination of foreign antigens. Dysfunction or deficiency of components of the immune system leads to a variety of clinical diseases of varying expression and severity, ranging from atopic disease to rheumatoid arthritis, severe combined immunodeficiency, and cancer. This chapter introduces the intricate physiology of the immune system and abnormalities that lead to diseases of hypersensitivity and immunodeficiency.

Anatomy

Cells of the Immune System

The immune system consists of both antigen-specific and nonspecific components that have distinct yet overlapping functions. The antibody-mediated and cell-mediated immune systems provide specificity and memory of previously encountered antigens. The nonspecific or innate defenses include epithelial barriers, mucociliary clearance, phagocytic cells, and complement proteins. Despite their lack of specificity, these components are essential because they are largely responsible for natural immunity to a vast array of environmental threats and microorganisms. Knowledge of the components and physiology of normal immunity is essential for understanding the pathophysiology of diseases of the immune system.

The major cellular components of the immune system consist of monocytes and macrophages, lymphocytes, and the family of granulocytic cells, including neutrophils, eosinophils, and basophils. Derived from hematopoietic stem cells, these fully differentiated effector cells have membrane receptors for various chemoattractants and mediators, facilitating the activation or destruction of target cells.

Mononuclear phagocytes play a central role in the immune response. Tissue macrophages are derived from blood monocytes and participate in antigen processing, tissue repair, and secretion of mediators vital to initiation of specific immune responses. These cells, abundant near mucosal surfaces that internalize microorganisms and debris, travel to secondary lymphoid organs where they process and present that antigen in a form recognizable to T lymphocytes. In addition, they function as effector cells for certain types of tumor immunity. Circulating monocytes are recruited to sites of inflammation where they mature into macrophages. Both monocytes and macrophages contain receptors for C3b (activated bound complement) and the Fc portion of both immunoglobulin G (IgG) and IgE, which facilitate the activation of these cells through antigen-specific and nonspecific immune pathways. Activation of these cells occurs both after binding to immune complexes through exposure to various cytokines and after phagocytosis of antigen or particulates such as silica and asbestos. Proteolytic enzymes and proinflammatory mediators including cytokines, arachidonic acid metabolites, and oxidative metabolites are utilized in the monocytes and macrophages. Macrophages constitutively express toll-like receptor 4 (TLR4), which can bind bacterial endotoxin, triggering cytokine release and bridging innate and adaptive immune responses. It is hypothesized that macrophage-derived interleukin 12 (IL-12) and tumor necrosis factor (TNF) influence T_H1 and T_H2 differentiation, thereby affecting the expression of atopy and allergic disease. Many epithelial dendritic cells (eg, Langerhans cells, oligodendrocytes, Kupffer cells) may share a common hematopoietic precursor and function to process and transport antigen from skin, respiratory, and gastrointestinal (GI) surfaces to regional lymphoid tissues.

Lymphocytes are responsible for the initial specific recognition of antigen. They are functionally and phenotypically divided into B and T lymphocytes. Structurally, B and T lymphocytes cannot be distinguished visually from each other under the microscope; they can be enumerated by flow cytometric phenotyping or by immunohistochemical methods. Approximately 70–80% of circulating blood lymphocytes are T cells (CD3) and 10–15% are B cells (CD19); the remainder are referred to as natural killer (NK) cells (CD56, CD161, also known as NK cells or null cells).

The thymus-derived cells (T lymphocytes or T cells) are involved in cellular immune responses. B lymphocytes or B cells are involved in humoral or antibody responses. Precursors of T cells migrate to the thymus, where they develop some of the functional and cell surface characteristics of mature T cells. Through positive and negative selection, clones of autoreactive T cells are eliminated, and mature T cells migrate to the peripheral lymphoid tissues. There, they enter the pool of long-lived lymphocytes that recirculate from the blood to the lymph.

T lymphocytes are heterogeneous with respect to their cell surface markers and functional characteristics. Numerous subpopulations of T cells are now recognized. Helper-inducer T cells (CD4) help to amplify B-cell production of immunoglobulin and amplify T-cell (CD8)–mediated cytotoxicity. Activated CD4 T cells regulate immune responses through cell-to-cell contact and by elaboration of soluble factors or cytokines.

Subsets of CD4 T cells can be identified on the basis of their pattern of cytokine production. T_H1 cells develop in the presence of IL-12, secreted from activated macrophages, especially in the presence of infection with intracellular microbes. T_H1 cells elaborate interferon-γ (IFN-γ) and TNF but not IL-4 and IL-5. They participate in cellular immune responses to intracellular pathogens and type IV delayed hypersensitivity reactions. T_H2 cells develop in the presence of IL-4 and secrete IL-4, IL-5, and IL-13, which facilitate humoral responses. Because IL-4 and IL-13 promote IgE production and IL-5 is an eosinophil proliferation and differentiation factor, T_H2 cells have been implicated in response to allergens and helminthes.

Cytotoxic or “killer” T cells (CTLs) are generated after mature T cells interact with certain foreign antigens. They are responsible for defense against intracellular pathogens (eg, viruses), tumor immunity, and organ graft rejection. Most killer T cells express the CD8 phenotype, although in certain circumstances, CD4 T cells can be cytotoxic. CTLs may kill their target through osmotic lysis, by secretion of TNF, or by induction of apoptosis, that is, programmed cell death.

A number of additional T-helper subsets have been discovered that contribute to immune regulation. Mucosal dendritic cells control the generation of regulatory T cells, which modulate inflammatory responses through the secretion of regulatory cytokines. T_H17 cell subsets appear to boost early phagocytic cell responses by recruiting neutrophils to sites of acute inflammation via elaboration of IL-17 and may play a role in autoimmune diseases. T_reg cells express high-affinity receptors for IL-2 (CD25) and FOXP3, a transcription factor that may suppress autoimmune disease. T_reg cells are inhibitory, suppressing activated T effector cells by their secretion of transforming growth factor-β (TGF-β), modulating responses to antigen, thereby regulating homeostasis and tolerance versus inflammation, allergy, and autoimmunity. Mutations of FOXP3 have been associated with inflammatory autoimmune disease, immune dysregulation, polyendocrinopathy, and X-linked syndrome (IPEX).

B-lymphocyte maturation proceeds in antigen-independent and antigen-dependent stages. Antigen-independent development occurs in the marrow where pre-B cells mature into immunoglobulin-bearing naive B cells (cells that have not been exposed to antigen previously). In peripheral lymphoid tissues, antigen-dependent activation produces circulating long-lived memory B cells and plasma cells found predominantly in primary follicles and germinal centers of the lymph nodes and spleen. All mature B cells bear surface immunoglobulin that is their antigen-specific receptor. The major role of B cells is differentiation to antibody-secreting plasma cells. However, B cells may also release cytokines and function as antigen-presenting cells (APCs).

Null cells probably include a number of different cell types, including a group called NK cells. These cells appear distinct from other lymphocytes in that they are slightly larger, with a kidney-shaped nucleolus, have a granular appearance (large granular lymphocytes), express distinct cell surface markers (CD56, CD161), but lack antigen-specific T-cell receptors (CD3, or TCRs). Recruited to sites of inflammation, NK cells possess membrane receptors for the IgG molecules (FcγR), facilitating antibody-dependent cell-mediated cytotoxicity (ADCC). Binding of an antibody-coated cell or foreign substance triggers release of perforin, a pore-forming protein that causes cytolysis. Other NK-cell functions include antibody-independent cellular killing, induction of apoptosis in Fas-expressing cells, and immunomodulation of responses to viruses, malignancy, and transplanted tissue through a potent release of IFN-γ, TNF, and other key cytokines.

Polymorphonuclear leukocytes (neutrophils) are granulocytes that phagocytose and destroy foreign antigens and microbial organisms. They are attracted to the site of antigen by chemotactic factors, including plasma-activated complement 5 (C5a), leukotriene B₄ (LTB₄), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, and platelet-activating factor (PAF). The presence of receptors for complement C3b and invariant/constant regions of IgG molecules (Fcγ) on the surface of neutrophils also facilitates the clearance of opsonized microbes through the reticuloendothelial system. Smaller antigens are phagocytosed and destroyed by lysosomal enzymes. Locally released lysosomal enzymes destroy particles too large to be phagocytosed. Neutrophils contain or generate a number of antimicrobial factors, including oxidative metabolites, superoxide, and hydrogen peroxide, as well as myeloperoxidase, which catalyzes the production of hypochlorite, and proteolytic enzymes, including collagenase, elastase, and cathepsin B.

Eosinophils are often found in inflammatory sites or at sites of immune reactivity and play a crucial role in the host’s defense against parasites. Despite many shared functional similarities to neutrophils, eosinophils are considerably less efficient than neutrophils at phagocytosis. Eosinophils play both a proactive and a modulatory role in inflammation. They are attracted to the site of the antigen-antibody reactions by PAF, C5a, chemokines, histamine, and LTB₄. They are important in the defense against parasites. When stimulated, they release numerous inflammatory factors, including major basic protein (MBP), eosinophil-derived neurotoxin, eosinophil cationic protein (ECP), eosinophil peroxidase, lysosomal hydrolases, and LTC₄. MBP destroys parasites, impairs ciliary beating, and causes exfoliation of respiratory epithelial cells; it may trigger histamine release from mast cells and basophils. Eosinophil-derived products may play a role in the development of airway hyperreactivity.

Basophils play an important role in both immediate- and late-phase allergic responses. These cells release many of the potent mediators of allergic inflammatory diseases, including histamine, leukotrienes (LTs), prostaglandins (PGs), and PAF, all of which have significant effects on the vasculature and on the inflammatory response. Basophils are present in the circulation, possess high-affinity receptors for IgE (FcεRI), and mediate immediate hypersensitivity (allergic) responses.

Mast cells are basophilic staining cells found chiefly in connective and subcutaneous tissue. They have prominent granules that are the source of many mediators of immediate hypersensitivity and have 30,000–200,000 cell surface membrane receptors for the Fc fragment of IgE. When an allergen molecule cross-links two adjacent mast cell surface–associated IgE antibodies, calcium-dependent cellular activation leads to the release of both preformed and newly generated mediators. Mast cells also have surface receptors for “anaphylatoxins” (activated complement fragments, C3a, C4a, and C5a), cytokines, and neuropeptides, such as substance P. Activation by these non–IgE-mediated mechanisms may contribute to host immunity and provide ties between the immune and neuroendocrine systems. Mast cell–deficient mice display a particular vulnerability to sepsis and rapid death after peritonitis, possibly due to insufficient TNF production during bacterial infection. Mast cells also appear in areas of wound healing and in fibrotic lung disease. Experimentally, mast cell–derived mediators promote angiogenesis and fibrogenesis, suggesting their presence in these sites is pathologically relevant.

Organs of the Immune System

Several tissues and organs play roles in host defenses and are functionally classified as the immune system. In mammals, the primary lymphoid organs are the thymus and the bone marrow.

All cells of the immune system are originally derived from bone marrow. Pluripotent stem cells differentiate into lymphocyte, granulocyte, monocyte, erythrocyte, and megakaryocyte populations. In humans, B lymphocytes, which are the antibody-producing cells, undergo early antigen-independent maturation into immunocompetent cells in the bone marrow. Deficiency or dysfunction of the pluripotent stem cell or the various cell lines developing from it can result in immune deficiency disorders of varying expression and severity.

The thymus, derived from the third and fourth embryonic pharyngeal pouches, functions to produce T lymphocytes and is the site of initial T-lymphocyte differentiation. Its reticular structure allows a significant number of lymphocytes to migrate through it to become fully immunocompetent thymus-derived cells. Developing T cells in the thymic cortex are first positively selected for their ability to recognize self-peptides (ie, major histocompatibility complex, MHC). In subsequent negative selection, T cells that avidly recognize self-peptides are destroyed, thus removing deleterious self-reactive clones. In some murine models, autoimmune diseases such as systemic lupus erythematosus may develop in mice with defective apoptotic (programmed cell death) pathways in T cells recognizing self-antigen. The thymus also regulates immune function by secretion of multiple hormones that promote T-lymphocyte differentiation and are essential for T-lymphocyte–mediated immunity.

In mammals, the lymph nodes, spleen, and gut-associated lymphoid tissue are secondary lymphoid organs connected by blood and lymphatic vessels. Lymph nodes are strategically dispersed throughout the vasculature and are the principal organs of the immune system that localize antigen, promote cell-cell interaction and lymphocyte activation, and prevent the spread of infection. Lymph nodes have a framework of reticular cells and fibers that are arranged into a cortex and medulla. B lymphocytes, the precursors of antibody-producing cells, or plasma cells, are found in the cortex (the follicles and germinal centers) as well as in the medulla. T lymphocytes are found chiefly in the medullary and paracortical areas of the lymph node (Figure 3–1). The spleen filters and processes antigens from the blood and is functionally and structurally divided into B-lymphocyte and T-lymphocyte areas, similar to those of the lymph nodes.

Gut-associated lymphoid tissue includes the tonsils, Peyer patches of the small intestine, and the appendix. Like the lymph nodes and spleen, these tissues exhibit separation into B-lymphocyte–dependent and T-lymphocyte–dependent areas. Mucosal immune responses tend to generate antigen-specific IgA, and with some orally administered antigens, T-cell anergy or tolerance may occur rather than immune stimulation.

Inflammatory Mediators

Mediators are released or generated during immune responses to coordinate and regulate immune cell activities to generate physiological or cytotoxic responses. They target many diverse cell types, can have antiviral, proinflammatory, or anti-inflammatory activities, act locally or systemically, and can be redundant in their actions (Table 3–1). Mediators may exist in a preformed state in the granules of mast cells and basophils or are newly synthesized at the time of activation of these and some other nucleated cells. Increased awareness of the immunologic and physiologic effects of mediators has led to a better understanding of immunopathology and provides potential targets for future pharmacotherapies.

Preformed mediators include histamine, eosinophil and neutrophil chemoattractants, proteoglycans (heparin, chondroitin sulfate), and various proteolytic enzymes. Histamine is a bioactive amine, packaged in dense intracellular granules, that when released binds to membrane-bound H₁, H₂, and H₃ receptors, resulting in significant physiologic effects. Binding to H₁ receptors causes smooth muscle contraction, vasodilatation, increased vascular permeability, and stimulation of nasal mucous glands. Stimulation of H₂ receptors causes enhanced gastric acid secretion, mucus secretion, and leukocyte chemotaxis. Histamine is important in the pathogenesis of allergic rhinitis, allergic asthma, and anaphylaxis.

Newly generated mediators include kinins, PAF, and arachidonic acid metabolites, including LTs and PGs. In many immune cells, arachidonic acid, liberated from membrane phospholipid bilayers, is metabolized either by the lipoxygenase pathway to form LTs or by the cyclooxygenase pathway to form PGs and thromboxanes A₂ and B₂ (TXA₂ and TXB₂). LTB₄ is a potent chemoattractant for neutrophils. LTC₄, LTD₄, and LTE₄ constitute slow-reacting substance of anaphylaxis, which has bronchial smooth muscle spasmogenic potency 100–1000 times that of histamine, and which also causes vascular dilation and vascular permeability.

Almost all nucleated cells generate PGs. The most important members are PGD₂, PGE₂, PGF₂, and PGI₂ (prostacyclin). Human mast cells produce large amounts of PGD₂, which causes vasodilatation, vascular permeability, and airway constriction. Activated polymorphonuclear neutrophils and macrophages generate PGF_2α, a bronchoconstrictor, and PGE₂, a bronchodilator. PGI₂ causes platelet disaggregation. TXA₂ causes platelet aggregation, bronchial constriction, and vasoconstriction.

Macrophages, neutrophils, eosinophils, and mast cells generate PAF, which causes platelet aggregation, vasodilatation, increased vascular permeability, and bronchial smooth muscle contraction. PAF is the most potent eosinophil chemoattractant described and also plays a role in anaphylaxis. The kinins are vasoactive peptides formed in plasma when kallikrein, released by basophils and mast cells, digests plasma kininogen. Kinins, including bradykinin, contribute to human angioedema and anaphylaxis by causing slow, sustained contraction of bronchial and vascular smooth muscle, vascular permeability, secretion of mucus, and stimulation of pain fibers.

Complement Cascades

The union of antigen with IgG or IgM antibody initiates activation of the classic complement pathway. Complement-fixing sites on these immune complexes are exposed, allowing binding of the first component of the complement sequence, C1q. Other components of the complement sequence are subsequently bound, activated, and cleaved, eventually leading to cell lysis. Important byproducts of the classic pathway include activated cleavage products, the anaphylatoxins C3a, C5a, and less-potent C4a. C5a is a potent leukocyte chemotactic factor and causes mediator release from mast cells and basophils. C4b and C3b mediate binding of immune complexes to phagocytic cells, facilitating opsonization.

Activation of the complement sequence by the alternative pathway is initiated by a number of agents, including lipopolysaccharides (LPSs), trypsin-like molecules, aggregated IgA and IgG, and cobra venom. Activation of the alternative pathway does not require the presence of antigen-antibody complexes or use the early components of the complement sequence, C1, C4, and C2. Ultimately, as a result of activation of the classic or alternative pathway, activation of the terminal complement sequence occurs, resulting in cell lysis and/or tissue inflammation. Soluble inhibitors regulate the complement pathway to prevent unchecked activation and prolonged inflammation. Deficiency of one factor, C1-esterase inhibitor, leads to recurrent, potentially life-threatening attacks of facial, laryngeal, and GI swelling in hereditary angioedema.

Cytokines

Many immune functions are regulated or mediated by cytokines, which are soluble factors secreted by activated immune cells. Cytokines can be functionally organized into groups according to their major activities: (1) those that promote inflammation and mediate natural immunity, such as IL-1, IL-6, IL-8, TNF, and IFN-γ; (2) those that support allergic inflammation, such as IL-4, IL-5, and IL-13; (3) those that control lymphocyte regulatory activity, such as IL-10, IL-12, and IFN-γ; and (4) those that act as hematopoietic growth factors, IL-3, IL-7, and GM-CSF (Table 3–1). A group of chemotactic factors (chemokines) regulate homing and migration of immune cells to sites of inflammation. Human immunodeficiency virus (HIV) may exploit certain chemokine receptors to infect host cells, and natural mutations in these same chemokine coreceptors may confer a susceptibility or resistance to infection.

Physiology

Innate & Adaptive Immunity

Living organisms exhibit two levels of response against external invasion: an innate system of natural immunity and an adaptive system that is acquired. Innate immunity is present from birth, does not require previous antigenic exposure, and is nonspecific in its activity. The skin and epithelial surfaces serve as the first line of defense of the innate immune system, whereas enzymes, the alternative complement system pathway, acute-phase proteins, phagocytic, NK cells, and cytokines provide additional layers of protection. Microbial cell walls or nucleic acids contain nonmammalian patterns or motifs that can bind to TLRs on innate immune cells including macrophages and dendritic cells. Their structure is highly conserved and each TLR binds to specific microbial products, such as LPS (or bacterial endotoxin), viral RNA, microbial DNA and yeast wall mannon proteins. Binding of TLR and ligand triggers transcription of proinflammatory factors and cytokine synthesis prior to adaptive responses. Through a series of proteolytic activations, the serum and membrane components of the complement cascade amplify and regulate microbial killing and inflammation. Despite the lack of specificity, innate immunity is largely responsible for protection against a vast array of environmental microorganisms and foreign substances.

Higher organisms have evolved an adaptive immune system, which is triggered by encounters with foreign agents that have evaded or penetrated the innate immune defenses. The adaptive immune system is characterized both by specificity for individual foreign agents and by immunologic memory, which makes possible an intensified response to subsequent encounters with the same or closely related agents. Primary adaptive immune responses require clonal expansion, leading to a delayed response to new exposures. Secondary immune responses are more rapid, larger, and more efficient. Stimulation of the adaptive immune system triggers a complex sequence of events that initiate the activation of lymphocytes, the production of antigen-specific antibodies (humoral immunity) and effector cells (cellular or cell-mediated immunity), and ultimately, the elimination of the inciting substance. Although adaptive immunity is antigen-specific, the repertoire of responses is tremendously diverse, with an estimated 10⁹ antigenic specificities.

Antigens (Immunogens)

Foreign substances that can induce an immune response are called antigens or immunogens. Immunogenicity implies that the substance has the ability to react with antigen-binding sites on antibody molecules or TCRs. Complex foreign agents possess distinct and multiple antigenic determinants or “epitopes,” dependent on the peptide sequence and conformational folding of immunogenic proteins. Most immunogens are proteins, although pure carbohydrates may be immunogenic as well. It is estimated that the human immune system can respond to 10⁷–10⁹ different antigens, an amazingly diverse repertoire.

Immune Response

The primary role of the immune system is to discriminate self from non-self and to eliminate the foreign substance. The physiology of the normal immune response to antigen is summarized in Figure 3–2. A complex network of specialized cells, organs, and biologic factors is necessary for the recognition and subsequent elimination of foreign antigens. These complex cellular interactions require specialized microenvironments in which cells can collaborate efficiently. Both T and B cells need to migrate throughout the body to increase the likelihood that they will encounter an antigen to which they have specificity. Soluble antigens are transported to regional lymph tissues through afferent lymphatic vessels, while other antigens are carried by phagocytic dendritic cells. Regional, peripheral lymphoid organs and the spleen are sites for concentrated immune responses to antigen by recirculating lymphocytes and APCs. Antigens encountered via inhaled or ingested routes activate cells in the mucosa-associated lymphoid tissues. The major pathways of antigen elimination include the direct killing of target cells by cytotoxic T lymphocytes (CTLs; cellular response) and the elimination of antigen through antibody-mediated events arising from T- and B-lymphocyte interactions (humoral response). The series of events that initiate the immune response includes antigen processing and presentation, lymphocyte recognition and activation, cellular or humoral immune responses, and antigenic destruction or elimination.

Antigen Processing & Presentation

Most foreign immunogens are not recognized by the immune system in their native form and require capture and processing by professional APCs, which constitutively express class II MHC molecules and accessory costimulatory molecules on their surfaces. Such specialized cells include macrophages, dendritic cells in lymphoid tissue, Langerhans cells in the skin, Kupffer cells in the liver, microglial cells in the nervous system, and B lymphocytes. Dendritic cells in the spleen and lymph nodes may be the primary APCs during a primary immune response. Following an encounter with immunogens, the APCs internalize the foreign substance by phagocytosis or pinocytosis, modify the parent structure, and display antigenic fragments of the native protein on its surfaces in association with MHC class II molecules (see later discussion). T-cell–independent antigens such as polysaccharides can activate B cells without assistance from T cells by binding to B-cell receptors (BCRs, or surface-bound antibody), leading to rapid IgM responses, without generation of memory cells or long-lived plasma cells. Most antigens, however, require internalization and processing by B cells or other APCs with subsequent recognition by CD4 T cells.

T-Lymphocyte Recognition & Activation

The recognition of processed antigen by specialized T lymphocytes known as helper T (CD4) lymphocytes and the subsequent activation of these cells constitute the critical events in the immune response. The helper T lymphocytes orchestrate the many cells and biologic signals (cytokines) that are necessary to carry out the immune response. Activated CD4 T lymphocytes are mainly cytokine-secreting helper cells, whereas CD8 T lymphocytes are mainly cytotoxic killer cells.

Helper T lymphocytes recognize processed antigen displayed by APCs only in association with polymorphic cell surface proteins called the major histocompatibility complex (MHC). MHC genes are highly polymorphic and determine immune responsiveness. They are known as human leukocyte antigen (HLA). The genes encoding MHC distinguish self from non-self, thereby determining immune responsiveness to foreign agents, enabling graft rejection, and conferring susceptibility to certain autoimmune disorders. All somatic cells express MHC class I, whereas only the specialized APCs can express MHC class II. Exogenous foreign antigens are expressed in association with MHC class II structures, expressed only by specialized APCs.

During cell-cell contact between T helper cells and APCs, the process of dual recognition is referred to as MHC restriction. The antigen–MHC class II complex forms the epitope that is recognized by antigen-specific TCRs on the surface of the CD4 molecules. The TCR is composed of six gene products, TCR α- and β-subunits, CD3 (γ-, δ-, and two ε-subunits), and ζ₂ chains. Besides binding to modified antigen, activation of T cells depends on the costimulation of accessory molecules. Accessory molecules on T cells bind to ligands found on APCs, epithelial cells, vascular endothelium, and extracellular matrix, controlling the subsequent T-cell function or homing (Table 3–2). In the absence of such signals, the T cell may be “tolerized” or may undergo apoptosis instead of being activated. Biologic products that block some of these costimulatory pathways are currently being investigated as potential therapeutic agents to prevent organ rejection in transplantation and in the management of some autoimmune diseases.

Before an activated T cell can differentiate, proliferate, produce cytokines, or participate in cell killing, the activation signal must be transduced into the cytoplasm or nucleus of the cell. The principal signaling molecules in the TCR complex appear to be the CD3 and the ζ homodimer or heterodimer. The presence of immunoreceptor tyrosine activation motifs associated with each TCR complex facilitates amplification of signaling. The binding of ZAP-70 (zeta-associated protein 70), a Syk-family protein tyrosine kinase (PTK), to CD3ε and ζ-subunits after they are phosphorylated is critical for downstream signaling. Another important enzyme in the activation of T cells is CD45, a protein tyrosine phosphatase. The critical nature of these enzymes in lymphocyte development is underscored by the discovery of ZAP-70 and CD45 deficiency syndromes, disorders that result in various forms of severe combined immunodeficiency disease (SCID, see Primary Immunodeficiency Diseases).

Activation of T cells does not occur in isolation but is also dependent on the cytokine milieu. In true autocrine fashion, the APCs involved in antigen presentation release IL-1, which induces the release of both IL-2 and IFN-γ from CD4 cells. IL-2 feeds back to stimulate the expression of additional IL-2 receptors on the surface of the CD4 cells and stimulates the production of various cell growth and differentiation factors (cytokines) by the activated CD4 cells. Induction of IL-2 expression is particularly critical for T cells. Cyclosporine and tacrolimus (FK506), two immunosuppressive agents used for prevention of organ transplant rejection, function by downregulating IL-2 production by T cells.

CD8 Effector Cells (Cellular Immune Response)

CTLs eliminate target cells (virally infected cells, tumor, or foreign tissues), thus constituting the cellular immune response. CTLs differ from helper T lymphocytes in their expression of the surface antigen CD8 and by the recognition of antigen complexed to cell surface proteins of MHC class I. All somatic cells can express MHC class I molecules. Pathogenic microorganisms, whose proteins gain access to the cell cytoplasm (eg, malarial parasites) or by de novo gene expression in the infected cell cytoplasm (eg, viruses) stimulate CD8 class I MHC-restricted T-cell responses. Killing of target cells by CTLs requires direct cell-to-cell contact. Two major mechanisms for killing target cells have been described: (1) CTL secretion of a pore-forming protein (perforin) that inserts in the plasma membrane of target cells along with serine proteases called granzymes, leading to osmotic lysis; and (2) expression of the Fas ligand on the surface of CTLs that bind to Fas on the target cell membrane inducing programmed cell death (apoptosis). In addition to killing infected cells directly, CD8 T cells can elaborate a number of cytokines, including TNF and lymphotoxin. Memory CTLs may be long-lived to provide “recall” responses and immunity against latent or persistent viral infections.

Activation of B Lymphocytes (Humoral Immune Response)

The primary function of mature B lymphocytes is to synthesize antibodies. Like T-cell activation, B-lymphocyte activation is triggered after antigen binds to BCRs (ie, surface-bound immunoglobulin) and is regulated through concomitant coreceptor binding. In secondary lymphoid tissues, release of cytokines IL-2, IL-4, IL-5, and IL-6 by activated helper T lymphocytes promotes the proliferation and terminal differentiation of B cells into high-rate antibody-producing cells called plasma cells, which secrete antigen-specific immunoglobulin. If complement fragments bind B-cell surface complement receptors at the same time antigen engages BCRs, cellular responses are heightened. T cells also modulate humoral immunity through their activation-dependent membrane expression of CD40 ligand protein. Through direct T- and B-cell contact, CD40 ligand binds to the CD40 receptor on the surface of B cells, inducing apoptosis (programmed cell death) or activation of immunoglobulin synthesis, depending on the situation. The importance of CD40 ligand-CD40 binding in normal humoral immunity is highlighted by the congenital immunodeficiency, X-linked hyper-IgM syndrome. A defect in the synthesis of CD40 ligand on activated T cells results in impaired “isotype switching” and hyper-IgM, with subsequent deficient production of IgG, IgA, and impaired humoral immunity.

Although their primary function is synthesis of immunoglobulin, B lymphocytes may also bind and internalize foreign antigen directly, process that antigen, and present it to CD4 T lymphocytes. A pool of activated B lymphocytes may differentiate into memory cells, which respond more rapidly and efficiently to subsequent encounters with identical or closely related antigenic structures.

Antibody Structure & Function

Antibodies (immunoglobulins) are proteins that possess “specificity,” enabling them to combine with one particular antigenic structure. Antigen-binding sites for immunoglobulin will recognize three-dimensional structures, whereas TCR will bind short peptide segments without tertiary structure. Humoral (antibody-mediated) immune responses result in the production of a diverse repertoire (estimated 10⁹–10¹¹) of antibody specificities, providing the ability to recognize and bind with a broad range of antigens. This diversity is a function of somatic recombination of gene segments within B lymphocytes early in ontogenetic development. Somatic mutations occurring after antigenic stimulation lead to affinity maturation, ie, the average affinity of antibody binding increases throughout the immune response. Somatic recombination, in both T cells and B cells, is dependent on recombination-activating genes (RAG1 and RAG2), the deficiency of which leads to a lack of T and B lymphocytes, an autosomal recessive form of SCID.

All immunoglobulin molecules share a four-chain polypeptide structure consisting of two heavy and two light chains (Figure 3–3). Each chain includes an amino terminal portion, containing the variable (V) region, and a carboxyl terminal portion, containing four or five constant (C) regions. V regions are highly variable structures that form the antigen-binding site, whereas the C domains support effector functions of the molecules. The five classes (isotypes) of immunoglobulins are IgG, IgA, IgM, IgD, and IgE and are defined on the basis of differences in the C region of the heavy chains. The isotype expressed by a particular B lymphocyte is dependent on the state of cellular differentiation and “isotype switching,” a process characterized by splicing of heavy chain mRNA prior to translation. Different isotypes contribute to different effector functions on the basis of the ability of the molecule to bind to specific receptors and their efficiency in fixing serum complement. IgG is the predominant immunoglobulin in serum with the longest half-life. Four subclasses—IgG₁, IgG₂, IgG₃, and IgG₄—differ in their relative quantities and targets (protein vs. carbohydrate antigens). IgA is the predominant immunoglobulin on mucous membrane surfaces. It exists predominantly as a monomer in serum and as a dimer or trimer when secreted on mucous membrane surfaces. IgA antibodies protect the host from foreign antigens on mucous membrane surfaces, but they do not fix complement by the classic pathway. IgM is a pentamer that is found almost exclusively in the intravascular compartment. IgM is expressed early in immune responses, providing rapid adaptive immunity and detection of antigen-specific IgM can be used diagnostically during certain infections. IgD is a monomeric immunoglobulin. Its biological function is unknown. IgE is the heaviest immunoglobulin monomer, with a normal concentration in serum varying from 20 to 100 IU, but the concentration may be 5 times normal or even higher in an atopic individual. The Fc portion of IgE binds to receptors on the surfaces of mast cells and basophils. IgE antibodies play an important role in immediate hypersensitivity reactions.

Humoral Mechanisms of Antigen Elimination

Antibodies induce the elimination of foreign antigen through a number of different mechanisms. Binding of antibody to bacterial toxins or foreign venoms may cause neutralization or promote elimination of these antigen-antibody immune complexes through the reticuloendothelial system. Antibodies may coat bacterial surfaces, enhancing phagocytosis by macrophages in a process known as opsonization. Some classes of antibodies may complex with antigen and activate the complement cascade (“complement fixation”), culminating in lysis of the target cell. Finally, the major class of antibody, IgG, can bind to NK cells that subsequently complex with target cells and release cytotoxins (see prior discussion of antibody-dependent cellular cytotoxicity). IgG passes transplacentally, providing passive immunization of neonates.

After the successful elimination of antigen, the immune system uses several mechanisms to return to basal homeostasis. IgG can switch off its own response to antigen through the binding of immune complexes that transmit inhibitory signals into the nuclei of B cells.

Mechanisms of Inflammation

Elimination of foreign antigen by cellular or humoral processes is integrally linked to the inflammatory response, in which cytokines and antibodies trigger the recruitment of additional cells and the release of endogenous vasoactive and proinflammatory enzymatic substances (inflammatory mediators).

Inflammation may have both positive and deleterious effects. Tight control of inflammatory mechanisms promotes efficient elimination of foreign substances, killing of microbes, infected cells, and tumors. Uncontrolled lymphocyte activation and unregulated antibody production, however, can lead to tissue damage and organ dysfunction. Pathogenic immune dysfunction is responsible for hypersensitivity reactions, immunodeficiency, and many of the clinical effects of autoimmunity. Imbalances in the inflammatory system may result from genetic defects, infection, neoplasms, and exposure to environmental triggers, although precise mechanisms that promote abnormal regulation and persistence of inflammatory processes are complex and poorly understood.

Hypersensitivity Immune Responses

Gell and Coombs classified the mechanisms of immune responses to antigen into four distinct types of reactions to allow for clearer understanding of the immunopathogenesis of disease.

Type I

Clinical allergy represents IgE-mediated hypersensitivity response arising from deleterious inflammation in response to the presence of normally harmless environmental antigens. Anaphylactic or immediate hypersensitivity reactions occur after binding of antigen to IgE antibodies attached to the surface of the mast cell or basophil and result in the release of preformed and newly generated inflammatory mediators that produce the clinical manifestations. Examples of type I–mediated reactions include anaphylactic shock, allergic rhinitis, allergic asthma, and allergic drug reactions.

Type II

Cytotoxic reactions involve the binding of either IgG or IgM antibody to antigens covalently bound to cell membrane structures. Antigen-antibody binding activates the complement cascade and results in destruction of the cell to which the antigen is bound. Examples of tissue injury by this mechanism include immune hemolytic anemia and Rh hemolytic disease in the newborn. Another example of the type II–mediated disease process without cell death is autoimmune hyperthyroidism, a disorder in which anti-thyroid antibodies stimulate thyroid tissue.

Type III

Antigen binding to antibodies with fixation of complement forms immune complex–mediated reactions. Complement-bound immune complexes facilitate opsonization by phagocytes and ADCC. Complexes are usually cleared from the circulation in the reticuloendothelial system. However, deposition of these complexes in tissues or in vascular endothelium can produce immune complex–mediated tissue injury through complement activation, anaphylatoxin generation, chemotaxis of polymorphonuclear leukocytes, mediator release and tissue injury. Cutaneous Arthus reaction, systemic serum sickness, some aspects of clinical autoimmunity, and certain features of infective endocarditis are clinical examples of type III–mediated diseases.

Type IV

Cell-mediated immunity is responsible for host defenses against intracellular pathogenic organisms, although abnormal regulation of this system may result in delayed-type hypersensitivity. Type IV hypersensitivity reactions are mediated not by antibody but by antigen-specific T lymphocytes. Classic examples are tuberculin skin test reactions and contact dermatitis.

Synthesis of IgE in Allergic Reactivity

Allergic hypersensitivity results from the inappropriate and sustained production of IgE in response to allergen. T_H2 cytokines IL-4 and IL-13 are critical to isotype switching through induction of germline transcription of IgE heavy chain genes. IL-13 has about 30% structural homology with IL-4 and shares much of the activities of IL-4 on mononuclear cells and B lymphocytes. There is a strong genetic predisposition toward the development of atopic disease. Evidence has been found for the linkage of 5q31.1 and the IL-4 gene, suggesting that IL-4 or a nearby gene in this chromosome locale regulates overall IgE production.

In contrast, T_H1-generated IFN-γ inhibits IL-4–dependent IgE synthesis in humans. Thus, an imbalance favoring IL-4 over IFN-γ may induce IgE formation. In one study, reduced cord blood IFN-γ at birth was associated with clinical atopy at age 12 months.

In allergic inflammatory processes, T_H2 lymphocytes represent a source of IL-4 as well as secondary signals necessary to drive the production of IgE by B lymphocytes. Another T_H2 cytokine, IL-5, promotes maturation, activation, chemotaxis, and prolongation of survival in eosinophils. In situ hybridization analyses of T-cell mRNA in airway mucosal biopsies from allergic rhinitis and asthma patients show a distinct T_H2 pattern. The demonstration of allergen-specific T-cell lines that proliferate and secrete large amounts of IL-4 on exposure to relevant antigen in vitro further supports the existence of specific T_H2-like clones. The original source of the IL-4 responsible for T_H2 differentiation is unclear, although some observations suggest that there exists a T_H2 bias during fetal development in both atopic and nonatopic individuals. The “hygiene hypothesis” posits that environmental exposures, possibly to bacterial products such as endotoxin or bacterial DNA, encourage a shift toward T_H1 and subsequent reduced risk of clinical atopic disease. Mononuclear phagocytes are the major source of IL-12, suggesting a mechanism whereby antigens more likely to be processed by macrophages, including bacterial antigens and intracellular pathogens, produce T_H1 responses. Epidemiologic studies of children suggest those exposed to daycare at early ages and those with numerous siblings are at reduced risk for atopy and asthma.

Since the discovery of IgE more than 3 decades ago, scientists have considered various therapeutic strategies to selectively inhibit IgE antibody production and action. Research has focused on understanding the mechanisms controlling IgE production, including the molecular events of B-cell switching to IgE synthesis, IL-4 and IL-13 signaling, T- and B-cell surface receptor interactions, and mechanisms driving T_H2 differentiation. Soluble cytokine receptors and genetically engineered monoclonal antibodies are currently under development for the purpose of cytokine neutralization in allergic diseases. Many of these specifically target IL-4, IL-5, IL-13, or CD23 (a low-affinity IgE receptor). Other experimental strategies include treatment with agents such as DNA oligonucleotides that are biased toward T_H1 immune responses. Conventional and modified immunotherapy may work by eliminating (“anergize”) rather than stimulating T_H2 responses to environmental allergen, potentially through generation of T_reg. Besides conventional immunotherapy (allergy shots), the only other U.S. Food and Drug Administration (FDA)–approved immunomodulatory strategy for treatment of allergic disease is omalizumab or “anti-IgE.” Omalizumab is a humanized monoclonal antibody directed against the region of IgE heavy chain involved in the interaction with IgE receptors. Clinical trials in asthma patients have shown that this antibody can reduce symptoms and medication requirements in patients with allergic asthma, though anaphylaxis has occurred both after first dose and after >1 year of use.

Allergic Rhinitis

Clinical Presentation

Allergic airway diseases such as allergic rhinitis and asthma are characterized by local tissue damage and organ dysfunction in the upper and lower respiratory tract arising from an abnormal hypersensitivity immune response to normally harmless and ubiquitous environmental allergens. Allergens that cause airway disease are predominantly seasonal tree, grass, and weed pollens or perennial inhalants (eg, house dust mite antigen, cockroach, mold, animal dander, and some occupational protein antigens). Allergic disease is a common cause of pediatric and adult acute and chronic airway problems. Both allergic rhinitis and asthma account for significant morbidity, and atopic disorders have increased in prevalence over the past few decades. In a Danish survey, the prevalence of skin test–positive allergic rhinitis in persons 15–41 years of age increased from 12.9% in 1990 to 22.5% in 1998. Allergic rhinitis is discussed here as a model for the pathophysiology of IgE-mediated allergic airway disease.

Etiology

Allergic rhinitis implies the existence of type I (IgE-mediated) immediate hypersensitivity to environmental allergens that impact the upper respiratory mucosa directly. Particles larger than 5 μm are filtered almost completely by the nasal mucosa. Because most pollen grains are at least this large, few intact particles would be expected to penetrate the lower airway when the nose is functioning normally. The allergic or atopic state is characterized by an inherited tendency to generate IgE antibodies to specific environmental allergens and the physiologic responses that ensue from inflammatory mediators released after the interaction of allergen with mast cell-bound IgE. The clinical presentation of allergic rhinitis includes nasal, ocular, and palatal pruritus, paroxysmal sneezing, rhinorrhea, and nasal congestion. A personal or family history of other allergic diseases such as asthma or atopic dermatitis supports a diagnosis of allergy. Evidence of nasal eosinophilia or basophilia by nasal smear or scraping may support the diagnosis also. Confirmation of allergic rhinitis requires the demonstration of specific IgE antibodies to common allergens by in vitro tests such as the radioallergosorbent test or in vivo (skin) testing in patients with a history of symptoms with relevant exposures.

Pathology & Pathogenesis

Inflammatory changes in the airways are recognized as critical features of both allergic rhinitis and chronic asthma. Cross-linking of surface-bound IgE by antigen activates tissue mast cells and basophils, inducing the immediate release of preformed mediators and the synthesis of newly generated mediators. Mast cells and basophils also have the ability to synthesize and release proinflammatory cytokines, growth and regulatory factors that interact in complex networks. The interaction of mediators with various target organs and cells of the airway can induce a biphasic allergic response: an early phase mediated chiefly by release of histamine and other stored mediators (tryptase, chymase, heparin, chondroitin sulfate, and TNF), whereas late-phase events are induced after generation of arachidonic acid metabolites (LTs and PGs), PAF, and de novo cytokine synthesis.

The early-phase response occurs within minutes after exposure to an antigen. After intranasal challenge or ambient exposure to relevant allergen, the allergic patient begins sneezing and develops an increase in nasal secretions. After approximately 5 minutes, the patient develops mucosal swelling leading to reduced airflow. These changes are secondary to the effects of vasoactive and smooth muscle constrictive mediators, including histamine, N-α-p-tosyl-L-arginine methylester-esterase (TAME), LTs, PGD₂, and kinins and kininogens from mast cells and basophils. Histologically, the early response is characterized by vascular permeability, vasodilatation, tissue edema, and a mild cellular infiltrate of mostly granulocytes.

The late-phase allergic response may follow the early-phase response (dual response) or may occur as an isolated event. Late-phase reactions begin 2–4 hours after initial exposure to antigen, reach maximal activity at 6–12 hours, and usually resolve within 12–24 hours. If the exposure is frequent or ongoing, however, the inflammatory response becomes chronic. The late-phase response is characterized by erythema, induration, heat, burning, and itching and microscopically by a significant cellular influx of mainly eosinophils and mononuclear cells. Changes consistent with airway remodeling and tissue hyperreactivity may also occur.

Mediators of the early-phase response—except for PGD₂—reappear during the late-phase response in the absence of antigen reexposure. Absence of PGD₂, an exclusive product of mast cell release, in the presence of continued histamine release suggests that basophils and not mast cells are an important source of mediators in the late-phase response. There is an early accumulation of neutrophils and eosinophils, with later accumulation of activated T cells, synthesizing T_H2 cytokines. Inflammatory cells infiltrating tissues in the late response may further elaborate cytokines and histamine-releasing factors that may perpetuate the late-phase response, leading to sustained hyperresponsiveness, mucus hypersecretion, IgE production, eosinophilia, and disruption of the target tissue (eg, bronchi, skin, or nasal mucosa).

There is strong circumstantial evidence that eosinophils are key proinflammatory cells in allergic airway disease. Eosinophils are frequently found in secretions from the nasal mucosa of patients with allergic rhinitis and in the sputum of asthmatics. Products of activated eosinophils such as MBP and eosinophilic cationic protein, which are destructive to airway epithelial tissue and predispose to persistent airway reactivity, have also been localized to the airways of patients with allergic disease.

The recruitment of eosinophils and other inflammatory cells to the airway is largely a product of activated chemokines and adhesion molecules. There are two subfamilies of chemokines, which differ in the cells they primarily attract and in the chromosome location of their genes. The C-C chemokines, including RANTES, MCP-1, MCP-3, and eotaxin, are located on chromosome segment 7q11-q21 and selectively recruit eosinophils. Leukocytes attach to vascular endothelial cells through receptor-ligand interaction of cell surface adhesion molecules of the integrin, selectin, and immunoglobulin supergene family. The interaction of these adhesion molecules and their counter receptors mediates a sequence of events that includes margination of leukocytes along the walls of the microvasculature, adhesion of leukocytes to the epithelium, transmigration of leukocytes through vessel walls, and migration along a chemotactic gradient to reach tissue compartments. Both chemokine production and adhesion molecule expression are upregulated by soluble inflammatory mediators. For instance, endothelial cell adhesion molecule receptors, ICAM-1, VCAM-1, and E-selectin, are upregulated by IL-1, TNF, and LPS.

Clinical Manifestations

The clinical manifestations of allergic airway disease (Table 3–3) arise from the interaction of mast cell and basophil mediators with target organs of the upper and lower airway. The symptoms of allergic rhinitis appear immediately after exposure to a relevant allergen (early-phase response), although many patients experience chronic and recurrent symptoms on the basis of the late-phase inflammatory response. Complications of severe or untreated allergic rhinitis include sinusitis, auditory tube dysfunction, hyposmia, sleep disturbances, asthma exacerbations, and chronic mouth breathing.

Sneezing, Pruritus, Mucus Hypersecretion

Patients with allergic rhinitis develop chronic or episodic paroxysmal sneezing; nasal, ocular, or palatal pruritus; and watery rhinorrhea triggered by exposure to a specific allergen. Patients may demonstrate signs of chronic pruritus of the upper airway, including a horizontal nasal crease from frequent nose rubbing (“allergic salute”) and palatal “clicking” from rubbing the itching palate with the tongue. Many tissue mast cells are located near terminal sensory nerve endings. Pruritus and sneezing are caused by histamine-mediated stimulation of these C fibers. Mucus hypersecretion results primarily from excitation of parasympathetic-cholinergic pathways. Early-phase symptoms are best treated with avoidance of relevant allergens and oral or topical antihistamines, which competitively antagonize H₁ receptor sites in target tissues. Anti-inflammatory treatment can reduce cellular inflammation during the late phase, providing more effective symptom relief than antihistamines alone. Allergen immunotherapy (hyposensitization) has shown effectiveness in reducing symptoms and airway inflammation by inhibiting both early- and late-phase allergic responses. Diverse mechanisms of immunotherapy have been observed, including reduction of seasonal increases in IL-4 and allergen-specific IgE, induction of allergen-specific IgG₁ and IgG₄ (blocking antibodies), modulation of T-cell cytokine synthesis by enhancing T_H1 and inhibiting T_H2 responses, upregulation of T_reg and downregulation of eosinophilic and basophilic inflammatory responses to allergen. One trial found that immunotherapy administered to patients with grass-pollen allergy for 3–4 years induced prolonged clinical remission accompanied by a persistent alteration in immunologic reactivity that included sustained reductions in the late skin response and associated T-cell infiltration and IL-4 mRNA expression.

Nasal Stuffiness

Symptoms of nasal obstruction may become chronic as a result of persistent late-phase allergic mechanisms. Nasal mucous membranes may appear pale blue and boggy. Children frequently show signs of obligate mouth breathing, including long facies, narrow maxillae, flattened malar eminences, marked overbite, and high-arched palates (so-called adenoid facies). These symptoms are not mediated by histamine and are, therefore, poorly responsive to antihistamine therapy. Oral sympathomimetics that induce vasoconstriction by stimulation of α-adrenergic receptors are often used in conjunction with antihistamines to treat nasal congestion. Topical decongestants may be used to relieve acute congestion but have limited value in patients with chronic allergic rhinitis because frequent use results in rebound vasodilation (rhinitis medicamentosa).

Airway Hyperresponsiveness

The phenomenon of heightened nasal sensitivity to reduced levels of allergen after initial exposures to the allergen is known as priming. Clinically, priming may be observed in patients who develop increased symptoms late in the pollen season compared with early in the season. Late-phase inflammation induces a state of nasal airway hyperresponsiveness to both irritants and allergens in patients with chronic allergic rhinitis and asthma. Airway hyperreactivity can cause heightened sensitivity to both environmental irritants such as tobacco smoke and noxious odors as well as to allergens such as pollens. There are no standardized clinical tools to accurately assess late-phase hyperresponsiveness in allergic rhinitis as there are for asthma (methacholine or histamine bronchoprovocation challenge). Genetic markers for bronchial airway hyperresponsiveness, however, have been identified. It also appears that late-phase cellular infiltration and eosinophil byproducts may inflict airway epithelial damage, which in turn can predispose to upper and lower airways hyperreactivity.

Accumulating evidence supports a relationship between allergic rhinitis and asthma. Many patients with rhinitis alone demonstrate nonspecific bronchial hyperresponsiveness, and prospective studies suggest that nasal allergy may be a predisposing risk factor for developing asthma. Treatment of patients with allergic rhinitis may result in improvement of asthma symptoms, airway caliber, and bronchial hyperresponsiveness to methacholine and exercise. Finally, mechanistic studies of airway physiology have demonstrated that nasal disease may influence pulmonary function via both direct and indirect mechanisms. Such mechanisms may include the existence of a nasal-bronchial reflex (with nasal stimulation causing bronchial constriction), postnasal drip of inflammatory cells and mediators from the nose into the lower airways, absorption of inflammatory cells and mediators into the systemic circulation and ultimately to the lung, and nasal blockage and subsequent mouth breathing, which may facilitate the entry of asthmagenic triggers to the lower airway.

In Vivo or In Vitro Measurement of Allergen-Specific IgE

This is the primary tool for the confirmation of suspected allergic disease. In vivo skin testing with allergens suspected of causing hypersensitivity constitutes an indirect bioassay for the presence of allergen-specific IgE on tissue mast cells or basophils. Percutaneous or intradermal administration of dilute concentrations of specific antigens elicits an immediate wheal-and-flare response in a sensitized individual. This response marks a “local anaphylaxis” resulting from the controlled release of mediators from activated mast cells. Positive skin test results to airborne allergens, combined with a history and examination suggestive of allergy, strongly implicate the allergen as a cause of the patient’s symptoms. Negative skin test results with an unconvincing allergy history argue strongly against an allergic origin. Major advantages to skin testing include simplicity, rapidity of performance, and low cost.

In vitro tests provide quantitative assays of allergen-specific IgE in the serum. In these assays, patient serum is reacted initially with antigen bound to a solid-phase material and then labeled with a radioactive or enzyme-linked anti-IgE antibody. These immunoallergosorbent tests show a 70–80% correlation with skin testing to pollens, dust mites, and danders and are useful in patients receiving chronic antihistamine therapy who are unable to undergo skin testing and in patients with extensive dermatitis.

Complications of Allergic Rhinitis

Serous otitis media and sinusitis are major comorbidities in patients with allergic rhinitis. Both conditions occur secondarily to the obstructed nasal passages and sinus ostia in patients with chronic allergic or nonallergic rhinitis. Complications of chronic rhinitis should be considered in patients with protracted rhinitis unresponsive to therapy, refractory asthma, or persistent bronchitis. Serous otitis results from auditory tube obstruction by mucosal edema and hypersecretion. Children with serous otitis media can present with conductive hearing loss, delayed speech, and recurrent otitis media associated with chronic nasal obstruction.

Sinusitis may be acute, subacute, or chronic depending on the duration of symptoms. Obstruction of osteomeatal drainage in patients with chronic rhinitis predisposes to bacterial infection in the sinus cavities. Patients manifest symptoms of persistent nasal discharge, cough, sinus discomfort, and nasal obstruction. Examination may reveal chronic otitis media, infraorbital edema, inflamed nasal mucosa, and purulent nasal discharge. Radiographic diagnosis by x-ray film or computed tomographic (CT) scan reveals sinus opacification, membrane thickening, or the presence of an air-fluid level. Effective treatment of infectious complications of chronic rhinitis requires antibiotics, systemic antihistamine and decongestants, and perhaps intranasal or systemic corticosteroids.

There are many potential sites where developmental aberrations in the immune system can lead to abnormalities in immunocompetence (Figure 3–4; Tables 3–4 and 3–5). When these defects are genetic in origin, they are referred to as primary immunodeficiency disorders. This is in contrast to compromised immunity secondary to pharmacologic therapy, HIV, malnutrition, or systemic illnesses such as systemic lupus erythematosus or diabetes mellitus.

Clinical investigations of various congenital defects have helped characterize many aspects of normal immune physiology. The very nature of a defect in host immune responses places the susceptible individual at high risk for a variety of infectious, malignant, and autoimmune diseases and disorders. The nature of the specific functional defect will significantly influence the type of infection that affects the host. Table 3–5 lists some of the typical organisms causing infection in patients with various immunodeficiency disorders. Any immunopathogenic mechanism that impairs T-lymphocyte function, or cell-mediated immunity, predisposes the host to the development of serious chronic and potentially life-threatening opportunistic infections with viruses, mycobacteria, fungi, and protozoa involving any or all organ systems. Similarly, immunopathogenic dysfunction of B lymphocytes resulting in antibody deficiency will predispose the host to pyogenic sinopulmonary and mucosal infections. As the molecular bases of many primary immunodeficiency disorders are being discovered, it has become apparent that different molecular defects can result in common clinical phenotypes.

The T lymphocyte plays a central role in inducing and coordinating immune responses, and dysfunction can be associated with an increased incidence of autoimmune phenomena. These include diseases clinically similar to rheumatoid arthritis, systemic lupus erythematosus, and immune hematologic cytopenias. Patients with impaired immune responses are also at greater risk for certain malignancies than the general population. The occurrence of cancer may be related to an underlying impairment of tumor surveillance, dysregulation of cellular proliferation and differentiation, chromosomal translocations during defective antigen receptor gene rearrangement, or the presence of infectious agents predisposing to or causing cellular transformation. Non-Hodgkin lymphoma or B-cell lymphoproliferative disease, skin carcinomas, and gastric carcinomas are the most frequently occurring tumors in patients with immunodeficiency.

Traditionally, the primary immunodeficiencies are classified according to which component of the immune response is principally compromised: the humoral response, cell-mediated immunity, complement, or phagocytic cell function (Table 3–4). Distinct developmental stages characterize the maturation and differentiation of the cellular components of the immune system. The underlying pathophysiologic abnormalities leading to primary immunodeficiency are diverse and include the following: (1) early developmental defects in cellular maturation, (2) specific enzyme defects, (3) abnormalities in cellular proliferation and functional differentiation, (4) abnormalities in cellular regulation, and (5) abnormal responses to cytokines.

Combined Immunodeficiency

Severe Combined Immunodeficiency Disease

Clinical Presentation

Clinically, many primary immunodeficiency disorders present early in the neonatal period. In patients with SCID, there is an absence of normal thymic tissue, and the lymph nodes, spleen, and other peripheral lymphoid tissues are devoid of lymphocytes. In these patients, the complete or near-complete failure of development of both the cellular and the humoral component of the immune system results in severe infections. The spectrum of infections is broad because these patients may also suffer from overwhelming infection by opportunistic pathogens, disseminated viruses, and intracellular organisms. Failure to thrive may be the initial presenting symptom, but mucocutaneous candidiasis, chronic diarrhea, and pneumonitis are common. Vaccination with live viral vaccines or bacillus Calmette-Guérin (BCG) may lead to disseminated disease. Without immune reconstitution by bone marrow transplantation, SCID is inevitably fatal within 1–2 years.

Pathology and Pathogenesis

SCID is a heterogeneous group of disorders characterized by a failure in the cellular maturation of lymphoid stem cells, resulting in reduced numbers and function of both B and T lymphocytes and hypogammaglobulinemia. The molecular basis for many types of SCID have been discovered (Table 3–4). The genetic and cellular defects can occur at many different levels, starting with surface membrane receptors but also including deficiencies in signal transduction or metabolic biochemical pathways. Although the different molecular defects may cause clinically indistinguishable phenotypes, identification of specific mutations allows for improved genetic counseling, prenatal diagnosis, and carrier detection. Moreover, specific gene transfer offers hope as a future therapy.

Defective Cytokine Signaling—

X-linked SCID (XSCID) is the most prevalent form, resulting from a genetic mutation in the common γ chain of the trimeric (αβγ) IL-2 receptor. This defective chain is shared by the receptors for IL-4, IL-7, IL-9, and IL-15, leading to dysfunction of all of these cytokine receptors. Defective signaling through the IL-7 receptor appears to block normal maturation of T lymphocytes. Circulating B-cell numbers may be preserved, but defective IL-2 responses inhibit proliferation of T, B, and NK cells, explaining the combined immune defects seen in XSCID patients. A defect in the α chain of the IL-7 receptor can also lead to an autosomal recessive form of SCID through mechanisms similar to XSCID but with intact NK cells.

Defective T-Cell Receptor—

The genetic defects for several other forms of the autosomal recessive SCID have also been identified. A deficiency of ZAP-70, a protein tyrosine kinase important in signal transduction through the TCR, leads to a total absence of CD8 T lymphocytes. ZAP-70 plays an essential role in thymic selection during T-cell development. Consequently, these patients possess functionally defective CD4 T lymphocytes and no circulating CD8 T lymphocytes but normal B-lymphocyte and NK-cell activity. Mutations of CD3δ, CD3γ, and CD3ε subunits may lead to partially arrested development of TCR expression and severe T-cell deficiency.

Deficiencies of both p56^lck and Jak3 (Janus kinase 3) can also lead to SCID through defective signal transduction. P56^lck is a TCR-associated tyrosine kinase that is essential for T-cell differentiation, activation, and proliferation. Jak3 is a cytokine receptor–associated signaling molecule.

Defective Receptor Gene Recombination—

Patients have been identified with defective recombination-activating gene (RAG1 and RAG2) products. RAG1 and RAG2 initiate recombination of antigen-binding proteins, immunoglobulins, and TCRs. The failure to form antigen receptors leads to a quantitative and functional deficiency of T and B lymphocytes. NK cells are not antigen specific and for that reason are unaffected. Artemis and DNA ligase-4 proteins are involved in double-stranded DNA breakage and repair, during VDJ recombination of T-cell receptors and BCRs. Mutations of Artemis may also lead to increased sensitivity to ionizing radiation. Because NK cells are invariant, their numbers are typically preserved, even as T- and B-cell numbers are severely deficient.

Defective Nucleotide Salvage Pathway—

Approximately 20% of SCID cases are caused by a deficiency of adenosine deaminase (ADA), which is an enzyme in the purine salvage pathway, responsible for the metabolism of adenosine. Absence of the ADA enzyme results in an accumulation of toxic adenosine metabolites within the cells. These metabolites inhibit normal lymphocyte proliferation and lead to extreme cytopenia of both B and T lymphocytes. The combined immunologic deficiency and clinical presentation of this disorder, known as SCID-ADA, is identical to that of the other forms of SCID. Skeletal abnormalities and neurologic abnormalities may be associated with this disease. In similar fashion, purine nucleoside phosphorylase deficiency leads to an accumulation of toxic deoxyguanosine metabolites. T-cell development is impaired, possibly through induced apoptosis of double-positive thymocytes in the corticomedullary junction of the thymus. B-cell dysfunction is more variable.

Cell-Mediated Immunodeficiency

Congenital Thymic Aplasia (DiGeorge Syndrome)

Clinical Presentation and Pathogenesis

The clinical manifestations of DiGeorge syndrome reflect the defective embryonic development of organs derived from the third and fourth pharyngeal arches, including the thymus, parathyroids, and cardiac outflow tract. Occasionally, the first and sixth pharyngeal pouches may also be involved. Cytogenetic abnormalities, most commonly chromosome 22q11 deletions, are associated with DiGeorge syndrome, especially in patients manifesting cardiac defects. DiGeorge syndrome is classified as complete or partial depending on the presence or absence of immunologic abnormalities. In this syndrome, the spectrum of immunologic deficiency is wide, ranging from immune competency to conditions in which there are life-threatening infections with organisms typically of low virulence. Patients affected by the complete syndrome have a profound T lymphocytopenia resulting from thymic aplasia with impaired T-lymphocyte maturation, severely depressed cell-mediated immunity, and decreased suppressor T-lymphocyte activity. B lymphocytes and immunoglobulin production are unaffected in most patients, although in rare instances patients may present with mild hypogammaglobulinemia and absent or poor antibody responses to neoantigens. In this subset of patients, inadequate helper T function as a result of dysfunctional T- and B-cell interaction and inadequate cytokine production leads to impaired humoral immunity.

DiGeorge syndrome is truly a developmental anomaly and can be associated with structural abnormalities in the cardiovascular system such as truncus arteriosus or right-sided aortic arch. Parathyroid abnormalities may lead to hypocalcemia, presenting with neonatal tetany or seizures. In addition, it is common for patients to exhibit facial abnormalities such as micrognathia, hypertelorism, low-set ears with notched pinnae, and a short philtrum.

Humoral Immunodeficiency

X-Linked Agammaglobulinemia

Clinical Presentation

Formerly called Bruton agammaglobulinemia, X-linked agammaglobulinemia (XLA) is thought to be pathophysiologically and clinically more homogeneous than SCID. It is principally a disease of childhood, presenting clinically within the first 2 years of life with multiple and recurrent sinopulmonary infections caused primarily by pyogenic bacteria and, to a much lesser extent, viruses. Because encapsulated bacteria require antibody binding for efficient opsonization, these humoral immune-deficient patients suffer from sinusitis, pneumonia, pharyngitis, bronchitis, and otitis media secondary to infection with Streptococcus pneumoniae, other streptococci, and Haemophilus influenzae. Although infections from fungal and opportunistic pathogens are rare, patients display a unique susceptibility to a rare but deadly enteroviral meningoencephalitis.

Pathology and Pathogenesis

Patients with XLA have pan-hypogammaglobulinemia, with decreased levels of IgG, IgM, and IgA. They exhibit poor to absent responses to antigen challenge even though virtually all demonstrate normal functional T-lymphocyte responses to in vitro as well as in vivo tests (eg, delayed hypersensitivity skin reactions). The basic defect in this disorder appears to be arrested cellular maturation at the pre-B-lymphocyte stage. Indeed, normal numbers of pre-B lymphocytes can be found in the bone marrow, although in the circulation B lymphocytes are virtually absent. Lymphoid tissues lack fully differentiated B lymphocytes (antibody-secreting plasma cells), and lymph nodes lack developed germinal centers. The gene that is defective in XLA has been isolated. The defective gene product, BTK (Bruton tyrosine kinase), is a B-cell–specific signaling protein belonging to the cytoplasmic tyrosine kinase family of intracellular proteins. Gene deletions and point mutations in the catalytic domain of the BTK gene block normal BTK function, necessary for B-cell maturation.

Common Variable Immunodeficiency Disease

Clinical Presentation

Common variable immunodeficiency disease is often referred to as acquired or adult-onset hypogammaglobulinemia. It is the most common serious primary immune deficiency disorder in adults. In North America, for example, it affects an estimated 1:75,000 to 1:50,000 individuals. The clinical spectrum is broad, and patients usually present within the first 2 decades of life. Affected individuals commonly develop recurrent sinopulmonary infections, including sinusitis, otitis, bronchitis, and pneumonia. Common pathogens are encapsulated bacteria such as S pneumoniae, H influenzae, and Moraxella catarrhalis. Bronchiectasis can be the result of recurrent serious respiratory infections, leading to infection with more virulent pathogens, including Staphylococcus aureus and Pseudomonas aeruginosa, which in turn can change the long-term prognosis. A number of important noninfectious disorders are commonly associated with common variable immunodeficiency, including GI malabsorption, autoimmune disorders, and neoplasms. The most frequently occurring malignancies are lymphoreticular, but gastric carcinoma and skin cancer also occur. Autoimmune disorders occur in 20–30% of patients and may precede the recurrent infections. Autoimmune cytopenias occur most frequently, but rheumatic diseases can also be seen. Serologic testing for infectious or autoimmune disease is unreliable in hypogammaglobulinemia. Monthly infusions of intravenous immunoglobulin can reconstitute humoral immunity, decrease infections, and improve quality of life.

Pathology and Pathogenesis

Common variable immunodeficiency is heterogeneous disorder in which the primary immunologic abnormality is a marked reduction in antibody production. The vast majority of patients demonstrate an in vitro defect in terminal differentiation of B lymphocytes. Peripheral blood lymphocyte phenotyping demonstrates normal or reduced numbers of circulating B lymphocytes, but antibody-secreting plasma cells are conspicuously sparse in lymphoid tissues. In sharp contrast to XLA, no single gene defect can be held accountable for the multitude of defects known to cause common variable immunodeficiency. In many patients, the defect is intrinsic to the B-lymphocyte population. Approximately 15% of patients with common variable immunodeficiency disease demonstrate defective B-cell surface expression of TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), a member of the TNF receptor family. Lacking a functional TACI, the affected B cells will not respond to B-cell–activating factors, resulting in deficient immunoglobulin production. Another defect that may lead to common variable immunodeficiency disease involves deficient expression of B-cell surface marker CD19. When complexed with CD21 and CD81, CD19 facilitates cellular activation through BCRs. B-cell development is not affected, but humoral function is deficient. A variety of T-cell abnormalities may also lead to immune defects with subsequent impairment of B-cell differentiation. A mutation of inducible T-cell costimulator gene (ICOS), expressed by activated T cells and responsible for B-cell activation/antibody production, may be the molecular defect in some cases of common variable immunodeficiency disease. More than 50% of patients also have some degree of T-lymphocyte dysfunction as determined by absent or diminished cutaneous responses to recall antigens. Immune dysregulation may contribute to the morbidity and the myriad autoimmune manifestations associated with common variable immunodeficiency.

Hyper-IgM Immunodeficiency

Clinical Presentation

In patients with hyper-IgM immunodeficiency, serum levels of IgG and IgA are very low or absent, but serum IgM (and sometimes IgD) levels are normal or elevated. Inheritance of this disorder may be autosomal, although it is most often X-linked. Clinically, this syndrome is manifested by recurrent pyogenic infections and an array of autoimmune phenomena such as Coombs-positive hemolytic anemia and immune thrombocytopenia.

Pathology and Pathogenesis

The principal abnormality is the defective expression of CD40-ligand (CD40L), a T-lymphocyte activation surface marker (also known as CD154 or gp39). In the course of normal immune responses, CD40L interacts with CD40 on B-cell surfaces during cellular activation, initiating proliferation and immunoglobulin isotype switching. In hyper-IgM syndrome, defective CD40 coreceptor stimulation during T- and B-cell interactions leads to impairment of B-cell isotype switching and subsequent production of IgM but no production of IgG or IgA. CD40L-CD40 interaction also promotes dendritic cell maturation and IL-12 and IFN-γ secretion, so CD40L deficiency can be associated with impaired cell-mediated immunity and increased risk of opportunistic infection.

Selective IgA Deficiency

This is the most common primary immunodeficiency in adults, with a prevalence of 1:700 to 1:500 individuals. Most affected individuals have few or no clinical manifestations, but there is an increased incidence of upper respiratory tract infections, allergy, asthma, and autoimmune disorders. Whereas serum levels of the other immunoglobulin isotypes are typically normal, serum IgA levels in these individuals are markedly depressed, often less than 5 mg/dL.

As in common variable immunodeficiency, the primary functional defect is an inability of B cells to terminally differentiate to IgA-secreting plasma cells. An associated deficiency of IgG subclasses (mainly IgG₂ and IgG₄) and low-molecular-weight monomeric IgM is not uncommon and can be clinically significant. Because of the role of secretory IgA in mucosal immunity, patients with this immunodeficiency frequently develop significant infections involving the mucous membranes of the gut, conjunctiva, and respiratory tract. There is no specific therapy, but prompt antibiotic treatment is necessary in patients with recurrent infections. A subset of patients may recognize IgA as a foreign antigen. These patients are at risk for transfusion reactions to unwashed red blood cells or other blood products containing trace amounts of IgA.

Disorders of Phagocytic Cells & Innate Immunity

Defective phagocytic cell function presents with infections at sites of interface between the body and the outside world. Recurrent skin infections, abscesses, gingivitis, lymphadenitis, and poor wound healing are seen in patients with macrophage or neutrophil disorders. More difficult to assay, clinical immunodeficiency can occur through defects in phagocytic cell migration, adhesion, opsonization, or killing.

Chronic Granulomatous Disease

Clinical Presentation

Chronic granulomatous disease is typically X-linked and characterized by impaired granulocyte function. This disorder of phagocytic cell function presents with recurrent skin infections, abscesses, and granulomas at sites of chronic inflammation. Abscesses can involve skin or viscera and may be accompanied by lymphadenitis. Catalase-positive organisms predominate; S aureus is thus the most common pathogen, although infections with Nocardia species, gram-negative Serratia marcescens, and Burkholderia cepacia can also occur. Aspergillus species and Candida represent common fungal pathogens in chronic granulomatous disease. Sterile noncaseating granulomas resulting from chronic inflammatory stimuli can lead to GI or genitourinary tract obstruction. Chronic granulomatous disease typically presents in childhood, although cases in adulthood are occasionally reported.

Pathology and Pathogenesis

Defects in the gene coding for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibit oxidative metabolism and severely compromise neutrophil killing activity. NADPH oxidase is assembled from two membrane and two cytosolic components after phagocytic cell activation, leading to catalytic conversion of molecular oxygen into superoxide. Oxidative burst and intracellular killing rely on production of superoxide, which is later converted to hydrogen peroxide and sodium hypochlorite (bleach). In patients with chronic granulomatous disease, other neutrophil functions such as chemotaxis, phagocytosis, and degranulation remain intact but microbial killing is deficient. Catalase-negative bacteria are effectively killed because microbes produce small amounts of peroxide, concentrated in phagosomes, leading to microbial death. Catalase-positive organisms scavenge these relatively small amounts of peroxide and are not killed without neutrophil oxidative metabolism. X-linked inheritance is most frequently seen, but autosomal recessive forms and spontaneous mutations can also lead to clinical disease.

Leukocyte Adhesion Deficiency, Type 1

Integrins and selectins are specialized molecules that play a role in leukocyte homing to sites of inflammation. These adhesion molecules facilitate cell-cell and cell–extracellular matrix interactions, allowing circulating leukocytes to stick and roll along endothelial cell surfaces prior to diapedesis into extravascular tissues. An autosomal recessive train, leukocyte adhesion deficiency type 1, and defective expression of β₂-integrin (CD11/CD18) adhesion molecules result in impaired trafficking of leukocytes, leading to recurrent infections, lack of pus formation, and poor wound healing. Leukocytosis occurs because cells cannot exit the circulation, and recurrent infections of skin, airways, bowels, perirectal area, and gingival and periodontal areas are common.

Mendelian Susceptibility to Mycobacterial Disease

In response to mycobacterial infection, macrophages secrete IL-12, stimulating cell-mediated immunity and increased T_H1 secretion of IFN-γ. At least a dozen Mendelian, ie, single gene product, mutations lead to impairment of the synthesis of or response to IL-12 or IFN-γ, that underlie Mendelian susceptibility to mycobacterial disease. Associated defects have been described in genes encoding for IFN-γ, IFN-γ receptors-1 and -2, JAK-1 and -2 (Janus kinase, a cytokine receptor signaling protein), STAT-1 and -4 (signal transducer and activator of transcription, a transcription factor activated by JAK), IL-12 and its receptors, and IL-12RB₁ and IL-12RB₂. Increased susceptibility to less virulent, nontuberculous species of mycobacteria; Mycobacterium intracellulare-avium complex (MAC), Mycobacterium kansasii, Mycobacterium fortuitum, and BCG are characteristic of affected individuals. Infection with non-typhoidal salmonellae may also be associated with Mendelian susceptibility to mycobacterial disease.

Hyper-IgE Immunodeficiency

Clinical Presentation

This disorder is often referred to as “Job syndrome” because affected individuals suffer from recurrent boils like the tormented biblical figure. The initial description of this immunodeficiency disorder was in two fair-skinned girls with recurrent staphylococcal “cold” skin abscesses associated with furunculosis, cellulitis, recurrent otitis, sinusitis, pneumatoceles, and a coarse facial appearance. The predominant organism isolated from sites of infection is S aureus, although other organisms such as H influenzae, pneumococci, gram-negative organisms, Aspergillus sp. and C albicans are often identified also. Characteristically, patients have a chronic pruritic eczematoid dermatitis, defective shedding of primary teeth, growth retardation, coarse facies, scoliosis, osteopenia, vascular abnormalities, and hyperkeratotic fingernails. Extremely high IgE levels (>3000 IU/mL) have also been observed in patients’ serum.

Pathology and Pathogenesis

The high IgE levels are thought to be a consequence of dysregulated immunologic responsiveness to cytokines, yet it is unclear whether the hyper-IgE contributes to the observed susceptibility to infection or is simply an immunologic epiphenomenon. Autosomal dominant forms have been associated with mutations in STAT3, a transcriptional factor involved in the activation of cytokine and growth factor receptors. Responses to numerous cytokines do appear impaired, along with decreased T_H17 function. A spectrum of immune abnormalities is also observed. Humoral immunodeficiency is suggested by poor antibody responses to neoantigens, deficiency of IgA antibody against S aureus, and low levels of antibodies to carbohydrate antigens. T-lymphocyte functional abnormalities are suggested by decreased absolute numbers of suppressor T lymphocytes, poor in vitro proliferative responses, and defects in cytokine production. Several reports have also documented highly variable abnormalities in neutrophil chemotaxis.

Toll-Like Receptor 3 Deficiency

Patients with TLR3 deficiency have shown specific susceptibility to herpes simplex 1 (HSV1) encephalitis. Typically, binding of pathogen-associated molecular patterns to TLR will activate transcription factors, such as nuclear factor kappa beta (NF-κβ), IFN regulatory factors, and activator protein 1, leading to immune responsiveness. Defects in this pathway impair viral immunity. In TLR3 deficiency, defective IFN-α, IFN-β, and IFN-λ synthesis leads to uninhibited HSV1 replication in neurons and oligodendritic cells. A similar phenotype is seen in autosomal recessive UNC-93b deficiency. UNC-93b is required for TLR3 function, as it translocates TLR3 to its endosomal site of action.

AIDS

AIDS is the most common immunodeficiency disorder worldwide, and HIV infection is one of the greatest epidemics in human history. AIDS is the consequence of a chronic retroviral infection that produces severe, life-threatening CD4 helper T-lymphocyte dysfunction, opportunistic infections, and malignancy. AIDS is defined by serologic evidence of HIV infection with the presence of a variety of indicator diseases associated with clinical immunodeficiency. Table 3–6 lists criteria for defining and diagnosing AIDS. HIV is transmitted by exposure to infected body fluids or sexual or perinatal contact. Vertical transmission from mother to infant may occur in utero, during childbirth, and also through breastfeeding. Transmissibility of the HIV virus is related to subtype virulence, viral load, and immunologic host factors.

Acute HIV infection may present as a self-limited, febrile viral syndrome characterized by fatigue, pharyngitis, myalgias, maculopapular rash, lymphadenopathy, and significant viremia, without detectable anti-HIV antibodies. Less commonly, primary HIV infection may also be associated with orogenital or esophageal ulcers, meningoencephalitis, or opportunistic infection. After an initial viremic phase, patients seroconvert and a period of clinical latency is usually seen. Lymph tissues become centers for massive viral replication during a “silent,” or asymptomatic, stage of HIV infection despite an absence of detectable virus in the peripheral blood. Over time, there is a progressive decline in CD4 T lymphocytes, a reversal of the normal CD4:CD8 T-lymphocyte ratio, and numerous other immunologic derangements. The clinical manifestations are directly related to HIV tissue tropism and defective immune function. Development of neurologic complications, opportunistic infections, or malignancy signal marked immune deficiency. The time course for progression is highly variable, but the median time before appearance of clinical disease is about 10 years in untreated individuals. Approximately 10% of those infected manifest rapid progression to AIDS within 5 years after infection. A minority of individuals are “long-term nonprogressors.” Genetic factors, host cytotoxic immune responses, viral load, and virulence appear to have an impact on susceptibility to infection and the rate of disease progression. Although not curative, modern antiretroviral therapies can significantly reduce viral replication, restore immune function, lead to clinical recovery, and markedly extend life expectancy.

Pathology and Pathogenesis

HIV is a group of related retroviruses, whose RNA encodes for nine genes (see Table 3–7). Chemokines (chemoattractant cytokines) regulate leukocyte trafficking to sites of inflammation and have been discovered to play a significant role in the pathogenesis of HIV disease. During the initial stages of infection and viral proliferation, virion entry and cellular infection requires binding to two coreceptors on target T lymphocytes and monocyte/macrophages. All HIV strains express the envelope protein gp120 that binds to CD4 surface receptor molecules, but different viral strains display tissue “tropism” or specificity on the basis of the coreceptor they recognize. Changes in viral phenotype during the course of HIV infection may lead to changes in tropism and cytopathology at different stages of disease. Viral strains isolated in early stages of infection and associated with mucosal and intravenous transmission (eg, R5-trophic viruses) bind macrophages expressing chemokine receptor CCR5. X4-trophic strains of HIV are more commonly seen in later stages of disease. X4-trophic viruses bind to chemokine receptor CXCR4, more broadly expressed on T cells, and are associated with syncytium formation. Since chemokine receptors play a role in viral cell entry, specific inherited polymorphisms of chemokine receptors influence susceptibility to infection and disease progression. Presence of certain HLA alleles has also been associated with differences in susceptibility and clinical course.

Mathematical models estimate that during HIV infection billions of virions are produced and cleared each day. The reverse transcription step of HIV replication is error prone. Mutations occur frequently, and even within an individual patient, HIV heterogeneity develops rapidly. Patients may be infected with more than one strain concomitantly, and through mechanisms of recombination, genes from separate strains may intermingle, contributing to genetic diversity. The development of antigenically and phenotypically distinct strains contributes to progression of disease, clinical drug resistance, and lack of efficacy of early vaccines.

Cellular activation is critical for viral infectivity and reactivation of integrated proviral DNA. After viral entry and capsid disassembly, HIV reverse transcriptase converts uncoated viral RNA into double-stranded viral DNA. Utilizing several host proteins, the double-stranded viral DNA complex penetrates the host cell nucleus and integrates into the host chromosome. Once integrated, the viral provirus may remain latent or become transcriptionally active, depending on the activation state of the host cell. Cellular activation triggers NF-κβ, a cytoplasmic transcription factor that migrates to the nucleus initiating viral gene expression. HIV protein Nef enhances viral replication and reduces host antiviral immune responses. New infectious virions are assembled. Viral proteins and RNA are packaged at the infected cell’s exterior membrane through a process called “budding.”

Although only 2% of mononuclear cells are found peripherally, lymph nodes from HIV-infected individuals can contain large amounts of virus sequestered among infected follicular dendritic cells in the germinal centers. For patients infected through vaginal or rectal mucosa, gut-associated lymphoid tissue is a major site of viral replication and persistence. Gut-associated lymphoid tissue harbors the majority of the host’s T cells, and when HIV-infected epidermal Langerhans cells migrate to draining lymph nodes, large numbers of lymphocytes encounter surface-bound virus. The persistence of virus in these secondary lymphoid structures triggers cellular activation and massive, irrevocable depletion of CD4 T-lymphocyte reservoirs, as well as disease latency. The marked decline in CD4 T-lymphocyte counts is due to several mechanisms: (1) direct HIV-mediated infection and destruction of CD4 T lymphocytes during viral replication; (2) depletion by fusion and formation of multinucleated giant cells (syncytium formation); (3) toxicity of viral proteins to CD4 T lymphocytes and hematopoietic precursors; (4) loss of T-lymphocyte costimulatory factors such as CD28; and (5) induction of apoptosis (programmed cell death) of uninfected T cells. CD8 CTL activity is initially brisk and effective at controlling viremia but later induces the generation of viral escape mutations. Ultimately, viral proliferation outstrips host responses, and HIV-induced immunosuppression leads to disease progression. Neutralizing antibodies are generated very late, but mutations in HIV-envelope proteins outfox protective humoral responses. Over time, the infection is characterized by systemic, generalized cytokine dysregulation and immune activation. Hyperactivity of the immune system increases naïve T-cell infection. Ultimately, these events prove deleterious to maintenance of lymphatic organs, bone marrow integrity, and effective immune responses.

In addition to the cell-mediated immune defects, B- lymphocyte function is altered such that many infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses. Both anamnestic responses and those to neoantigens can be impaired.

The development of assays to measure viral burden (plasma HIV-RNA quantification) has led to a better understanding of HIV dynamics and has provided a tool for assessing response to therapy. It is now well recognized that viral replication continues throughout the disease, and immune deterioration occurs despite clinical latency. The risk of progression to AIDS appears correlated with an individual’s viral load after seroconversion. Data from several large clinical cohorts have shown that there is a direct correlation between the CD4 T-lymphocyte count and the risk of AIDS-defining opportunistic infections and malignancy. The viral load and the degree of CD4 T-lymphocyte depletion serve as important clinical indicators of immune status in HIV-infected individuals. CD4 count may be better for disease staging, but viral load may be a better proxy for disease progression or monitoring response to therapy. Prophylaxis for opportunistic infections such as pneumocystis pneumonia (PCP) is started when CD4 T-lymphocyte counts reach the 200–250 cells/μL range. Similarly, patients with HIV infection with fewer than 50 CD4 T lymphocytes/μL are at significantly increased risk for cytomegalovirus (CMV) retinitis and M avium complex (MAC) infection. Unfortunately, some complications of HIV infection, including tuberculosis infection, non-Hodgkin lymphoma, and cardiovascular, hepatic, and neurocognitive diseases, may occur even with robust CD4 counts.

Monocytes, macrophages, and dendritic cells also express HIV receptors (CD4) and can be infected with HIV. This facilitates transfer of virus to lymphoid tissues and immunoprivileged sites, such as the CNS. HIV-infected monocytes will also release large quantities of the acute-phase reactant cytokines, including IL-1, IL-6, and TNF, contributing to constitutional symptomatology. TNF, in particular, has been implicated in the severe wasting syndrome seen in patients with advanced disease. Concomitant infections may serve as cofactors for HIV infection, facilitate mucosal entry, and increase expression of HIV through enhanced cytokine production, coreceptor surface expression, or increased cellular activation mechanisms. Epidemiologic studies of HSV-2–infected patients demonstrate a 2- to 7-fold increased risk of acquisition of HIV compared with similar cohorts.

Clinical Manifestations

The clinical manifestations of AIDS are the direct consequence of the progressive and severe immunologic deficiency induced by HIV. Patients are susceptible to a wide range of atypical or opportunistic infections with bacterial, viral, protozoal, and fungal pathogens. Common nonspecific symptoms include fever, night sweats, and weight loss. Weight loss and cachexia can be due to nausea, vomiting, anorexia, or diarrhea. They often portend a poor prognosis.

The incidence of infection increases as the CD4 T- lymphocyte number declines. Fungal pathogens may affect immunocompetent hosts but are frequently opportunistic in HIV-infected patients. Infections with Cryptococcus neoformans meningoencephalitis, disseminated Histoplasma capsulatum, and disseminated Coccidioides immitis are typically seen in late stages of disease, when CD4 counts are below 200 cells/mm³. C neoformans meningoencephalitis is manifested by fevers, malaise, headache, photophobia, and nausea. Presentation with altered mental status or elevated intracranial pressure is associated with a higher risk of death or neurologic sequelae. Occasionally, a cerebral cryptococcoma presents as a mass lesion.

Found endemically in regional soil contaminated with bird and bat droppings, H capsulatum infection is characterized by prominent constitutional symptoms, frequent pulmonary symptoms, and subacute meningoencephalitis. Disseminated disease may represent reactivation of latent disease when cellular immunity fails.

Previously thought to be a protozoan, now classified as a fungus, Pneumocystis jirovecii is the most common opportunistic infection, affecting 75% of patients. Patients present clinically with fevers, cough, shortness of breath, and hypoxemia, ranging in severity from mild to life threatening. PCP may represent new acquisition or activation of old infections. A diagnosis of PCP can be made by substantiation of the clinical and radiographic findings with Wright-Giemsa or silver methenamine staining of induced sputum samples. A negative sputum stain does not rule out disease in patients in whom there is a strong clinical suspicion of disease, and further diagnostic maneuvers such as bronchoalveolar lavage or fiberoptic transbronchial biopsy may be required to establish the diagnosis. Complications of PCP include pneumothoraces, progressive parenchymal disease with severe respiratory insufficiency, and, most commonly, adverse reactions to the medications used for treatment and prophylaxis.

As a consequence of chronic immune dysfunction, HIV-infected individuals are also at high risk for other pulmonary infections, including bacterial infections with S pneumoniae, H influenzae, and P aeruginosa; mycobacterial infections with Mycobacterium tuberculosis or MAC; and fungal infections with C neoformans, H capsulatum, Aspergillus sp, or C immitis. Clinical suspicion followed by early diagnosis of these infections should lead to aggressive treatment.

The risk of M tuberculosis reactivation is estimated to be 5–10% per year in HIV-infected patients compared with a lifetime risk of 10% in those without HIV. The development of active tuberculosis is significantly accelerated in HIV infection as a result of compromised cellular immunity. Furthermore, diagnosis may be delayed because of anergic skin responses. Respiratory symptoms of cough, dyspnea, or pleuritic chest pain may be associated with the insidious onset of fever, malaise, weight loss, and anorexia. Extrapulmonary manifestations occur in up to 70% of HIV-infected patients with tuberculosis, with miliary tuberculosis and meningitis representing more serious complications. The emergence of multidrug resistance may compound the problem. M avium is a less virulent pathogen than M tuberculosis, and disseminated infections usually occur only with severe clinical immunodeficiency. M avium survives intracellularly within macrophages due to defective cytokine (IFN-γ, IL-2, IL-12, TNF) synthesis, leading to impaired killing of phagocytosed organisms. Symptoms of MAC are nonspecific and typically consist of fever, weight loss, anemia, and GI distress with diarrhea.

The presence on physical examination of oral candidiasis (thrush) and hairy leukoplakia is highly correlated with HIV infection and portends rapid progression to AIDS. Oral candidiasis develops when reduced local and systemic immune function, sometimes combined with metabolic imbalances, contributes to opportunistic outgrowth of Candida, which is normally a common commensal organism. HIV-infected individuals with oral candidiasis are at much greater risk for esophageal candidiasis, which may present as substernal pain and dysphagia. This infection and its characteristic clinical presentation are so common that most practitioners treat with empiric oral antifungal therapy. Should the patient not respond rapidly, other explanations for the esophageal symptoms should be explored, including herpes simplex and CMV infections. Epstein-Barr virus (EBV) is the cause of hairy leukoplakia, another oral complication of HIV, manifested by white thickening of mucosal folds, prominent in the buccal mucosa, the soft palate, and the floor of the mouth.

Diarrhea has been a hallmark feature of AIDS and leads to significant wasting, morbidity, and mortality. Persistent diarrhea, especially when accompanied by high fevers and abdominal pain, may signal infectious enterocolitis. The degree of CD4-lymphopenia is significantly correlated with the risk of opportunistic GI tract infections. The list of potential pathogens in such cases is long and includes bacteria, MAC, protozoans (cryptosporidium, microsporidia, Isospora belli, Entamoeba histolytica, Giardia lamblia), and even HIV itself. Because of their reduced gastric acid concentrations, patients also have an increased susceptibility to nonopportunistic infectious gastroenteritis with Campylobacter, Salmonella, and Shigella. Co-infection with viral hepatitis (HBV, HCV, CMV) can lead to accelerated cirrhosis and end-stage liver disease, but fortunately, institution of highly active antiretroviral therapy (HAART) can lead to a reduction in clinical disease.

Skin lesions commonly associated with HIV infection are typically classified as infectious (viral, bacterial, fungal), neoplastic, or nonspecific. Herpes simplex virus (HSV) and herpes zoster virus (HZV) may cause chronic persistent or progressive lesions in patients with compromised cellular immunity. HSV commonly causes oral and perianal lesions but can be an AIDS-defining illness when involving the lung or esophagus. The risk of disseminated HSV or HZV infection and the presence of molluscum contagiosum appear to be correlated with the extent of immunoincompetence. Seborrheic dermatitis caused by Pityrosporum ovale and fungal skin infections (C albicans, dermatophyte species) are also commonly seen in HIV-infected patients. Staphylococcus including methicillin-resistant S aureus can cause the folliculitis, furunculosis, and bullous impetigo commonly observed in HIV-infected patients, which may require aggressive treatment to prevent dissemination and sepsis. Bacillary angiomatosis is a potentially fatal dermatologic disorder of tumor-like proliferating vascular endothelial cell lesions, the result of infection by Bartonella quintana or Bartonella henselae. The lesions may resemble those of Kaposi sarcoma but respond to treatment with erythromycin or tetracycline.

CNS manifestations in HIV-infected patients include infections and malignancies. Toxoplasmosis frequently presents with space-occupying lesions, causing headache, altered mental status, seizures, or focal neurologic deficits. Cryptococcal meningitis commonly manifests as headache and fever. Up to 90% of patients with cryptococcal meningitis exhibit a positive serum test for C neoformans antigen.

Patients with HIV-associated neurocognitive disorder typically have difficulty with cognitive tasks, poor short-term memory, slowed motor function, personality or affective changes, and waxing and waning dementia. In the severe form, AIDS dementia may be characterized by severe psychomotor retardation, akinesis, and language impairment, associated with widespread cortical atrophy and ventricular enlargement. Up to 50% of patients with AIDS suffer from this disorder, perhaps caused by glial or macrophage infection by HIV resulting in destructive inflammatory changes within the CNS. R5 viruses are trophic for cells of monocytic lineage in the CNS. The differential diagnosis can be broad, including metabolic disturbances and toxic encephalopathy resulting from drugs. Other causes of altered mental status include neurosyphilis, CMV or herpes simplex encephalitis, mycobacterial or cryptococcal meningitis, lymphoma, and progressive multifocal leukoencephalopathy, a progressive demyelinating disease caused by a JC papovavirus.

Peripheral nervous system manifestations of HIV infection include sensory, motor, and inflammatory polyneuropathies. Almost 33% of patients with advanced HIV disease develop peripheral tingling, numbness, and pain in their extremities. These symptoms are likely to be due to loss of nerve axons from direct neuronal HIV infection. Alcoholism, thyroid disease, syphilis, vitamin B₁₂ deficiency, drug toxicity (ddI, ddC), CMV-associated ascending polyradiculopathy, and transverse myelitis also cause peripheral neuropathies. Less commonly, HIV-infected patients can develop an inflammatory demyelinating polyneuropathy similar to Guillain-Barré syndrome; however, unlike the sensory neuropathies, this inflammatory demyelinating polyneuropathy typically presents before the onset of clinically apparent immunodeficiency. The origin of this condition is not known, although an autoimmune reaction is suspected. Retinitis resulting from CMV infection is the most common cause of rapidly progressive visual loss in HIV infection. The diagnosis can be difficult to make because Toxoplasma gondii infection, microinfarction, and retinal necrosis can all cause visual loss.

HIV-related malignancies commonly seen in AIDS include Kaposi sarcoma, non-Hodgkin lymphoma, primary CNS lymphoma, invasive cervical carcinoma, and anal squamous cell carcinoma. Impairment of immune surveillance and defense and increased exposure to oncogenic viruses appear to contribute to the development of neoplasms.

Kaposi sarcoma is the most common HIV-associated cancer. In San Francisco, 15–20% of HIV-infected homosexual men develop this tumor during the progression of their disease. Kaposi sarcoma is uncommon in women and children for reasons that are not clear. Unlike classic Kaposi sarcoma, which affects elderly men in the Mediterranean, the disease in HIV-infected patients may present with either localized cutaneous lesions, lymphatic or disseminated visceral involvement. It is often a progressive disease, and pulmonary involvement can be fatal. Histologically, the lesions of Kaposi sarcoma consist of a mixed cell population that includes vascular endothelial cells and spindle cells within a collagen network. Human herpesvirus 8 (HHV-8) in immunocompromised patients appears to promote angiogenesis through growth factor and proinflammatory gene product production. HIV itself appears to induce cytokines and growth factors that stimulate tumor cell proliferation rather than causing malignant cellular transformation. Clinically, cutaneous Kaposi sarcoma typically presents as a purplish nodular skin lesion or painless oral lesion. Sites of visceral involvement include the lung, lymph nodes, liver, and GI tract. In the GI tract, Kaposi sarcoma can produce chronic blood loss or acute hemorrhage. In the lung, it often presents as coarse nodular infiltrates bilaterally, frequently associated with pleural effusions.

Non-Hodgkin lymphoma is particularly aggressive in HIV-infected patients and usually indicative of significant immune compromise. The majority of these tumors are high-grade B-cell lymphomas with a predilection for dissemination. Chronic B-cell stimulation, immune dysfunction, and loss of immunoregulation of EBV-infected cells are all risk factors for transformation of clonally selected cells and development of non-Hodgkin lymphoma. Large-cell and Burkitt-type lymphoma are often associated with EBV but only account for about half of cases. Many cases are diagnosed at advanced stages of disease, and the CNS is frequently involved either as a primary site or as an extranodal site of widespread disease.

Anal dysplasia and squamous cell carcinoma are also more commonly found in HIV-infected homosexual men. These tumors appear to be associated with concomitant anal or rectal infection with human papillomavirus (HPV). In HIV-infected women, the incidence of HPV-related cervical dysplasia is as high as 40%, and dysplasia can progress rapidly to invasive cervical carcinoma.

Adherence to multidrug regimens remains a challenge, but clearly antiretroviral therapy improves immune function. For reasons that are not clear, HIV-infected patients have an unusually high rate of adverse reactions to a wide variety of antibiotics and frequently develop severe debilitating cutaneous reactions. Drug hypersensitivity and toxicity can be severe, potentially life-threatening, and limiting with certain agents. Immune reconstitution syndrome is a described reaction occurring days to weeks after initiation of HAART. Clinical relapse or worsening of mycobacterial, pneumocystis, hepatitis, or neurological infections occurs as a result of a resurgence of immune activity, causing paradoxical worsening of inflammation, possibly as residual antigens or subclinical pathogens are attacked.

Other complications of HIV infection include arthritides, myopathy, GI syndromes, dysfunction of the adrenal and thyroid glands, hematologic cytopenias, and nephropathy. As patients are living longer due to potent antiretroviral therapy (ART), cardiovascular complications are more prominent. ART has been associated with dyslipidemia and metabolic abnormalities including insulin resistance. HIV infection may be atherogenic as well, through effects on lipids and proinflammatory mechanisms.

Since the disease was first described in 1981, medical knowledge of the underlying pathogenesis of AIDS has increased at a rate unprecedented in medical history. This knowledge has led to the rapid development of therapies directed at controlling HIV infection as well as the multitude of complicating opportunistic infections and cancers.

Yeong Kwok, MD

Case 6

Allergic Rhinitis

A 40-year-old woman comes to the clinic with a history of worsening nasal congestion and recurrent sinus infections. She had been healthy until about 1 year ago when she first noticed persistent rhinorrhea, sneezing, and stuffiness. She noted that when she went on a 2-week vacation to Mexico, her rhinorrhea disappeared, only to return when she came home again. She has lived in the same house for the past 5 years along with her husband and one child. They have had a dog for 4 years and a cat for 1 year. On physical examination, she has boggy, swollen nasal turbinates and a cobblestone appearance of her posterior pharynx.

Questions

A. What are the pathophysiologic mechanisms in allergic rhinitis?

Cross-linking of surface-bound IgE by antigen activates tissue mast cells and basophils, inducing the immediate release of preformed mediators and the synthesis of newly generated mediators. Mast cells and basophils also have the ability to synthesize and release proinflammatory cytokines, which are growth and regulatory factors that interact in complex networks. The interaction of mediators with various target organs and cells of the airway can induce a biphasic allergic response: an early phase mediated chiefly by release of histamine and other stored mediators (tryptase, chymase, heparin, chondroitin sulfate, and tumor necrosis factor [TNF]), whereas late-phase events are induced after generation of arachidonic acid metabolites (leukotrienes and prostaglandins), platelet-activating factor, and de novo cytokine synthesis.

Histologically, the early response is characterized by vascular permeability, vasodilatation, tissue edema, and a mild cellular infiltrate of mostly granulocytes. The late-phase response is characterized by erythema, induration, heat, burning, and itching and microscopically by a significant cellular influx of mainly eosinophils and mononuclear cells. Changes consistent with airway remodeling and tissue hyper-reactivity may also occur.

B. What symptoms and signs of allergic rhinitis?

Patients with allergic rhinitis develop chronic or episodic paroxysmal sneezing; nasal, ocular, or palatal pruritus; and watery rhinorrhea triggered by exposure to a specific allergen. Patients may demonstrate signs of chronic pruritus of the upper airway, including a horizontal nasal crease from frequent nose rubbing (“allergic salute”) and palatal “clicking” from rubbing the itching palate with the tongue. Symptoms of nasal obstruction may become chronic as a result of persistent late-phase allergic mechanisms. Nasal mucous membranes may appear pale blue and boggy. Children frequently show signs of obligate mouth breathing, including long facies, narrow maxillae, flattened malar eminences, marked overbite, and high-arched palates (so-called adenoid facies).

C. What are possible complications of allergic rhinitis?

Serous otitis media and sinusitis are major comorbidities in patients with allergic rhinitis. Both conditions occur secondarily to the obstructed nasal passages and sinus ostia in patients with chronic allergic or nonallergic rhinitis. Complications of chronic rhinitis should be considered in patients with protracted rhinitis unresponsive to therapy, refractory asthma, or persistent bronchitis. Serous otitis results from auditory tube obstruction by mucosal edema and hypersecretion. Children with serous otitis media can present with conductive hearing loss, delayed speech, and recurrent otitis media associated with chronic nasal obstruction.

Sinusitis may be acute, subacute, or chronic depending on the duration of symptoms. Obstruction of osteomeatal drainage in patients with chronic rhinitis predisposes to bacterial infection in the sinus cavities. Patients manifest symptoms of persistent nasal discharge, cough, sinus discomfort, and nasal obstruction. Examination may reveal chronic otitis media, infraorbital edema, inflamed nasal mucosa, and purulent nasal discharge. Radiographic diagnosis by x-ray film or computed tomographic (CT) scan reveals sinus opacification, membrane thickening, or the presence of an air-fluid level.

Case 7

Severe Combined Immunodeficiency Disease

A 2-month-old child is admitted to the ICU with fever, hypotension, tachycardia, and lethargy. The medical history is notable for a similar hospitalization at 2 weeks of age. Physical examination is notable for a temperature of 39°C, oral thrush, and rales in the right lung fields. Chest x-ray film reveals multilobar pneumonia. Given the history of recurrent severe infection, the pediatrician suspects an immunodeficiency disorder.

Questions

A. What is the most likely immunodeficiency in this child? Why?

The most likely cause of this child’s recurrent infections is severe combined immunodeficiency disease (SCID). These patients have complete or near-complete failure of development of both cellular and humoral components of the immune system. Placental transfer of maternal immunoglobulin is insufficient to protect these children from infection, and for that reason they present at a very early age with severe infections.

B. What are the underlying genetic and cellular defects associated with this disease?

SCID is a heterogeneous group of genetic and cellular disorders characterized by a failure in the cellular maturation of lymphoid stem cells, resulting in reduced numbers and function of both B and T lymphocytes and hypogammaglobulinemia. The genetic and cellular defects can occur at many different levels, starting with surface membrane receptors, but also including deficiencies in signal transduction or metabolic biochemical pathways. Although the different molecular defects may cause clinically indistinguishable phenotypes, identification of specific mutations allows for improved genetic counseling, prenatal diagnosis, and carrier detection.

The most common genetic defect is an X-linked form of SCID (XSCID) in which the maturation defect is mainly in the T-lymphocyte lineage and is due to a point mutation in the γ chain of the IL-2 receptor. This defective γ chain is shared by the receptors for IL-4, IL-7, IL-9, and IL-15, leading to dysfunction of all of these cytokine receptors. Defective signaling through the IL-7 receptor appears to block normal maturation of T lymphocytes. Circulating B-cell numbers may be preserved, but defective IL-2 responses inhibit proliferation of T, B, and NK cells, explaining the combined immune defects seen in XSCID patients.

Several autosomally inherited defects have also been identified. A defect in the α chain of the IL-7 receptor can lead to an autosomal recessive form of SCID through mechanisms similar to XSCID but with intact NK cells.

About 20% of SCID cases are caused by a deficiency of adenosine deaminase (ADA), which is an enzyme in the purine salvage pathway, responsible for the metabolism of adenosine. Absence of the ADA enzyme results in an accumulation of toxic adenosine metabolites within the cells. These metabolites inhibit normal lymphocyte proliferation and lead to extreme cytopenia of both B and T lymphocytes. The combined immunologic deficiency and clinical presentation of this disorder, known as SCID-ADA, are identical to those of the other forms of SCID. Skeletal abnormalities and neurologic abnormalities may be associated with this disease.

An alternate autosomally recessive form of SCID is a deficiency of ZAP-70, a tyrosine kinase important in normal T-lymphocyte function. Deficiency of this tyrosine kinase results in total absence of CD8 T lymphocytes and functionally defective CD4 T lymphocytes, but normal B-lymphocyte and NK activity. Mutations of CD3δ, CD3γ, and CD3ε subunits may lead to partially arrested development of TCR expression and severe T-cell deficiency.

Deficiencies of both p56^kk and Jak3 (Janus kinase 3) can also lead to SCID through defective signal transduction; p56^kk is a T-cell receptor–associated tyrosine kinase that is essential for T-cell differentiation, activation, and proliferation. Jak3 is a cytokine receptor–associated signaling molecule. Finally, patients have been identified with defective recombination activating gene (RAG-1 and RAG-2) products. RAG-1 and RAG-2 initiate recombination of antigen-binding proteins, immunoglobulins and T-cell receptors. The defect leads to both quantitative and qualitative (functional) deficiencies of T and B lymphocytes.

C. What is the overall prognosis for patients with this disorder?

Without treatment, most patients with SCID die within the first 1–2 years.

Case 8

X-Linked Agammaglobulinemia

An 18-month-old boy is brought to the emergency department by his parents with a high fever, shortness of breath, and cough. The boy was well until he was 6 months old. Since then, he has had four bouts of otitis media, and because of their severity and recurrence, he was placed for several months on prophylactic antibiotics. He was recently taken off the antibiotics to see how he would do. The day before presentation, he developed a cough that has quickly progressed into an illness with high fevers and lethargy. Both of his parents are healthy, and he has a healthy older sister. His father’s family history is unremarkable, but his maternal uncle died of pneumonia in infancy. Examination is remarkable for a normally developed toddler who is lethargic and tachypneic. His temperature is 39°C, and he has decreased breath sounds at both lung bases. Chest x-ray film shows consolidation of the right and left lower lobes, as well as bilateral pleural effusions. He is admitted to the hospital, and the boy’s blood cultures grow out Streptococcus pneumoniae the next day. Immunologic testing shows very low levels of IgG, IgM, and IgA antibodies in the serum, and flow cytometry shows the absence of circulating B lymphocytes.

Questions

A. What is the likely diagnosis in this patient and why?

This child has X-linked agammaglobinemia, formerly called Bruton agammaglobinemia. The history of multiple infections occurring after the age of 6 months, the family history of a maternal uncle with lethal infection, the severe current infection with Streptococcus pneumoniae, and the absence of circulating B lymphocytes are characteristic of this disorder.

B. What is the primary pathophysiologic defect in the condition, and how does it lead to this clinical presentation?

The main defect is a mutation in the BTK (Bruton tyrosine kinase) gene, which is located on the X chromosome. This gene’s product is a B-cell–specific signaling protein necessary for normal B-cell maturation. The mutation affects the catalytic domain of the protein, halting B-cell maturation. This, in turn, leads to absence or greatly reduced levels of the immunoglobulins IgA, IgG, and IgM. Their absence or reduction is a particular problem with fighting infections from encapsulated bacteria because these bacteria require antibody binding for efficient opsonization. Therefore, patients are particularly susceptible to infections with bacteria such as Haemophilus influenzae and S pneumoniae. Because they cannot mount an antibody response, they also develop very little immunity to these infections and are thus susceptible to repeated infections with the same organism.

C. Why are the affected children generally fine until they reach 4–6 months of age?

The affected child is relatively protected by circulating maternal antibodies until 4–6 months of age. The child’s immune system is otherwise unaffected, but as the levels of maternal antibodies decrease, the child becomes increasingly susceptible to infection, particularly from encapsulated bacteria.

Case 9

Common Variable Immunodeficiency

An 18-year-old man presents with complaints of fever, facial pain, and nasal congestion consistent with a diagnosis of acute sinusitis. His medical history is notable for multiple sinus infections, two episodes of pneumonia, and chronic diarrhea, all suggestive of primary immunodeficiency syndrome. Workup establishes a diagnosis of common variable immunodeficiency.

Questions

A. What are the common infectious manifestations of common variable immunodeficiency?

Individuals with common variable immunodeficiency (CVI) commonly develop recurrent sinopulmonary infections such as sinusitis, otitis media, bronchitis, and pneumonia. Common pathogens are encapsulated bacteria such as S pneumoniae, H influenzae, and Moraxella catarrhalis. Bronchiectasis may develop as a result of these recurrent infections. They may also develop GI malabsorption from bacterial overgrowth or chronic Giardia infection in the small bowel.

B. What are the underlying immunologic abnormalities responsible for these infectious manifestations?

CVI is a heterogeneous disorder in which the primary immunologic abnormality is a marked reduction in antibody production, with normal or reduced numbers of circulating B cells. This is most commonly caused by a defect in the terminal differentiation of B lymphocytes in response to T-lymphocyte–dependent and T-lymphocyte–independent stimuli. However, defects in B-lymphocyte development have been shown to occur at any stage of the maturation pathway.

In many patients, the defect is intrinsic to the B-lymphocyte population. Approximately 15% of patients with CVI demonstrate defective B-cell surface expression of TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), a member of the TNF receptor family. Lacking a functional TACI, the affected B cells will not respond to B-cell–activating factors, resulting in deficient immunoglobulin production. Another defect, which may lead to CVI, involves deficient expression of the B-cell surface marker, CD19. When complexed with CD21 and CD81, CD19 facilitates cellular activation through B-cell receptors. B-cell development is not affected but humoral function is deficient. A variety of T-cell abnormalities may also lead to immune defects with subsequent impairment of B-cell differentiation. A mutation of inducible T-cell costimulator gene (ICOS), expressed by activated T cells and responsible for B-cell activation and antibody production, may be the molecular defect in some cases of CVI. T-lymphocyte dysfunction can be manifested as increased suppressor T-lymphocyte activity, decreased cytokine production, defective synthesis of B-lymphocyte growth factors, defective cytokine gene expression in T cells, decreased T-cell mitogenesis, and deficient lymphokine-activated killer cell function.

C. What other diseases is this patient at increased risk for?

Individuals with CVI are at increased risk of autoimmune disorders and malignancies. The autoimmune disorders most commonly seen in association with CVI include immune thrombocytopenic purpura, hemolytic anemia, and symmetric seronegative arthritis. The malignancies associated with CVI include lymphomas, gastric carcinoma, and skin cancers.

D. What treatment is indicated?

Treatment is mainly symptomatic along with replacement of immune globulin with monthly infusions of IVIG.

Case 10

Acquired Immunodeficiency Syndrome (AIDS)

A 31-year-old male injection drug user presents to the emergency department with a chief complaint of shortness of breath. He describes a 1-month history of intermittent fevers and night sweats associated with a nonproductive cough. He has become progressively more short of breath, initially only with exertion, but now he feels dyspneic at rest. He appears to be in moderate respiratory distress. His vital signs are abnormal, with fever to 39°C, heart rate of 112 bpm, respiratory rate of 20/minute, and oxygen saturation of 88% on room air. Physical examination is otherwise unremarkable but notable for the absence of abnormal lung sounds. Chest x-ray film reveals a diffuse interstitial infiltrate characteristic of pneumocystis pneumonia, an opportunistic infection.

Questions

A. What is the underlying disease most likely responsible for this man’s susceptibility to pneumocystis pneumonia?

Pneumocystis pneumonia is commonly seen in AIDS. An HIV-1 antibody test should be obtained whenever the diagnosis of Pneumocystis jirovecii is suspected.

B. What is the pathogenesis of the immunosuppression caused by this underlying disease?

AIDS is the consequence of infection with HIV-1, a retrovirus that infects multiple cell lines, including lymphocytes, monocytes, macrophages, and dendritic cells. With HIV infection, there is an absolute reduction of CD4 T lymphocytes, an accompanying deficit in CD4 T-lymphocyte function, and an associated increase in CD8 cytotoxic T lymphocytes (CTLs). In addition to the cell-mediated immune defects, B-lymphocyte function is altered such that many infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses. The resultant immunosuppression predisposes patients to the constellation of opportunistic infections that characterizes AIDS.

The loss of CD4 cells seen in HIV infection is the result of multiple mechanisms, including (1) autoimmune destruction, (2) direct viral infection and destruction, (3) fusion and formation into multinucleated giant cells, (4) toxicity of viral proteins to CD4 T lymphocytes and hematopoietic precursors, and (5) apoptosis (programmed cell death).

C. What is the natural history of this disease? What are some of the common clinical manifestations seen during its progression?

The clinical manifestations of HIV infection and AIDS are the direct consequence of progressive and severe immunosuppression and can be correlated with the degree of CD4 T-lymphocyte destruction. HIV infection may present as an acute, self-limited febrile syndrome. This is often followed by a long, clinically silent period, sometimes associated with generalized lymphadenopathy. The time course of disease progression may vary; the majority of individuals remain asymptomatic for 5–10 years. Approximately 70% of HIV-infected individuals will develop AIDS after a decade of infection. Approximately 10% of those infected manifest rapid progression to AIDS within 5 years after infection. A minority of individuals are “long-term nonprogressors.” Genetic factors, host cytotoxic immune responses, and viral load and virulence all appear to have an impact on susceptibility to infection and the rate of disease progression. Multidrug antiretroviral therapy has dramatically changed this natural history and markedly prolonged survival.

As the CD4 count declines, the incidence of infection increases. At CD4 counts between 200/μL and 500/μL, patients are at an increased risk for bacterial infections, including pneumonia and sinusitis. As CD4 counts continue to drop—generally below 250/μL—they are at high risk for opportunistic infections such as pneumocystic pneumonia, candidiasis, toxoplasmosis, cryptococcal meningitis, cytomegalovirus (CMV) retinitis, and Mycobacterium avium complex infection. HIV-infected individuals are also at increased risk for certain malignancies, including Kaposi sarcoma, non-Hodgkin lymphoma, primary CNS lymphoma, invasive cervical carcinoma, and anal squamous cell carcinoma. Other manifestations of AIDS include AIDS dementia complex, peripheral neuropathy, monoarticular and polyarticular arthritides, unexplained fevers, and weight loss. Since patients are living longer due to potent antiretroviral therapies (ART), cardiovascular complications are more prominent. ART has been associated with dyslipidemia and metabolic abnormalities including insulin resistance. HIV infection may be atherogenic as well, through effects on lipids and proinflammatory mechanisms.