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 p56kk and Jak3 (Janus kinase 3) can also lead to SCID through defective signal transduction; p56kk 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.