Immunological and Molecular Classification of SCID

Immunological and Molecular Classification of SCID

SCID can be classified in two groups based on the blood lymphocyte phenotype.

â–     Patients lacking T cells with normal or increased B cells: T−B+ SCID

â–     Patients lacking T and B cells: T−B−SCID

Defects in one of four functionally related genes causes T−B + SCID. X-linked SCID, which is the commonest form, is due to a mutation of the gene encod-ing the IL-2 receptor Î³ chain, which is the signal-transducing chain common to the receptors for six cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21). The absence of responses to these cytokines causes defects in a broad range of T- and B-cell func-tions. IL-7 is required for early stages of T-cell development. Lack of response to this cytokine results in T lymphopenia. IL-15 is required for NK-cell development and its lack results in the failure of NK-cell development. Signal transduction through the aforementioned cytokine receptors involves the interaction of the common Î³ chain with the tyrosine kinase JAK3. This explains why mutations of the JAK3 gene result in an autosomal recessive form of SCID, with a phenotype similar to X-linked SCID. Mutations of the Î± chain of IL-2 or IL-7 receptors result in two rare forms of SCID.

T- and B-cell receptors consist of invari-ant signal-transducing elements combined with elements that make up the variable regions, which contribute to the antigen-binding portion of the receptor. The gene recombination required for generating these receptors requires the function of the product of recombination activating genes 1 and 2 and a number of proteins that are required for DNA repair (DNA-PKcs, KU70, KU80, XRLC4, and DNA-IV). In mice, mutations in any one of these genes produces analogues of SCID.

In humans, T−B−SCID is most common (50 percent of total) caused by mutations of the recombinase-activating genes, RAG1 or RAG2. RAG1 and RAG2 are enzymes responsible for introducing double-stranded DNA breaks, which initiate V(D)J gene rearrangements, required for gener-ating T- and B-cell receptors for antigen. Without normal RAG1 and RAG2 func-tion, T- and B-cell development is arrested early in ontogeny, producing T−B−SCID

Hypomorphic mutations of RAG1 or RAG2 result in a leaky form of SCID called Omenn’s syndrome. In Omenn’s syn-drome, a few T- and B-cell clones may be generated but the full T- and B-cell reper-toire fails to develop. The few T- and B-cell clones that leak through may undergo secondary expansion. As a result, patients with Omenn’s syndrome may not be mark-edly lymphopenic but the lymphocyte rep-ertoire is oligoclonal and severe immuno-deficiency is the outcome.

T- and B-cell antigen receptors are assembled from the recombination of variable region V(D)J and constant region genes. A protein called ARTEMIS is required for DNA repair, including the repair of DNA breaks generated during V(D)J recombination. Mutation of the gene encoding ARTEMIS results in a rare form of T−B−SCID. These patients also exhibit increased sensitivity to ionizing radiation.

About 15 percent of SCID cases are caused by deficiency of adenosine deami-nase (ADA), an enzyme required for the sal-vage of nucleotides within lymphoid cells. The lack of ADA causes the accumulation of toxic metabolites of adenosine (deoxy-adenosine and deoxy-ATP) within lym-phoid cells, resulting in their demise. ADA deficiency results in profound lymphopenia affecting T cells, B cells, and NK cells. Rarely, mutations of ADA causing milder forms of enzyme deficiency lead to a milder form of combined immunodeficiency presenting at a later stage in life. Purine nucleoside phos-phorylase (PNP) is an enzyme required for purine salvage within lymphocytes, and PNP deficiency causes a milder phenotype of SCID than seen in ADA deficiency. SCID due to PNP deficiency not treated with HSCT is fatal in childhood.

Mutations in proteins required for nor-mal functioning and signal transduction through the T-cell receptor (TCR) cause rare forms of SCID. Mutations of the tyro-sine phosphatase, CD45, which helps to initiate signaling by the TCR, results in T−B+ SCID in humans. Mutation of com-ponents of CD3-complex (CD3 Î³, Îµ, and Î´) result in a SCID phenotype. During signal transduction via TCRs, the protein tyrosine kinases Lck and ZAP70 are required for phosphorylation of ITAMs on the intracy-toplasmic segment of the TCR. Deficiency of either of these kinases results in rare forms of SCID.

TCRs of CD8 cells recognize antigenic peptides that are complexed to MHC class I antigens, and TCR of CD4 cells recog-nize antigen bound to MHC class II on the surface of antigen-presenting cells. Cell-surface expression of MHC class I mol-ecules fails if either of the two transport-ers of antigenic peptides (TAP1 or TAP2) is lacking. TAP1 and TAP2 help to transfer peptides from the cytosol into the endo-plasmic reticulum, for subsequent loading onto newly synthesized MHC class I mol-ecules. In the absence of peptide loading, MHC class I molecules are degraded before reaching the cell surface. In the absence of MHC class I antigen expression, CD8 cell function is deficient, and these cells are not generated within the thymus. The result-ing immunodeficiency is milder than SCID and often presents in later life. Paradoxi-cally, viral infections are not a problem in these patients. Some MHC class I deficient patients develop progressive bronchiecta-sis, while others develop vasculitis affect-ing the face and upper respiratory tract. It has been postulated that vasculitis seen in these patients may be due to self-destruc-tion of vascular endothelial cells by the unrestrained cytotoxicity of NK cells.

In contrast, MHC class II deficiency results in a profound failure of CD4 cell functions. Lack of thymic CD4+ CD8− cell selection for survival results in peripheral CD4 lymphopenia. Because CD4 func-tion is required for normal cell-mediated immunity, as well as antibody production, MHC class II deficiency results in a severe form of SCID with a fatal outcome. MHC class II deficiency is due to a mutation in one of four transcription factors (RFXAP, CIITA, RFX5, RFXANK), which regulate MHC class II expression.