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Chapter: Essential Clinical Immunology: Immunological Aspects of Immunodeficiency Diseases

Immunological and Molecular Classification of SCID

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

Immunological and Molecular Classification of SCID


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

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

    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 γ 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 γ 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 α 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 TBSCID. 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 γε, and δ) 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.


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