Xscid

The gene that causes X-SCID has been mapped to Xql3 by linkage studies. The cloning of IL-2Ry chain (common 7 chain, 7c) and the localization of this gene to Xql3 led to the hypothesis, subsequently confirmed, that mutation of -yc causes X-SCID. 7c is a subunit of the IL-2 receptor which consists of an a, ^ and 7 chain, and is shared by IL-4R, IL-7R, IL-9R and IL-15R (Figure 2). Thus, 7c chain plays an important role in the signal transduction of multiple cytokine receptors. Subsequent studies of the yc gene confirmed that all patients with X-SCID have mutations within the 7c gene. Approximately 100 unique mutations of 7c have been reported and registered in the worldwide database. They include mis-sense and nonsense mutations, deletions, insertions and splice site mutations and affect all domains of 7c. The missense mutations of the extracellular domain of 7c result in impaired binding of IL-2. Mutations affecting the four cysteine residues that are conserved in the cytokine receptor family and the mutations affecting the WSXWS motif disrupt the configuration of the yc chain. Missense mutations at the transmembrane domain cause unstable expression of the yc chain either by the replacement of hydrophobic amino acids or the disruption of anchoring residues. Mutations within the intracellular domain affect the signal transduction pathway of IL-2R. Deletion of 62 amino acid residues at the C-terminal region of 7c caused a severe phenotype of X-SCID. A missense mutation at amino acid residue 271 (L271Q) interferes with the association of 7c and JAK3 (Figure 3).

Although T cells and natural killer (NK) cells are absent in X-SCID patients, B cell numbers in the peripheral blood are normal or elevated. The pheno-types of B cells are relatively immature and the diversity of Ig rearrangement is limited. This could be caused by the lack of appropriate T cell help or by the fact that 7c is shared by IL-2R, IL-4R, IL-7R, IL-9R and IL-15R, resulting in a lack of B cell activation by cytokines. B cell function after allogeneic bone marrow transplant (BMT) of patients not undergoing conditioning is known to be impaired when major histocompatibility complex (M HQ-matched normal donor-derived T cells but not B cells were engrafted. Immunoglobulin (Ig) rearrangements of recipient-derived B cells are often limited.

7c-deficient mice made by gene targeting show defective lymphocyte development. However, in contrast to human X-SCID, the number of mature B cells is decreased and CD4J CD8 and CD4 CD8 h thymocytes are present, although the absolute numbers are low. The discrepancy between the phenotype of 7c-deficient mice and that of human X-SCID indicates that the requirement of cytokines during lymphocyte development is different between human and mouse. The difference can be explained in part by the observation that IL-7 is indispensable for murine but not human B cell development. (1.-7 receptor knockout mice show severe reduction of both T cells and B cells. The exact role of cytokines for human lymphocyte development has not been determined. In vitro culture systems that allow the maturation of functional B cells and T cells from human lymphoid stem cells will facilitate our understanding of defective lymphoid development in X-SCID.

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