The molecular basis of X-linked agammaglobulinemia, hyper-IgM syndrome, and severe combined immunodeficiency in humans.
The molecular basis for X-linked agammaglobulinemia, hyper-IgM syndrome, and severe combined immunodeficiency was recently identified. In X-linked agammaglobulinemia the molecular defect was found to reside in the gene encoding a novel cytoplasmic tyrosine kinase (bpk, atk, or btk) expressed by B and myeloid cells. This kinase belongs to a new subfamily of tyrosine kinases that contains SH1, SH2, and SH3 domains. A defect in the murine homologue of this kinase has been shown to be responsible for X-linked immunodeficiency in mice. Currently, the role of btk in B- and myeloid cell signaling is unknown. The molecular defect in X-linked hyper-IgM syndrome has been shown to reside in the gene encoding the T-cell activation protein gp39 (CD40L, TRAP). This protein binds to its counter receptor, CD40, on B cells and has been shown to participate in T-cell-dependent B-cell help leading to B-cell proliferation and isotype switching. X-linked severe combined immunodeficiency patients were found to have defects in the gene encoding the gamma-chain of the interleukin-2 receptor. This chain of the interleukin-2 receptor is constitutively expressed by T cells and is involved in the formation of high and intermediate affinity interleukin-2 receptor complexes. These two interleukin-2 receptor complexes are responsible for mediating interleukin-2-dependent signals.
Aruffo
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Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington, USA.
Hollenbaugh
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Wu
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Ochs
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D000361:Agammaglobulinemia / Q000235:genetics*; D000818:Animals; D002874:Chromosome Mapping; D017074:Common Variable Immunodeficiency / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D007075:Immunoglobulin M; D016511:Severe Combined Immunodeficiency / Q000235:genetics*; D014960:X Chromosome
D007075:Immunoglobulin M