TY - JOUR
T1 - Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM
AU - Korthäuer, Ulf
AU - Graf, Daniel
AU - Mages, Hans W.
AU - Brière, Francine
AU - Padayachee, Munoreedevi
AU - Malcolm, Sue
AU - Ugazio, Alberto G.
AU - Notarangelo, Luigi D.
AU - Levinsky, Roland J.
AU - Kroczek, Richard A.
PY - 1993/2/11
Y1 - 1993/2/11
N2 - X CHROMOSOME-LINKED immunodeficiency with hyper-IgM (HIGM1, MIM number 308230) is a rare disorder characterized by recurrent bacterial infections, very low or absent IgG, IgA and IgE, and normal to increased IgM and IgD serum levels1-3. HIGM1 has been suggested to result from ineffective T-cell help for B cells4. We and others5-8 have identified a novel, TNF-related activation protein (TRAP) that is exclusively expressed on the surface of stimulated T cells6,8. TRAP, a type II transmembrane protein of Mr 33,000, is the physiological ligand for CD40 (refs 5-8). Crosslinking of CD40 on B cells induces, in the presence of lymphokines, immunoglobulin class switching from IgM to IgG, IgA or IgE5,9-11. Mapping of the TRAP gene to the X-chromosomal location q26.3-q27.1 (ref. 6) suggested a causal relationship to HIGM1, which had previously been assigned to Xq26 (refs 12-14). Here we present evidence that point mutations in the TRAP gene give rise to nonfunctional or defective expression of TRAP on the surface of T cells in patients with HIGM1. The resultant failure of TRAP to interact with CD40 on functionally intact B cells is responsible for the observed immunoglobulin isotype defect in HIGM1.
AB - X CHROMOSOME-LINKED immunodeficiency with hyper-IgM (HIGM1, MIM number 308230) is a rare disorder characterized by recurrent bacterial infections, very low or absent IgG, IgA and IgE, and normal to increased IgM and IgD serum levels1-3. HIGM1 has been suggested to result from ineffective T-cell help for B cells4. We and others5-8 have identified a novel, TNF-related activation protein (TRAP) that is exclusively expressed on the surface of stimulated T cells6,8. TRAP, a type II transmembrane protein of Mr 33,000, is the physiological ligand for CD40 (refs 5-8). Crosslinking of CD40 on B cells induces, in the presence of lymphokines, immunoglobulin class switching from IgM to IgG, IgA or IgE5,9-11. Mapping of the TRAP gene to the X-chromosomal location q26.3-q27.1 (ref. 6) suggested a causal relationship to HIGM1, which had previously been assigned to Xq26 (refs 12-14). Here we present evidence that point mutations in the TRAP gene give rise to nonfunctional or defective expression of TRAP on the surface of T cells in patients with HIGM1. The resultant failure of TRAP to interact with CD40 on functionally intact B cells is responsible for the observed immunoglobulin isotype defect in HIGM1.
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M3 - Article
C2 - 7679206
AN - SCOPUS:0027533185
VL - 361
SP - 539
EP - 541
JO - Nature
JF - Nature
SN - 0028-0836
IS - 6412
ER -