Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM

Ulf Korthäuer, Daniel Graf, Hans W. Mages, Francine Brière, Munoreedevi Padayachee, Sue Malcolm, Alberto G. Ugazio, Luigi D. Notarangelo, Roland J. Levinsky, Richard A. Kroczek

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)539-541
Number of pages3
Issue number6412
Publication statusPublished - Feb 11 1993

ASJC Scopus subject areas

  • General


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