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

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 levels. HIGM1 has been suggested to result from ineffective T-cell help fo...

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Bibliographic Details
Published in:Nature (London) 1993-02, Vol.361 (6412), p.539-541
Main Authors: Korthäuer, Ulf, Graf, Daniel, Mages, Hans W, Brière, Francine, Padayachee, Munoreedevi, Malcolm, Sue, Ugazio, Alberto G, Notarangelo, Luigi D, Levinsky, Roland J, Kroczek, Richard A
Format: Article
Language:English
Subjects:
Antigens, CD - immunology
Antigens, Differentiation, B-Lymphocyte - immunology
Bacterial diseases
Base Sequence
Biological and medical sciences
CD40 Antigens
CD40 Ligand
defects
DNA Mutational Analysis
expression
Flow Cytometry
Genetic Linkage
Humans
hyper-immunoglobulin M syndrome
Hypergammaglobulinemia - etiology
Immunity (Disease)
Immunodeficiencies
Immunodeficiencies. Immunoglobulinopathies
Immunoglobulin M - immunology
Immunologic Deficiency Syndromes - etiology
Immunopathology
Ligands
Lymphocyte Activation
man
Medical research
Medical sciences
Membrane Glycoproteins
Molecular Sequence Data
Point Mutation
Proteins
T-Lymphocytes - immunology
TRAP protein
X Chromosome
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Summary: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 levels. HIGM1 has been suggested to result from ineffective T-cell help for B cells. We and others have identified a novel, TNF-related activation protein (TRAP) that is exclusively expressed on the surface of stimulated T cells. TRAP, a type II transmembrane protein of M(r) 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 IgE. 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/361539a0