title: Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM.
abstract: 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.
authors.affiliation: Max-Planck-Gesellschaft, Arbeitsgruppe Immunologie, Universität Erlangen, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Korthäuer
authors.forename: D
authors.initials: D
authors.lastname: Graf
authors.forename: H W
authors.initials: HW
authors.lastname: Mages
authors.forename: F
authors.initials: F
authors.lastname: Brière
authors.forename: M
authors.initials: M
authors.lastname: Padayachee
authors.forename: S
authors.initials: S
authors.lastname: Malcolm
authors.forename: A G
authors.initials: AG
authors.lastname: Ugazio
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: R J
authors.initials: RJ
authors.lastname: Levinsky
authors.forename: R A
authors.initials: RA
authors.lastname: Kroczek
mesh_terms: D015703:Antigens, CD / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D001483:Base Sequence; D019013:CD40 Antigens; D023201:CD40 Ligand; D004252:DNA Mutational Analysis; D005434:Flow Cytometry; D008040:Genetic Linkage; D006801:Humans; D006942:Hypergammaglobulinemia / Q000209:etiology*; D007075:Immunoglobulin M / Q000276:immunology*; D007153:Immunologic Deficiency Syndromes / Q000209:etiology*; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins; D008969:Molecular Sequence Data; D017354:Point Mutation; D013601:T-Lymphocytes / Q000276:immunology*; D014960:X Chromosome
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D007075:Immunoglobulin M; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand