Document Detail

Defective expression of CD40 ligand on T cells causes "X-linked immunodeficiency with hyper-IgM (HIGM1)".
MedLine Citation:
PMID:  7915248     Owner:  NLM     Status:  MEDLINE    
X-linked immunodeficiency with hyper-IgM (HIGM1) is a rare disorder, characterized by recurrent infections associated with very low or absent IgG and IgA, and normal to increased IgM serum levels. The disease has been earlier mapped to the q26-27 region of the X-chromosome. We have identified a novel molecule expressed on the surface of activated T cells, which was designated TRAP (Tumor necrosis factor Related Activation Protein), and could demonstrate that TRAP is a ligand for the CD40 receptor expressed on B cells. Our mapping of the TRAP gene to the Xq26.3-27.1 region suggested a causal relationship to HIGM1. Further work revealed that various mutations of the TRAP/CD40 ligand (CD40L) gene may lead to a defective expression of the TRAP/CD40L molecule on the T-cell surface in HIGM1 patients. A combination of structural and functional analyses finally demonstrated that the failure of TRAP/CD40L on T cells to interact with CD40 on B cells is responsible for the inefficient T-cell help for B cells observed in HIGM1. The observations made in HIGM1 allowed us to conclude that TRAP/CD40L is not required for IgM synthesis. In contrast, functional expression of TRAP is a prerequisite for effective immunoglobulin isotype switching and subsequent production of IgG, IgA and IgE by B cells in vivo. The interaction of TRAP/CD40L with CD40 thus provides a very critical link between the cellular and the humoral part of the immune system. The knowledge of TRAP/CD40L cDNA sequence, the availability of various reagents for the testing of expression and function of TRAP/CD40L, and our recent elucidation of the exon-intron structure of the TRAP/CD40L gene now provide all necessary tools for early diagnosis of affected patients and the detection of female carriers of HIGM1. The available information will also provide a basis for future attempts at gene therapy in this disease.
R A Kroczek; D Graf; D Brugnoni; S Giliani; U Korthüer; A Ugazio; G Senger; H W Mages; A Villa; L D Notarangelo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Immunological reviews     Volume:  138     ISSN:  0105-2896     ISO Abbreviation:  Immunol. Rev.     Publication Date:  1994 Apr 
Date Detail:
Created Date:  1994-09-27     Completed Date:  1994-09-27     Revised Date:  2012-02-27    
Medline Journal Info:
Nlm Unique ID:  7702118     Medline TA:  Immunol Rev     Country:  DENMARK    
Other Details:
Languages:  eng     Pagination:  39-59     Citation Subset:  IM    
Molecular Immunology, Robert Koch-Institute, Berlin, Germany.
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MeSH Terms
Antigens, Differentiation, T-Lymphocyte / metabolism*
CD40 Ligand
Gene Expression Regulation / genetics
Genetic Linkage
Hypergammaglobulinemia / genetics*
Immunoglobulin M*
Immunologic Deficiency Syndromes / genetics*
Membrane Glycoproteins / genetics,  metabolism*
X Chromosome
Grant Support
Reg. No./Substance:
0/Antigens, Differentiation, T-Lymphocyte; 0/Immunoglobulin M; 0/Ligands; 0/Membrane Glycoproteins; 147205-72-9/CD40 Ligand

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