title: The 77C->G mutation in the human CD45 (PTPRC) gene leads to increased intensity of TCR signaling in T cell lines from healthy individuals and patients with multiple sclerosis.
abstract: The 77C-->G mutation in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of 77C-->G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, and HIV-1. To investigate the mechanisms by which the variant allele may contribute to disease susceptibility, we compared T cell reactivity in heterozygous carriers of the mutation (healthy individuals and multiple sclerosis patients) and wild-type controls. In vitro-generated T cell lines and freshly isolated CD4+CD45R0+ primed/memory T cells from 77C-->G individuals aberrantly expressed CD45RA isoforms and showed enhanced proliferation and IL-2 production when stimulated with anti-TCR/CD3 mAb or Ag. Mutant T cell lines contained a more active pool of p56lck tyrosine kinase and responded with increased phosphorylation of Zap70 and TCR-zeta and an enhanced Ca2+ flux to TCR/CD3 stimulation. These data suggest that 77C-->G may act as a risk factor for certain diseases by increasing the intensity of TCR signaling.
authors.affiliation: Transplantationslabor, Klinik für Viszeral-und Transplantationschirurgie, Hannover, Germany.
authors.forename: Hue-Tran
authors.initials: HT
authors.lastname: Do
authors.forename: Wiebke
authors.initials: W
authors.lastname: Baars
authors.forename: Katja
authors.initials: K
authors.lastname: Borns
authors.forename: Anja
authors.initials: A
authors.lastname: Windhagen
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schwinzer
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D004247:DNA / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007156:Immunologic Memory; D066298:In Vitro Techniques; D007519:Isoantigens / Q000008:administration & dosage; D017493:Leukocyte Common Antigens / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology*; D017354:Point Mutation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D007519:Isoantigens; D011948:Receptors, Antigen, T-Cell; D004247:DNA; D017493:Leukocyte Common Antigens