Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 influences immunological parameters of healthy carriers of the haplotype.

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  • Additional Information
    • Source:
      Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 8213295 Publication Model: Print Cited Medium: Print ISSN: 0753-3322 (Print) Linking ISSN: 07533322 NLM ISO Abbreviation: Biomed Pharmacother Subsets: MEDLINE
    • Publication Information:
      Publication: Paris : Editions Scientifiques Elsevier
      Original Publication: New York, N.Y. : Masson Pub. USA, Inc., c1982-
    • Subject Terms:
      Autoimmune Diseases/*etiology ; Complement C4/*genetics ; HLA Antigens/*genetics ; Haplotypes/*genetics; Adult ; Alleles ; Autoimmune Diseases/genetics ; Autoimmune Diseases/immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Gene Frequency/genetics ; HLA-B8 Antigen/genetics ; HLA-DR3 Antigen/genetics ; Haplotypes/immunology ; Humans ; Male ; Middle Aged
    • Abstract:
      Subjects with certain HLA alleles have a higher risk of specific autoimmune diseases than those without these alleles. The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype carried by most people who type for HLA-B8,DR3. It is unique in its association with a wide range of immunopathological diseases. To gain insight into the identification of the mechanism(s) of disease susceptibility of 8.1 AH carriers, we have investigated the prevalence of circulating immune complexes and non-organ-specific autoantibodies in healthy carriers of the haplotype. The results show that carriers of 8.1 AH display both a significant increased prevalence of immune complexes and higher titers of anti-nuclear autoantibodies. This AH carries a single segment characterized by no C4A gene. This null allele does not code for a functional C4A protein that likely plays an anti-inflammatory role being specialized in the opsonization and immunoclearance processes. So, this genetic defect has been claimed to allow that an increased production of autoantibodies directed vs. cells that have undergone apoptosis and are not efficiently disposed because a reduced antigenic clearance. The results obtained in the present study fit very well with this hypothesis. In the AH carriers the simultaneous high setting of tumor necrosis factor (TNF)-alpha may supply the autoantigens (providing an excess of apoptotic cells) that drive the autoimmune response. In conclusion, the C4 defect associated to the increased spontaneous release of TNF-alpha, modifying a certain number of immunological parameter may be the most characterizing feature of the 8.1 AH. In the majority of individuals, an autoimmune response clinically relevant will develop only in the presence of other immunological abnormalities.
    • Accession Number:
      0 (Complement C4)
      0 (HLA Antigens)
      0 (HLA-B8 Antigen)
      0 (HLA-DR3 Antigen)
    • Publication Date:
      Date Created: 20030923 Date Completed: 20040206 Latest Revision: 20191026
    • Publication Date:
      20240829
    • Accession Number:
      10.1016/s0753-3322(03)00079-9
    • Accession Number:
      14499172