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

详细信息    查看全文

• 作者：Candore ; Giuseppina ; Modica ; Maria Assunta ; Lio ; Domenico ; Colonna-Romano ; Giuseppina ; Listì ; Florinda ; et. al.
• 关键词：AH 8.1 ; C4 ; HLA-B8 ; DR3 ; AH ; ancestral haplotype ; ANA ; anti-nuclear antibodies ; HLA ; human leukocyte antigens ; TNF-α ; tumor necrosis factor-α
• 刊名：Biomedicine and Pharmacotherapy
• 出版年：2003
• 出版时间：September, 2003
• 年：2003
• 卷：57
• 期：7
• 页码：274-277
• 全文大小：61.4 K

文摘

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)-α 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-α, 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.