Reports from Vanderbilt University, Department of Medicine highlight recent research in glomerulonephritis immunology
2007 JUL 3 -- Scientists discuss in "Autoepitopes and alloepitopes of type IV collagen: role in the molecular pathogenesis of anti-GBM antibody glomerulonephritis" new findings in glomerulonephritis. According to recent research from the United States, "Anti-glomerular basement membrane (anti-GBM) antibodies elicited by autoimmune or alloimmune mechanisms are associated with aggressive forms of rapid progressive glomerulonephritis. Pathogenic anti-GBM autoantibodies and alloantibodies target the noncollagenous (NC1) domains of the alpha3alpha4alpha5(IV) collagen, a major GBM component." "In autoimmune anti-GBM glomerulonephritis, a breakdown of immune self-tolerance leads to the activation of autoreactive B and T cells recognizing epitopes within the alpha3NC1 subunit. In the GBM, the conformational epitopes targeted by anti-GBM autoantibodies are structurally sequestered within the alpha3alpha4alpha5NC1 hexamer complex formed upon assembly of collagen IV chains into trimeric molecules and networks. Autoantibodies selectively bind to and dissociate a subset of alpha3alpha4alpha5NC1 hexamers composed of monomer subunits, whereas hexamers containing NC1 dimer subunits are resistant to dissociation by autoantibodies. The crypticity of alpha3NC1 autoepitopes suggests that self-tolerance to alpha3(IV) collagen is broken by structural alterations of the native alpha3alpha4alpha5NC1 hexamer that unmask normally sequestered epitopes, triggering an autoimmune reaction. Post-transplant anti-GBM nephritis in the renal allograft of transplanted Alport patients is mediated by an alloimmune reaction to the NC1 domains of alpha3alpha4alpha5(IV) collagen, present in the allograft GBM but absent from Alport basement membranes. Alloantibodies from patients with autosomal-recessive Alport syndrome predominantly bind to the alpha3NC1 domain, whereas alloantibodies from X-linked Alport patients target preferentially, though not exclusively, epitopes within the alpha5NC1 subunit. The accessibility of the alloantigenic sites within the alpha3alpha4alpha5NC1 hexamers, contrasting with the crypticity of autoantigenic sites, suggest that different molecular forms of alpha3alpha4alpha5(IV) collagen initiate the immunopathogenic responses in the two forms of anti-GBM disease," wrote D.B Borza and colleagues, Vanderbilt University, Department of Medicine. The researchers concluded: "Advances in elucidating the structure of the GBM antigen and the identification of the pathogenic B and T cell epitopes, along with new insights into the pathogenic mechanisms at cellular and molecular level will facilitate the development of targeted strategies for prevention, detection, and treatment of human anti-GBM antibody glomerulonephritis." Borza and colleagues published their study in Nephron Experimental Nephrology (Autoepitopes and alloepitopes of type IV collagen: role in the molecular pathogenesis of anti-GBM antibody glomerulonephritis. Nephron Experimental Nephrology, 2007;106(2):e37-43). For additional information, contact D.B. Borza, Dept. of Medicine, Division of Nephrology, Vanderbilt University School of Medicine, Nashville, TN 37232-2372 USA. Publisher contact information for the journal Nephron Experimental Nephrology is: Karger, Allschwilerstrasse 10, CH-4009 Basel, Switzerland. Keywords: United States, Nashville, Glomerulonephritis Immunology, Autoimmune Disease, Autoimmune Disorder, Glomerulonephritis, Immunology, Nephrology. This article was prepared by Disease Prevention Week editors from staff and other reports. Copyright 2007, Disease Prevention Week via NewsRx.com.
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