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Effector mechanisms of ANCA-associated glomerulonephritis

By Betty Sita van der Veen

Abstract

The ANCA-associated small-vessel vasculitides (ANCA-SVV) Wegener’s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and renal-limited vasculitis are severe diseases that have a high mortality rate when left untreated. Current treatment protocols are based on non-specific immunosuppression, which is insuffi cient in preventing relapses and is characterized by severe side-eff ects. More eff ective and less toxic therapies are therefore needed. A better understanding of the pathogenic eff ector mechanisms underlying ANCA-SVV can improve the development of specific therapeutic strategies. The aim of this thesis was therefore to explore further the eff ector mechanisms involved in ANCA-associated glomerulonephritis, focusing on the discovery of targets for treatment and the testing of experimental therapies. More specifi cally, we concentrated on the importance of infl ammatory stimuli and ANCA IgG characteristics in disease and the therapeutic potential of interfering with leukocyte behaviour. ANCA-SVV: COMPLEX MULTIFACTORIAL DISEASES By definition, patients with autoimmune diseases have a loss of immunological tolerance towards an autoantigen, but it is usually less clear why such a break in tolerance occurs. In line with this, it is not known why ANCA autoantibodies develop in ANCA-SVV patients. In recent years, several theories have been proposed to explain the immunogenesis of ANCA-SVV. The theory of antigen complementarity assumes that antibodies directed against a protein or peptide (antisense) that is complementary to the ANCA antigen (sense) are generated. 1 A subsequent immune response against the antigen-binding part of these antibodies generates idiotypic antibodies that cross-react with the ANCA antigen. The antisense protein or peptide in this theory may be derived from aberrant antisense transcription or from pathogens. A second theory involves molecular mimicry of exogenous proteins with ANCA antigens. This theory assumes that the initial immune response is evoked against pathogen-derived peptides that are highly homologous to peptide sequences within the ANCA-antigens, resulting in a cross-reactive immune response against the ANCA self antigens. Evidence for the occurrence of molecular mimicry in ANCA-SVV is provided by a study showing that circulating autoantibodies against lysosomal associated membrane protein 2 (LAMP-2), a heavily glycosylated type 1 membrane protein involved in cellular adhesion and homeostasis, were highly prevalent in patients with MPO-ANCA- and Pr3- ANCA-positive crescentic glomerulonephritis.2. These anti-LAMP-2 antibodies were able to activate neutrophils and endothelial cells in vitro, whereas injection of these antibodies into rats induced pauci-immune crescentic glomerulonephritis. Most interestingly, the authors showed that a major epitope recognized by anti-LAMP-2 antibodies was highly homologous to FimH-1, a bacterial adhesin of common gram-negative bacteria. When rats were immunized with FimH-1, antibodies directed against FimH-1 were generated that cross-reacted with LAMP-2. Importantly, these rats also developed necrotizing crescentic glomerulonephritis.

Topics: ANCA, Glomerulonefritis; Glomerulus; Auto-immuunziekten; Vaatontstekingen; Neutrofiele granulocyten; Proefschriften (vorm); urologie
Year: 2010
OAI identifier: oai:ub.rug.nl:dbi/4cb42c76d1500
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