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In the secondary vasculitides, associated with infectious disorders, connective tissue diseases and other conditions, immune complexes play a major immunopathogenic role. Immune complexes are absent in most of the primary vasculitides. T-cells are, probably, involved in the large vessel vasculitides, particularly giant cell arteritis, whereas the small vessel vasculitides are associated with anti-neutrophil cytoplasmic autoantibodies (ANCA). Clinical observations, in vitro experimental findings, and in vivo data from animal experiments suggest that ANCA in those diseases, which are directed to proteinase 3 (PR3) or myeloperoxidase (MPO), are involved in their pathogenesis.
Most in vitro studies have focussed on ANCA-induced neutrophil activation. More recently the interaction between ANCA, neutrophils and endothelial cells has been studied in flow systems. ANCA appear to activate integrin-mediated adhesion of neutrophils and adhesion-dependent degranulation. ANCA-induced monocyte activation has been studied to a lesser extent. The role of ANCA-specific T-cells is still under investigation. Epitope analysis showed T-cell reactivity to peptides from PR3 but no specific PR3 sequence could be identified that was preferentially recognized by T-cells of vasculitis patients compared to controls. In vivo experimental studies, in which an MPO-directed autoimmune response is generated, show the phlogistic potential of this response. Apoptotic neutrophils may, under certain circumstances, induce the induction of ANCA. Data from clinical and experimental studies suggest that ANCA alone are not sufficient to induce disease. Exogenous factors, in particular carriage of Staphylococcus aureus and silica exposure, may be involved as well. S. aureus products may elicit antibody responses resulting in focal immune complex deposition, e.g. in the kidneys. ANCA may aggregate the inflammatory response resulting in destruction of complexes and the development of severe necrotizing glomerulonephritis without immune deposits.
Taken together, the interplay between genetic and exogenous factors may induce autoimmunity to myeloid enzymes which, in concert, lead to the clinical expression of the ANCA-associated vasculitides.