Factors involved in the pathogenesis of neutrophilic vasculitis in MRL/Mp-lpr/lpr mice: A model for human microscopic angiitis

Anti-neutrophil cytoplasm antibodies (ANCA) directed against myeloperoxidas e (MPO) are detected in patients with microscopic angiitis. Human MPO autoa ntibodies stimulate neutrophil degranulation in vitro and are thought to be pathogenic. We have previously shown that MRL-lpr mice with MPO autoantibo dies have a higher incidence of vasculitis than their seronegative litterma tes. The aim of the present study is to determine the relationship between MPO autoantibodies and microscopic angiitis. The neutrophil binding propert ies of anti-MPO monoclonal antibodies (mAbs) from MRL-lpr mice were tested using murine heterophils (neutrophils) present in blood and induced periton eal exudates, MRL anti-MPO mAbs selectively bind activated neutrophils whic h express MPO in vitro. The pathogenicity of an IgG2b anti-MPO mAb, C6, was investigated in vivo. Anti-MPO mAb, C6 was administered to young MRL mice which had been primed with exogenous TNF alpha to induce neutrophil activat ion and expression of MPO. Neutrophilic vasculitis similar to microscopic a ngiitis occurred in 33% of MRL mice which had been treated with anti-MPO mA b, The lesions were mainly restricted to sites of previous endothelial insu lt which suggests an active role for injured endothelium in this pathology.