B cell-mediated pathogenesis of ANCA-mediated vasculitis.
B cells and their progeny that produce and release anti-neutrophil cytoplasmic autoantibodies (ANCA) are the primary cause for an aggressive form of necrotizing small vessel vasculitis. Cytoplasmic ANCA antigens are released at the surface and in the microenvironment of cytokine-primed neutrophils. Binding of ANCA to ANCA antigens activates neutrophils by both Fc receptor engagement and direct Fab'2 binding to antigen on the cell surface. ANCA-activated neutrophils release factors that induce alternative complement pathway activation, which establishes a potent inflammatory amplification loop that causes severe necrotizing vascular inflammation. The origin of the ANCA autoimmune response is unknown but appears to involve genetically determined HLA specificities that allow the autoimmune response to develop. One putative immunogenic mechanism begins with an immune response to a peptide that is complementary to the autoantigen and evolves through an anti-idiotypic network to produce autoantibodies to the autoantigen. Another putative immunogenic mechanism begins with an immune response to a microbe-derived molecular mimic of the autoantigen resulting in antibodies that cross-react with the autoantigen. Release of neutrophil extracellular traps, apoptosis, and increased granule protein expression of ANCA antigens may facilitate the initiation of an ANCA autoimmune response, augment established pathogenic ANCA production, or both. The ANCA B cell autoimmune response is facilitated by quantitatively and qualitatively impaired T cell and B cell suppression and by release from activated neutrophils of B cell-activating factors that enhance B cell proliferation and retard B cell apoptosis.
Department of Pathology and Laboratory Medicine, and Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, 308 Brinkhous-Bullitt Building, CB#7525, Chapel Hill, NC, 27599-7525, USA, jcj@med.unc.edu.
J Charles
JC
Jennette
Ronald J
RJ
Falk
D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000175:diagnosis / Q000276:immunology*; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D006801:Humans; D056747:Immunomodulation; D009504:Neutrophils / Q000276:immunology
D019268:Antibodies, Antineutrophil Cytoplasmic; D001324:Autoantigens