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B cell-mediated pathogenesis of ANCA-mediated vasculitis

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Abstract

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.

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Acknowledgments

This study was funded by NIH NIDDK P01-DK058335.

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  1. 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

    J. Charles Jennette & Ronald J. Falk

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  1. J. Charles Jennette
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  2. Ronald J. Falk
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Correspondence to J. Charles Jennette.

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This article is a contribution to the special issue on B cell-mediated autoimmune diseases - Guest Editors: Thomas Winkler and Reinhard Voll

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Jennette, J.C., Falk, R.J. B cell-mediated pathogenesis of ANCA-mediated vasculitis. Semin Immunopathol 36, 327–338 (2014). https://doi.org/10.1007/s00281-014-0431-y

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