Pathogenesis of antineutrophil cytoplasmic autoantibody vasculitis

Abstract

Purpose of review: Antineutrophil cytoplasmic autoantibodies (ANCAs) are associated with vasculitis. Current therapy involves administration of toxic therapy that is not optimally effective. This review will summarize evidence for the pathogenicity of ANCAs, which will suggest possible strategies for improving treatment.

Recent findings: Pauci-immune small vessel vasculitis is associated with antibodies against myeloperoxidase (MPO-ANCA) and proteinase 3 (PR3-ANCA). One research group has reported a high frequency of autoantibodies against lysosomal-associated membrane protein 2 (LAMP-2) in patients with MPO-ANCA or PR3-ANCA. Epigenetic dysregulation appears to be the basis for increased MPO and PR3 neutrophil gene expression in ANCA disease. Release of neutrophil extracellular traps may be involved in initiating the ANCA autoimmune response and causing vessel injury. Generation of C5a by alternative pathway activation is involved in pathogenesis in mouse models. Intervention strategies in mice that target antigens, antibodies and inflammatory signaling pathways may translate into novel therapies. Animal models of LAMP-ANCA and PR3-ANCA disease have been proposed. Molecular mimicry and responses to complementary peptides may be initiating events for ANCAs. T cells, including regulatory T cells, have been implicated in the origin and modulation of the ANCAs, as well as in the induction of tissue injury.

Summary: Our basic understanding of the origins and pathogenesis of ANCA disease is advancing. This deeper understanding already has spawned novel therapies that are being investigated in clinical trials. This brief review shows that there are more questions than answers, and new questions are emerging faster than existing questions are being answered.

Figure 1. Immunogenesis and pathogenesis of ANCA disease

Diagram of putative events in the pathogenesis of ANCA disease based on in vitro and in vivo experimental observations. In the upper left, the theory of autoimmunity induced by an immune response to a complementary peptide is depicted. The lower left proposes that T cell regulation is disturbed to allow persistence and progression of autoimmunity. In the upper right, the aberrant increased production of ANCA antigens by epigenetic dysregulation of gene expression is illustrated. Once ANCA antibodies are present along with neutrophils with increased antigens, the sequence of pathogenic events illustrated in the lower right can occur, i.e. cytokines or other priming factors induce neutrophils to express more ANCA antigens at the cell surface where they are available for binding to ANCA, which activates neutrophils by both Fc receptor engagement and Fab’2 binding. Factors released by neutrophils activate the alternative complement pathway, which generates factors that amplify recruitment and activation of neutrophils. Activated neutrophils release toxic factors that cause inflammatory injury to endothelial cells and vessel walls. (Reproduced with permission of J.C. Jennette)