Unraveling the Immunopathogenesis and Genetic Variants in Vasculitis Toward Development of Personalized Medicine

Abstract

Leukocytoclastic vasculitis (LCV) is a systemic autoimmune disease characterized by the inflammation of the vascular endothelium. Cutaneous small vessel vasculitis (CSVV) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are two examples of LCV. Advancements in genomic technologies have identified risk haplotypes, genetic variants, susceptibility loci and pathways that are associated with vasculitis immunopathogenesis. The discovery of these genetic factors and their corresponding cellular signaling aberrations have enabled the development and use of novel therapeutic strategies for vasculitis. Personalized medicine aims to provide targeted therapies to individuals who show poor response to conventional interventions. For example, monoclonal antibody therapies have shown remarkable efficacy in achieving disease remission. Here, we discuss pathways involved in disease pathogenesis and the underlying genetic associations in different populations worldwide. Understanding the immunopathogenic pathways in vasculitis and identifying associated genetic variations will facilitate the development of novel and targeted personalized therapies for patients.

Keywords: autoimmune disorder; immunopathogenesis; personalized medicine; susceptibility loci; vasculitis.

Figure 1

(A) cutaneous small-vessel vasculitis (CSVV) begins with pre-exposure to microbial pathogens or certain drugs can induce pro-inflammatory cytokine secretion by macrophages leading to increased endothelial selectin, ICAM-1 and VCAM-1 expression, neutrophil diapedesis and degranulation that damages the vascular wall and surrounding tissues. Activation of the adaptive immune system leads to recruitment of cytotoxic lymphocytes and production of IgG and IgM immune complexes that deposit along the endothelium and induce neutrophil degranulation; (B) ANCA-associated vasculitis (AAV) can be caused by APC recognition of surface or secreted neutrophil autoantigens, MPO and PR3, which leads to the production of anti-neutrophil cytoplasmic antigen antiboodies (ANCAs). ANCA can bind to primed neutrophils expression MPO or PR3 on the surface and induce degranulation or NETosis, which forms an amplification loop of antigen release and recognition. Activation of the alternative complement pathway through C5a-mediated upregulation of tissue factor and platelet activation also forms an amplification loop, where C5a binding on neutrophils results in migration of cytoplasmic MPO and PR3 to be displayed on the cell surface.