The discovery of
anti-neutrophil cytoplasmic antibodies (
ANCA) and their antigenic targets,
myeloperoxidase (MPO) and
proteinase 3 (PR3), has led to further understanding as to the pathophysiologic processes that underlie vascular and tissue damage in
ANCA vasculitis.
ANCA trigger neutrophil activation leading to vascular damage in
ANCA vasculitis. However, decades of study have determined that neutrophil activation alone is not sufficient to cause disease. Inflammatory stimuli are drivers of
ANCA autoantigen expression and
ANCA production. Certain
infections or bacterial
peptides may be crucial players in the initial steps of
ANCA immunopathogenesis. Genetic and epigenetic alterations of gene encoding for MPO and PR3 provide additional disturbances to the immune homeostasis which provide a substrate for pathogenic
ANCA formation from an adaptive immune system predisposed to autoreactivity. Promoted by inflammatory
cytokines,
ANCA binding leads to neutrophil activation, a process characterized by conformational changes, production and release of cytotoxic substances, and alternative complement pathway activation, thus creating an intense inflammatory milieu. This cascade of events perpetuates a vicious cycle of further inflammatory cell recruitment and activation, culminating in tissue
necrosis. Our understanding of the pathogenic process in
ANCA vasculitis paves the way for the development of
therapies targeting crucial steps in this process. The greater appreciation of the role for
complement, monocytes, and the adaptive immune system has already led to novel
complement blockers and is poised to lead to further innovations which will allow for tailored
antigen- or cell-specific
immunotherapy targeting the autoimmune process without exposure to undue risks or toxicities.