Haptenization as the missing link between vasculitis and myeloperoxidase

Abstract

A wide variety of medications can induce adverse immune events and autoimmune responses such as vasculitis. Mechanistically, small molecule drugs known as haptens bind and modify endogenous proteins, triggering such immune reactions. In this issue of the JCI, Xi and colleagues investigated the immunological mechanism of autoimmune vasculitis associated with hydralazine. Notably, hydralazine-based haptenization modified myeloperoxidase (MPO), inducing the enzyme conformational change. The hydralazine-modified MPO induced IgM antibody specific for the modified enzyme, followed by immune complex precipitation, tissue deposition, and complement activation. These findings provide a mechanism by which hydralazine induces a type III hypersensitivity reaction associated with mild to severe vasculitis. The study serves as an example for understanding haptenation and may inform the development of diagnostics for determining susceptibility to drug-induced allergic or autoimmune responses.

Figure 1. The mechanism of Hydralazine-induced vasculitis involves IgM reactivity to hydralazine-modified MPO.

Hydralazine may function as a prehapten, from which enzymatic reaction or direct oxidation generates radical haptens, for example, hyralazyl radicals, that readily bind MPO. Alternatively, hydralazine can bind to MPO by linking through carbonyl derivatives already found on the protein itself. One of the molecules generated through the carbonyl-modified haptenization process is hydrazone-MPO, which induces anti-IgM specific for the modified, but not native, MPO. The IgM generates an antineutrophil cytoplasmic antibody (ANCA) response and neutrophil degranulation. IgM-bound hydrazone-MPO immune complexes induce a type III hypersensitivity reaction and activate the classical complement pathway, generating vasculitis and tissue damage.