Wegener's granulomatosis,
microscopic polyangiitis,
Churg-Strauss syndrome and idiopathic pauci-immune necrotizing crescentic
glomerulonephritis are strongly associated with the presence of
anti-neutrophil cytoplasmic antibodies (
ANCA). These
ANCA-associated vasculitides can serologically be separated into
myeloperoxidase (MPO)-
ANCA and
proteinase 3 (PR3)-ANCA positive patients. The unique properties of the
antigen targeted by the anti-MPO
antibodies could help to explain the specific characteristics of MPO-
ANCA associated disease. Recently, an animal model has been developed that proves that anti-mouse MPO
immunoglobulins alone are capable of causing disease similar to that in humans. Also, the in vitro pathologic effects of binding of MPO-
ANCA to MPO are better understood. MPO-
ANCA can activate (primed) neutrophils directly causing extensive
reactive oxygen species formation and degranulation of neutrophil constituents, including MPO, resulting in a destructive inflammatory response towards the vessel wall. MPO-
ANCA can prevent the clearing and inactivation of MPO by
ceruloplasmin as well, resulting in increased
myeloperoxidase activity.
Myeloperoxidase produces not only the strong
oxidant bleach (
hypochlorous acid) out of
hydrogen peroxide and
chloride ions but also oxidizes
LDL into a macrophage high-uptake form, inactivates
protease inhibitors, and consumes
nitric oxide. These may contribute to endothelial dysfunction and add to the chronic renal lesions observed in patients with MPO-
ANCA. MPO levels are influenced by genetic factors including two, MPO463 and MPO129, single nucleotide polymorphisms. The MPO 463 polymorphism has been associated with an increased risk of development of MPO-
ANCA associated disease.