The mystery of the antineutrophil cytoplasmic antibodies

Abstract

A NTINEUTROPHIL cytoplasmic antibodies (ANCAs) were first reported in eight patients with segmental necrotizing glomerulonephritis and serologic evidence for acute Ross River virus infection, an arbovirus endemic in Australia that causes a febrile polyartbritis syndrome.’ Subsequently ANCAs were reported in patients with systemic vasculitis.’ Two major types of ANCA staining patterns are recognized; a cytoplasmic (c-ANCA) pattern, in which the primary antigen target is the serine protease, proteinase 3, and a perinuclear (p-ANCA) pattern, in which the primary antigen target is myeloperoxidase (MP0).3.4 Cytoplasmic ANCAs have been reported in approximately 90% of patients with Wegener’s granulomatosis, as well as in some cases of polyarteritis nodosa and microscopic polyangiitis.5*6 Perinuclear ANCAs are more likely to be associated with idiopathic crescentic segmental necrotizing glomerulonephritis, which probably is a type of vasculitis primarily limited to the kidney.4-9 In general, c-ANCAs are associated with greater organ involvement and a more severe course than p-ANCAs.” Various investigators have proposed that ANCAs are not just markers of vasculitis, but may be responsible for its pathogenesis.“-‘5 Falk et al have suggested that ANCAs induce intravascular neutrophil activation with subsequent injury to blood vessel walls.” According to their paradigm, a minor viral infection may result in generation of cytokines, such as tumor necrosis factor-a or interleukin-1, which “primes” the neutrophil to express proteinase 3 and MPO on their surface.‘2*‘3 Neutrophils are then recognized by the ANCAs, which activate the neutrophil on binding.‘*,13 Although any proteinases or oxidants released by the neutrophil in the circulation would be rapidly inactivated by inhibitors in the plasma, local production of these mediators by neutrophils bound to endothelial cells via tumor necrosis factor-cl! or interleukin-1 -induced leukocyte adhesive proteins could theoretically induce injury. In support of this hypothesis, it has been shown that ANCAs induce tumor necrosis factor-a “primed” neutrophils to release oxidants that mediate endothelial cell killing in vitro.14 Brouwer et al have suggested that ANCAs may augment neutrophil-mediated injury to vessel walls by binding to released MPO or proteinase 3.15 Neutrophils release MPO and proteinase 3 on activation.16 Myeloperoxidase, which is highly cationic (isoelectric point > 10) will bind transiently to basement membrane based on charge.” We have shown that the infusion of MPO into the renal artery of rats results in this localization of the MPO to the glomerular capillary wall, and that subsequent perfusion of its substrates hydrogen peroxide (H,O,) and a halide (chloride) results in capillary wall injury and proteinuria. ” Antimyeloperoxidase antibodies, which often do not block MPO activity, may act by binding to basement membrane-bound MPO, resulting in its persistence at the site, thereby allowing reaction with H202 generated locally. Local immune complex formation with MPO and anti-MPO antibodies may be another mechanism for injury. In support of this hypothesis, Brouwer et al have shown that the infusion of neutrophil release products (containing MPO) and H202 into the renal artery of MPO-immunized rats results in severe glomerular injury with crescent formation.” Kobayashi et al also have shown that infusion of anti-MPO antibodies into rats with nephrotoxic nephritis can augment injury in association with persistence of MPO in the capillary wall.” A role for cell-mediated immunity to ANCA antigens also is possible. In the model reported by Brouwer et al, the maximal glomeru-