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Experimentally-induced anti-myeloperoxidase vasculitis does not require properdin, MASP-2 or bone marrow-derived C5.

ABSTRACT: Anti-neutrophil cytoplasmic antibody vasculitis is a systemic autoimmune disease with glomerulonephritis and pulmonary haemorrhage as major clinical manifestations. The name reflects the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind to both neutrophils and monocytes. Evidence of the pathogenicity of these autoantibodies is provided by the observation that injection of anti-myeloperoxidase antibodies into mice causes a pauci-immune focal segmental necrotizing glomerulonephritis which is histologically similar to the changes seen on renal biopsy in patients. Previous studies in this model have implicated the alternative pathway of complement activation and the anaphylatoxin C5a. Despite this progress, the factors that initiate complement activation have not been defined. In addition, the relative importance of bone marrow-derived and circulating C5 is not known. This is of interest given the recently identified roles for complement within leukocytes. We induced anti-myeloperoxidase vasculitis in mice and confirmed a role for complement activation by demonstrating protection in C3-deficient mice. We showed that neither MASP-2- nor properdin-deficient mice were protected, suggesting that alternative pathway activation does not require properdin or the lectin pathway. We induced disease in bone marrow chimaeric mice and found that circulating and not bone marrow-derived C5 was required for disease. We have therefore excluded properdin and the lectin pathway as initiators of complement activation and this means that future work should be directed at other potential factors within diseased tissue. In addition, in view of our finding that circulating and not bone marrow-derived C5 mediates disease, therapies that decrease hepatic C5 secretion may be considered as an alternative to those that target C5 and C5a. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

SUBMITTER: Freeley SJ

PROVIDER: S-EPMC4996338 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionIncreasing evidence has suggested that linear epitopes of antineutrophil cytoplasmic antibody (ANCA) directed to myeloperoxidase (MPO) might provide clues to the pathogenesis of propylthiouracil (PTU)-induced ANCA-associated vasculitis (AAV). This study mapped epitopes of MPO-ANCA in sera from patients with PTU-induced MPO-ANCA (with or without vasculitis) and primary AAV, aiming to analyze certain epitopes associated with the development of PTU-induced AAV.MethodsSix recombinant linear fragments, covering the whole amino acid sequence of a single chain of MPO, were produced from Escherichia coli. Sera from 17 patients with PTU-induced AAV, 17 patients with PTU-induced MPO-ANCA but without clinical evidence of vasculitis, and 64 patients with primary AAV were collected at presentation. Of the 17 patients with PTU-induced AAV, 12 also had sera at remission. The epitope specificities were detected by enzyme-linked immunosorbent assay by using the recombinant fragments as solid-phase ligands.ResultsCompared with patients with PTU-induced MPO-ANCA but without clinical vasculitis, sera from PTU-induced AAV patients showed significantly higher reactivity against the H1 fragment of MPO (optical density values: 0.17 (0.10 to 0.35) versus 0.10 (0.04 to 0.21), P?=?0.038) and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P?=?0.026). Compared with sera from primary AAV patients, sera from PTU-induced AAV patients had significantly higher reactivity to the P fragment and the H4 fragment (47.1% versus 14.1% P?<?0.001; 41.2% versus 14.1%, P?=?0.034, respectively), and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P?=?0.013]. Among the 12 PTU-induced AAV patients with sequential samples, the number of fragments recognized in remission was significantly less than that in initial onset (two (none to four) versus none (none to 0.75), P?<?0.001].ConclusionsLinear epitopes of MPO molecules might be associated closely with PTU-induced AAV. In particular, the P and H4 fragments may be important epitopes in PTU-induced AAV.

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Experimentally-induced anti-myeloperoxidase vasculitis does not require properdin, MASP-2 or bone marrow-derived C5.

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