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Experimental models of vasculitis and glomerulonephritis induced by antineutrophil cytoplasmic autoantibodies.

ABSTRACT: Antineutrophil cytoplasmic autoantibodies (ANCA) are closely associated with systemic small vessel vasculitis characterized by segmental vessel wall necrotizing inflammation and a paucity of immunoglobulin deposition. Clinically, in vitro and experimental animal model observations indicate a direct pathogenic role for ANCA. This review focuses on the results of experiments utilizing a mouse model of ANCA disease induced by transfer of mouse anti-MPO IgG or anti-MPO lymphocytes into recipient mice, which causes small vessel vasculitis and glomerulonephritis that closely mimics human disease. Evidence for the following conclusion about this model, and by implication about human ANCA disease, will be summarized as follows: (1) anti-MPO IgG is sufficient even in the absence of functional T cells to cause disease and anti-MPO T lymphocytes are not sufficient to cause acute injury; (2) neutrophils are required; (3) ANCA antigens in bone marrow-derived cells are sufficient targets; (4) increased circulating pro-inflammatory cytokines and microbial products exacerbate disease, and concurrent viral infection exacerbates and modulates the phenotype of disease; (5) Fcγ receptor engagement is required for disease induction, and Fcγ receptor repertoire modulates the phenotype of disease, especially pulmonary disease; (6) activation of the alternative pathway of complement is required, complement is activated by factors released by neutrophils stimulated by ANCA IgG and engagement of C5a receptors is a primary event in complement-mediated amplification; and (7) genetic background has a marked influence on the severity and outcome of disease, and modified gene expression in bone marrow-derived cells is the primary basis for genetically determined differences in disease susceptibility. Investigations using this animal model of ANCA disease have provided important insights into the cellular, molecular and genetic factors involved in the pathogenesis of ANCA disease which are likely to lead to the identification of improved markers of disease activity and response to therapy, as well as more effective and less toxic therapies.

SUBMITTER: Jennette JC

PROVIDER: S-EPMC5507587 | biostudies-other | 2011

REPOSITORIES: biostudies-other

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Project description:BackgroundMuch epidemiological evidence suggests that hydrocarbon exposure may induce glomerulonephritis and worsen its course in many patients. The mechanisms are unknown, however, no specific microscopic pattern has been identified, and it has also been argued that hydrocarbon exposure causes tubular damage mainly. Studying experimental animals may best answer these questions, and as no systematic review of glomerulonephritis produced experimentally by hydrocarbon exposure has been performed previously, I found it relevant to search for and analyse such studies.MethodsAnimal experiments having mimicked human glomerulonephritis by hydrocarbon exposure were sought on Medline and ToxnetResultsTwenty-six experiments using thirteen different hydrocarbons were identified. Several human subtypes were observed including IgA nephritis, mesangial, proliferative and extracapillary glomerulonephritis, focal and focal-segmental sclerosis, minimal change nephropathy, anti-GBM and anti-TBM nephritis, and glomerulonephritis associated with peiarteritis nodosa. Glomerular proteinuria was seen in 10/12 experiments that included urine analyses, and renal failure in 5/8 experiments that included measurements of glomerular function. All experiments resulted in various degrees of tubular damage as well. In most studies, where the animals were examined at different times during or after the exposure, the renal microscopic and functional changes were seen immediately, whereas deposits of complement and immunoglobulins appeared late in the course, if at all.ConclusionThese experiments are in accord with epidemiological evidence that hydrocarbon exposure may cause glomerulonephritis and worsen renal function. Probable mechanisms include an induction of autologous antibodies and a disturbance of normal immunological functions. Also, tubular damage may increase postglomerular resistance, resulting in a glomerular deposition of macromolecules. In most models a causal role of glomerular immune complex formation was unlikely, but may rather have been a secondary phenomenon. As most glomerulonephritis subgroups were seen and as some of the hydrocarbons produced more than one subgroup, the microscopic findings in a patient cannot be used as a clue to the causation of his disease. By the same reason, the lack of a specific histological pattern in patients with glomerulonephritis assumed to have been caused by hydrocarbon exposure is not contradictive.

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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Experimental models of vasculitis and glomerulonephritis induced by antineutrophil cytoplasmic autoantibodies.

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