Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of autoimmune disorders including Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) and renal-limited vasculitis (RLV). This paper reviews updated information on the pathogenesis of AAV. Additional clinical evidence for a pathogenic role of ANCA comes from the observation that patients with severe acute renal failure treated with plasma exchange had a lower risk for progression to end-stage renal disease than patients who received intravenous methylprednisolone therapy, both in addition to standard treatment. Recent data also suggest that antibodies to complementary proteinase-3 (cPR3), probably cross-reacting with plasminogen, may induce PR3-ANCA. Furthermore, a new ANCA, directed against human lysosome membrane protein-2 (LAMP-2), concurrent with PR3-ANCA or MPO-ANCA, was described as a sensitive and specific marker for renal AAV. In vitro, ANCA can further activate primed neutrophils to release reactive oxygen species and lytic enzymes, and, in conjunction with neutrophils, damage and lyse endothelial cells. In vivo, transfer of splenocytes from myeloperoxidase-deficient mice immunized with mouse myeloperoxidase into wild-type mice resulted in pauci-immune systemic vasculitis. A similar experiment in PR3-deficient mice did not cause significant vasculitic lesions. In the anti-MPO induced vasculitis mouse model, a critical role of complement activation was suggested. The anti- LAMP-2 antibody can also induce pauci-immune necrotizing crescentic glomerulonephritis in rats. Rats developed both cross-reactive antibodies to LAMP-2 and crescentic glomerulonephritis when immunized with FimH, an adhesin from Gram-negative bacteria which has strong homology with human LAMP-2. Together, clinical, in vitro and in vivo data support a pathogenic role for ANCA in AAV, although this role is more evident for myeloperoxidase-ANCA than for PR3-ANCA. The role of anti- LAMP-2 requires further studies.
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PMID:New advances in the pathogenesis of ANCA-associated vasculitides. 1964 56

Much has been learned in recent years on the pathogenesis of ANCA-associated small-vessel vasculitis. The interaction of primed neutrophils with ANCA and endothelial cells is crucial to the disease. Next we gained a better understanding, from animal models, of the pathogenetic importance of the ANCA antibody. Very recent evidence provides intriguing data regarding the link between infection and vasculitis, LAMP-2 antibodies as novel markers, and NETs as a novel pathogenetic mechanism. It remains to be seen whether others are able to corroborate these findings and whether testing for LAMP-2 antibodies will become part of the clinical routine in vasculitis. Recent years also saw the emergence of various new markers of endothelial damage and the disease itself, such as circulating endothelial cells and endothelial microparticles. These novel markers correlate well with disease activity; they may well complement traditional diagnostic tools, such as ANCA testing. Preliminary evidence has provided some insight into the balance between endothelial damage and repair. Exciting preliminary data also indicate that circulating endothelial cells may not only be markers of disease activity but that these cells may have pathogenetic importance in their own right. These findings may have profound implications for the pathogenesis of vasculitis and vascular disease in general. Recent years also saw the publication of a number of seminal studies for the treatment of ANCA-associated vasculitis. We now have a much better understanding of the role of pulse intravenous cyclophosphamide and plasma exchange than ten or even five years ago. Further studies must now show whether plasma exchange is also beneficial for less severely ill patients with AASV. Finally, as ever, it is hoped that further progress in understanding the disease pathogenesis will also provide more tailored and less toxic therapies.
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PMID:ANCA-associated vasculitis: pathogenesis, novel markers of the disease and emerging therapies. 1981 93

The aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis has not been well defined. Here we review two factors which may play a role in the pathogenesis of the disease: genetics and infection. In particular, we discuss the role of autoantibodies to LAMP-2, which may arise following infection with Gram-negative bacteria, and may contribute to the development of ANCA-associated systemic vasculitis in genetically susceptible individuals.
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PMID:The contribution of genetic variation and infection to the pathogenesis of ANCA-associated systemic vasculitis. 2023 93

The involvement of autoantibodies to human lysosome-associated membrane protein-2 (hLAMP-2) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is controversial because of the absence of confirmatory data subsequent to the initial reports of their high prevalence in this disease. We characterized three assays for anti-hLAMP-2 antibodies: ELISA and Western blotting assays using unglycosylated recombinant hLAMP-2 expressed in Escherichia coli, and an indirect immunofluorescence assay using stably transfected ldlD cells that expressed glycosylated full-length hLAMP-2 on the plasma membrane. The assays detected autoantibodies to hLAMP-2 in human sera reproducibly and with comparable sensitivity and the assays gave the same results in 80.5% of the test panel of 40 selected positive and negative sera. In untreated patients at presentation, the frequencies of autoantibodies to LAMP-2 were 89%, 91%, and 80%, respectively, among three groups of patients with ANCA-associated vasculitis from Vienna, Austria (n=19); Groningen, the Netherlands (n=50) and Cambridge, United Kingdom (n=53). Prevalence of LAMP-2 autoantibodies was similar in both those with myeloperoxidase-ANCA and proteinase 3-ANCA. Furthermore, we detected LAMP-2 autoantibodies in two ANCA-negative patients. LAMP-2 autoantibodies rapidly became undetectable after the initiation of immunosuppressive treatment and frequently became detectable again during clinical relapse. We conclude that when robust assays are used, circulating autoantibodies to hLAMP-2 can be detected in most European patients with ANCA-associated vasculitis. Large-scale prospective studies are now needed to determine whether they are pathogenic or merely an epiphenomenon.
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PMID:High prevalence of autoantibodies to hLAMP-2 in anti-neutrophil cytoplasmic antibody-associated vasculitis. 2232 43

ANCA-associated vasculitis (AAV) is a potentially life-threatening disease with frequent and often severe kidney involvement which may result in end-stage renal disease. Anti-PR3 and anti-MPO disease are genetically distinct diseases and may have a different pathogenesis. Recent discovery of new autoantibodies (anti-LAMP-2) and the role of complement activation in the pathogenesis of AAV could result in better monitoring of the activity of the disease and identification of new treatment targets. The outcome of patients with AAV has dramatically improved, but long-term mortality still remains relatively high partly due to effective but relatively toxic immunosuppressive treatment. Recent studies demonstrated that B-cell depletion with rituximab is comparable to cyclophosphamide as induction treatment in newly diagnosed AAV patients and better than cyclophosphamide in relapsing patients. Rituximab-based maintenance treatment is superior to standard treatment with azathioprine. The use of more targeted treatment will hopefully be translated into a better long-term outcome of AAV patients.
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PMID:ANCA-associated renal vasculitis - an update. 2368 83