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Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis.

ABSTRACT: Clinical, in vitro, and experimental animal observations indicate that antineutrophil cytoplasmic autoantibodies (ANCA) are pathogenic. The genesis of the ANCA autoimmune response is a multifactorial process that includes genetic predisposition, environmental adjuvant factors, an initiating antigen, and failure of T cell regulation. ANCA activate primed neutrophils (and monocytes) by binding to certain antigens expressed on the surface of neutrophils in specific inflammatory microenvironments. ANCA-activated neutrophils activate the alternative complement pathway, establishing an inflammatory amplification loop. The acute injury elicits an innate inflammatory response that recruits monocytes and T lymphocytes, which replace the neutrophils that have undergone karyorrhexis during acute inflammation. Extravascular granulomatous inflammation may be initiated by ANCA-induced activation of extravascular neutrophils, causing tissue necrosis and fibrin formation, which would elicit an influx of monocytes that transform into macrophages and multinucleated giant cells. Over time, the neutrophil-rich acute necrotizing lesions cause the accumulation of more lymphocytes, monocytes, and macrophages and produce typical granulomatous inflammation.

SUBMITTER: Jennette JC

PROVIDER: S-EPMC5507606 | biostudies-other | 2013 Jan

REPOSITORIES: biostudies-other

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Project description:OBJECTIVE:To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS:A genome-wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta-analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function. RESULTS:Among the genome-wide significant associations identified, the largest effect on risk of AAV came from the single-nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA-DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA-DPB1 gene and HLA-DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)-reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top-scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3-ANCAs and those with myeloperoxidase-ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%. CONCLUSION:This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

Project description:Predictors of treatment resistance and relapse have been identified in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in the Glomerular Disease Collaborative Network (GDCN) in the southeastern US. This study was undertaken to evaluate the applicability of those predictors in an independent cohort followed up by the French Vasculitis Study Group.Predictors of treatment resistance were evaluated using logistic regression models and reported as odds ratios (ORs) with 95% confidence intervals (95% CIs). Predictors of relapse were evaluated using Cox proportional hazards models and reported as hazard ratios (HRs) with 95% CIs. Models were controlled for age, sex, race, baseline serum creatinine level, and cyclophosphamide therapy.The French cohort (n = 434) and the GDCN cohort (n = 350) had similar median followup periods (44 months versus 45 months) and initial percentages of patients taking cyclophosphamide (82% versus 78%). The French cohort included more patients with proteinase 3 (PR3) ANCA (58% versus 40%), lung involvement (58% versus 49%), and upper respiratory tract involvement (62% versus 31%). Of the predictors of treatment resistance in the GDCN cohort (female sex, African American race, presence of myeloperoxidase ANCA, elevated creatinine level, and age), only age predicted treatment resistance in the French cohort (OR 1.32 per 10 years [95% CI 1.05-1.66]). Predictors of relapse in the GDCN cohort were PR3 ANCA (HR 1.77 [95% CI 1.11-2.82]), lung involvement (HR 1.68 [95% CI 1.10-2.57), and upper respiratory tract involvement (HR 1.58 [95% CI 1.00-2.48]), while predictors in the French cohort were PR3 ANCA (HR 1.66 [95% CI 1.15-2.39]) and lung involvement (HR 1.56 [95% CI 1.11-2.20]), but not upper respiratory tract involvement (HR 0.96 [95% CI 0.67-1.38]).Our findings indicate that older age is a predictor of treatment resistance, and that PR3 ANCA and lung involvement are predictors of relapse in both cohorts. Discrepancies in predictors of treatment tract resistance may reflect differences in access to care, and differences in predictors of relapse may reflect variations in disease expression.

Project description:To estimate the annual incidence, prevalence, and mortality of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) and its subsets, granulomatosis with polyangiitis (Wegener's) (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), in a US-based adult population.All medical records of patients with a diagnosis of, or suspicion of having, AAV in Olmsted County, Minnesota from January 1, 1996 to December 31, 2015 were reviewed. AAV incidence rates were age- and sex-adjusted to the 2010 US white population. Age- and sex-adjusted prevalence of AAV was calculated on January 1, 2015. Survival rates observed in the study cohort were compared with expected rates in the Minnesota population.Of the 58 incident cases of AAV in Olmsted County during the study period, 23 (40%) were cases of GPA, 28 (48%) were cases of MPA, and 7 (12%) were cases of EGPA. Overall, 28 (48%) of the patients with AAV were women and 57 (98%) were white. The mean ± SD age at diagnosis was 61.1 ± 16.5 years. Thirty-four patients (61%) had myeloperoxidase (MPO)-ANCAs, and 17 (30%) were positive for proteinase 3 (PR3)-ANCAs; 5 (9%) were ANCA-negative. The annual incidence of AAV was 3.3 per 100,000 population (95% confidence interval [95% CI] 2.4-4.1). The incidence rates of GPA, MPA, and EGPA were 1.3 (95% CI 0.8-1.8), 1.6 (95% CI 1.0-2.2), and 0.4 (95% CI 0.1-0.6), respectively. The overall prevalence of AAV was 42.1 per 100,000 (95% CI 29.6-54.6). The mortality rate among AAV patients overall, and among patients with EGPA, those with MPA, and those with MPO-ANCAs, was increased in comparison to the Minnesota general population (each P < 0.05), whereas mortality rates among patients with GPA, those with PR3-ANCAs, and ANCA-negative patients did not differ from that in the general population.The annual incidence of AAV in Olmsted County, Minnesota over the 20 years of the study was 3.3 per 100,000, with a prevalence of 42.1 per 100,000, which is substantially higher than the rates reported in other areas worldwide. The incidence of GPA was similar to that of MPA. Patients with MPA and those with EGPA, but not patients with GPA, experienced higher rates of mortality than that in the Minnesota general population. MPO-ANCAs were a marker of poor survival in this population of patients with AAV.

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Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis.

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