Antineutrophil Cytoplasmic Autoantibodies Research Articles

Renal Expression of Annexin A1 Is Associated With the Severity of Renal Injury in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

BackgroundIncreasing studies demonstrated the importance of activation of neutrophils in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Previous studies showed that annexin A1 (ANXA1) inhibited the recruitment, transendothelial migration and respiratory burst of neutrophils and induced apoptosis of neutrophils. The current study aimed to investigate the plasma and renal levels of ANXA1 as well as their association with the disease severity in AAV patients.MethodsThirty-one AAV patients in active stage and 35 AAV patients in remission stage were recruited. The expression of ANXA1 in renal specimens was assessed by immunohistochemistry. The co-localization of ANXA1 with renal intrinsic and infiltrating cells was detected by double immunofluorescence. The plasma levels of ANXA1 were determined by ELISA. The association of plasma and renal levels of ANXA1 with clinicopathological parameters was further analyzed.ResultsPlasma levels of ANXA1 were significantly higher in active AAV patients than those in AAV patients in remission as well as healthy controls. The renal expression of ANXA1 was significantly higher in active AAV patients than in healthy controls and disease controls. Double immunofluorescence assay showed that ANXA1 was expressed in glomerular endothelial cells, mesangial cells, podocytes, proximal tubular epithelial cells, neutrophils, monocytes/macrophages and T cells in AAV patients. The mean optical density of ANXA1 in glomeruli was correlated with serum creatinine levels (r = −0.491, P = 0.005) and eGFR (r = 0.492, P = 0.005) at renal biopsy and the proportion of crescents (r = −0.423, P = 0.018) in renal specimens of AAV patients. The expression of ANXA1 in glomeruli of AAV patients achieving complete renal recovery was significantly higher than those achieving partial renal recovery.ConclusionIn AAV patients, the renal expression of ANXA1 was associated with the severity of renal injury.

Diagnostic and Therapeutic Approach in ANCA-Associated Glomerulonephritis: A Review on Management Strategies.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a destructive small vessel vasculitis affecting multiple organs. Renal involvement often leads to end-stage renal disease and increases mortality. Prompt diagnosis and initiation of adequate immunosuppressive therapy are critical for the best patient and kidney outcomes. However, considerable heterogeneity in symptoms and severity across the patients frequently hinder the diagnosis and management. The objective of this review is to emphasize the heterogeneity of the ANCA-associated vasculitis, facilitate the recognition and give guidance to the therapeutical possibilities. We present epidemiologic and risk factors, pathogenesis, and provide comprehensive clinical features of the disease. This article also focuses on the currently available therapeutic options and emerging cellular and molecular targets for the management of systemic and especially renal disease. We conducted extensive literature research published on PubMed and Google Scholar. We systematically reviewed, analyzed, and assembled databases, covering a broad spectrum of aspects of the disease. We compared and summarized the recommendations of two recent guidelines on ANCA-associated vasculitis. The incidence of ANCA-associated vasculitis, hence glomerulonephritis shows a steady increase. Familiarity with the presenting symptoms and laboratory abnormalities are necessary for rapid diagnosis. Early initiation of treatment is the key aspect for favorable patient and renal outcomes. A better understanding of the pathogenesis constantly leads to more targeted and therefore more efficient and less toxic treatment.

Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Glomerulonephritis in a 15-Year-Old Patient After Receiving the Second Dose of the BBIBP-CorV (Sinopharm) COVID-19 Vaccine: A Case Report

Introduction: Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a group of multisystemic autoimmune diseases that can involve organs such as kidneys and respiratory tracts. Since the initiation of COVID-19 vaccines, there have been few cases of antineutrophil cytoplasmic antibody (ANCA) glomerulonephritis development after receiving vaccine doses. Case Presentation: This report describes a 15-year-old man who has developed ANCA-associated glomerulonephritis (AAGN) after receiving the second dose of BBIBP-CorV (Sinopharm) COVID-19 vaccine. Conclusions: Development of AAGN after both natural SARS-CoV-2 infection and following other vaccinations raises the question of the possible causality between the two. Considering the widespread use of COVID-19 vaccines, it is highly important to investigate their possible side effects.

Analysis of Various Types of Glomerulonephritis with Crescents at a Single Center

Background The importance of crescent formation in glomerulonephritis has increased. However, detailed analysis of crescentic glomerulonephritis in Asia is scarce. In addition, advances in serological diagnostic techniques (antineutrophil cytoplasmic and antiglomerular basement membrane autoantibodies) and early diagnosis have reduced the number of cases meeting the strict definition of crescentic glomerulonephritis (>50% of glomeruli are crescentic). Therefore, we analyzed the clinicopathological features and renal prognosis of glomerulonephritis cases that exhibited at least one crescentic lesion. Methods We retrospectively evaluated 265 adult patients diagnosed with glomerulonephritis with at least one crescent formation based on the results of renal biopsy. We divided the patients into two groups based on the four types of glomerulonephritis, namely, the immune-complex (type II: IgA nephropathy, IgA vasculitis with nephritis, and lupus nephritis) and pauci-immune (type III: microscopic polyangiitis) groups. Factors affecting renal prognosis (end-stage renal failure requiring renal replacement therapy) were examined in a multivariate analysis using the Cox proportional hazards model. Kaplan–Meier curves and log-rank test were used to analyze and compare time from entry to renal death. Results Renal prognosis differed significantly between the immune-complex and pauci-immune groups. Among the four types of glomerulonephritis, IgA nephropathy was the most prevalent. Multivariate analysis showed that renal function at renal biopsy and the ratio of global sclerosis independently predicted renal prognosis, but the type of glomerulonephritis was not a factor. Conclusions Renal dysfunction at renal biopsy and the ratio of global sclerosis predicted renal prognosis, because it reflects the degree of irreversible renal damage. We also suspect that the formation of at least one crescentic lesion led to the development of these predictive factors, regardless of the type of glomerular disease and degree of crescent formation.

A past medical history of autoimmune disease predicts a future with fewer relapses in patients with ANCA-associated vasculitis

To explore the frequency and impact of an autoimmune disease past-medical history (PMH) in the clinical picture and outcomes of patients with antineutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV). This was a retrospective study of patients with biopsy-proven AAV, >16 years old, with detailed information about their PMH. Outcomes of interest included remission, treatment resistance, relapse, end-stage kidney disease (ESKD), and death. 206 patients with biopsy-proven AAV and available information regarding their PMH were studied. 63(30.6%) of them had a history of autoimmune disease prior to AAV diagnosis. The mean age overall was 54.1 years. One hundred and five patients (51%) were positive for PR3-ANCA, 101 (49%) for MPO-ANCA. Granulomatosis with polyangiitis was diagnosed in 79 (38.3%), microscopic polyangiitis in 97 (47.1%) and renal-limited vasculitis in 30 (14.6%) individuals. Remission rate was similar among patients with and without a PMH of autoimmune disease. Time-to-event analysis indicated that the relapse-free survival was significantly longer in patients with PMH of autoimmune disease (148.2 vs. 61.9 months, p-value <0.001). After adjusting for covariates, autoimmune disease history was associated with significantly lower risk of relapse (HR: 0.33, 95% CI: 0.15-0.72), which remained significant in males, patients ≥60 years old and those with C/PR3-ANCA, kidney and lung involvement. Patients with a PMH of autoimmune disease, prior to AAV diagnosis, experienced significantly fewer relapses after achievement of remission, compared to patients without such a history, underlining the importance of individualisation of maintenance immunosuppressive therapy, given the different aetiopathogenetic settings the disease was developed.

FC064: Histopathological and Clinical Outcomes of Anca Negative Versus Anca Positive Pauci-Immune Glomerulonephritis

Abstract BACKGROUND It has been suggested that pauci-immune small vessel vasculitis exhibits a different spectrum of disease in the absence of detectable circulating anti-neutrophil cytoplasmic autoantibodies (ANCA). This study aims to investigate the differences in clinical presentation, renal histopathological and clinical outcomes amongst vasculitis patients with or without detectable circulating ANCA. METHOD A cohort study of biopsy proven pauci-immune glomerulonephritis was constructed from a single centre between 2006 and 2016 and followed up until June 2021. Patients were stratified by ANCA status at the time of diagnosis and primary outcomes compared the histopathological classification, clinical presentation and outcomes including mortality and end stage renal disease (ESRD) of those with ANCA negative and positive disease. Secondary outcomes looked at multivariate survival and logistic models comparing remission and relapse rates between the two groups. RESULTS From 146 patients, 21.9% (n = 32) had ANCA negative disease with a male predominance of 66% (n = 21) and a younger mean age at diagnosis compared to those with positive ANCA serology; 51.44 ± 19.57 years versus 65.6 ± 12.10 years, respectively (P ≤ 0.001). ANCA negative serology was associated with more renal limited disease (n = 20, 62.3% versus n = 44, 38.6% ANCA positive) and the presence of extra-renal disease with ENT and constitutional symptoms occurred more frequently in ANCA positive patients (27% versus 0%; P = 0.0013). There was a comparable spread across the Berden classification, with no significant difference seen between the positive and negative groups (Table 1). The predominant class across both cohorts was focal classification. At the time of diagnosis, ANCA-negative patients had lower eGFR than those with positive ANCA serology (14.0 versus 18.0 mL/min/1.73 m2; P = 0.09 922). At the end of follow-up, 53.1% (n = 17) of ANCA-negative patients had progressed to end stage renal disease (ESRD) which was higher than those with ANCA positivity (n = 13, 11.7%). When adjusting for age, sex and induction therapy, the hazard ratio (HR) for ESRD was five times higher in ANCA-negative patients compared to ANCA positive [HR 5.20 (2.02–13.39); P ≤ 0.001]. Mortality rates were higher in the ANCA-negative cohort (Figure 1). Following HR calculations and multivariate analysis, age was associated with a higher risk of death. In addition, despite the ANCA-negative cohort being younger, when adjusting for age, sex and induction therapy, the HR of death was three times higher in the ANCA-negative cohort [HR 3.0 (1.36–6.63); P = 0.007]. CONCLUSION Our single-centre experience suggests that ANCA negative disease tends to occur in younger patients, with a higher rate of renal limited disease. Seronegative disease is less likely to relapse but is associated with a high mortality rate. The reasons for these differences between ANCA-positive and ANCA-negative cohorts are complex and multifaceted. Some reports hypothesize that the cause for severe disease at presentation in the absence of circulating ANCA is due to a delay in diagnosis and treatment by clinicians [1,2]. This study provides the impetus for further trials looking at ANCA-negative and ANCA-positive disease.

Autoimmune markers in screening for orbital inflammatory disease

PurposeImmunogenic causes of inflammation may be difficult to differentiate in the work-up of orbital inflammatory disease. The study aims to investigate the utility of autoimmune markers in the screening for orbital inflammation. Markers studied included angiotensin-converting enzyme (ACE), antinuclear antibody (ANA), anti-neutrophilic cytoplasmic autoantibodies (ANCA), extractable nuclear antigen (ENA), anti-cyclic citrullinated peptide (Anti-CCP) and anti-double stranded DNA antibody (Anti-dsDNA antibody).MethodsA retrospective single-centre study of consecutive patients with non-infective orbital inflammation screened for autoimmune markers at presentation. Serology was interpreted alongside clinical course and other investigations (e.g. radiographic features and histopathology). Tabulated data and Pearson’s Chi-square allowed analysis of trends between serology, diagnosis and the decision to biopsy.Results79 patients, between 1999 and 2021, were included (50 females, mean age was 50.4 ± 17.4 years). 28 (34.6%) patients had specific orbital inflammation and 53 (65.4%) patients had non-specific orbital inflammation (NSOI). Of the 12 patients with positive serology and a specific diagnosis, only 5 (41.7%) patients had concordant serological results. There was no association between serology results and the patient undergoing biopsy (P = 0.651). Serology was unable to exclude nor differentiate NSOI from other specific conditions and ANA had limited discriminatory value between specific conditions and NSOI.ConclusionSerological testing alone may not provide a clear direction for further investigation of orbital inflammation and a biopsy may occur independently of the serological results. The value of autoimmune markers may lie in subsequent follow-up as patients may develop suggestive symptoms after an indeterminate positive result or initially seronegative disease.

Automated Computational Detection of Disease Activity in ANCA-Associated Glomerulonephritis Using Raman Spectroscopy: A Pilot Study.

Biospectroscopy offers the ability to simultaneously identify key biochemical changes in tissue associated with a given pathological state to facilitate biomarker extraction and automated detection of key lesions. Herein, we evaluated the application of machine learning in conjunction with Raman spectroscopy as an innovative low-cost technique for the automated computational detection of disease activity in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAGN). Consecutive patients with active AAGN and those in disease remission were recruited from a single UK centre. In those with active disease, renal biopsy samples were collected together with a paired urine sample. Urine samples were collected immediately prior to biopsy. Amongst those in remission at the time of recruitment, archived renal tissue samples representative of biopsies taken during an active disease period were obtained. In total, twenty-eight tissue samples were included in the analysis. Following supervised classification according to recorded histological data, spectral data from unstained tissue samples were able to discriminate disease activity with a high degree of accuracy on blind predictive modelling: F-score 95% for >25% interstitial fibrosis and tubular atrophy (sensitivity 100%, specificity 90%, area under ROC 0.98), 100% for necrotising glomerular lesions (sensitivity 100%, specificity 100%, area under ROC 1) and 100% for interstitial infiltrate (sensitivity 100%, specificity 100%, area under ROC 0.97). Corresponding spectrochemical changes in paired urine samples were limited. Future larger study is required, inclusive of assigned variables according to novel non-invasive biomarkers as well as the application of forward feature extraction algorithms to predict clinical outcomes based on spectral features.

Retrospective study on the epidemiology of antineutrophil cytoplasmic autoantibodies-associated vasculitis in two Australian health districts.

Antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV) is more prevalent in rural Australia compared with metropolitan areas, suggesting a role of environment in disease pathogenesis. However, the prevalence of environmental risk factors in Australian AAV patients has not been described. To compare the incidence of AAV between two health districts (Illawarra Shoalhaven Local Health District (ISLHD), a mixed rural/metropolitan region, and South Eastern Sydney Local Health District (SESLHD), a metropolitan region) in Australia and its relationship to environmental exposures. Cases of AAV from 2002 to 2017 were retrospectively identified from ISLHD and SESLHD using electronic medical records. Eligible participants were invited to complete a standardised questionnaire examining their exposure to silica, solvents, metal, dust, farming, gardening and sunlight. One hundred and fifty-six cases of AAV were identified from 2002 to 2017. A higher cumulative incidence of AAV was observed in the ISLHD (184.2 (95% confidence interval (CI) 143.6-232.7) per million) compared with SESLHD (102.6 (95% CI 82.1-126.8) per million). Over 50% of the cohort had high levels of silica and solvents exposure, based on self-reported questionnaires. There was no significant relationship between region and exposure to silica (P = 0.96), solvents (P = 0.44), metal (P = 0.33), dust (P = 0.25), farming (P = 0.90), gardening (P = 0.93) or sunlight (P = 0.55). We found a higher incidence of AAV in ISLHD compared with SESLHD with high levels of exposure to silica and solvents in both regions based on self-reported questionnaires. Prospective systematic collection of data, such as a registry of AAV, is warranted to further explore the relationship between environmental exposures and AAV.

New Drugs Update: Finerenone, Difelikefalin, and Avacopan.

Three drugs are discussed in this article: finerenone, difelikefalin, and avacopan. Finerenone (Kerendia™) is FDA-indicated to reduce the risk of sustained estimated glomerular filtration rate (eGFR) decline, end stage kidney disease (ESKD), cardiovascular (CV) death, non-fatal myocardial infarction (MI), and hospitalization for heart failure (HF) in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). Difelikefalin (Korsuva™) is FDA-indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD). Avacopan (Tavneos™) is FDA-indicated as an adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard therapy including glucocorticoids.

Working Algorithms and Detection Methods of Autoantibodies in Autoimmune Liver Disease: A Nationwide Study.

Autoantibody detection is the cornerstone of autoimmune liver diseases (AILD) diagnosis. Standardisation of working algorithms among autoimmunity laboratories, as well as being aware of the sensitivity and specificity of various commercial techniques in daily practice, are still necessary. The aim of this nationwide study is to report the results of the 2020 Autoimmunity Workshop organised by the Autoimmunity Group of the Spanish Society of Immunology and to provide useful information to clinicians and laboratory specialists to improve the management of autoantibody detection in AILD diagnoses. Serum samples from 17 patients with liver diseases were provided by the organisers of the 2020 Autoimmunity Workshop and were subsequently analysed by the 40 participating laboratories. Each laboratory used different techniques for the detection of autoantibodies in each patients’ serum sample, according to their working algorithm. Thus, almost 680 total complete patient reports were obtained, and the number of results from different autoantibody detection techniques was >3000. Up to eight different working algorithms were employed, including indirect immunofluorescence assays (IFA) and antigen-specific techniques (AgST). The IFA of HEp-2 cells was more sensitive than IFA of rat triple tissue for the study of anti-nuclear autoantibodies (ANA) associated with AILD. The IFA of a human neutrophil study for the analysis of anti-neutrophil cytoplasmic autoantibodies was not carried out systemically in all patients, or by all laboratories. AgSTs were the most sensitive methods for the detection of anti-smooth muscle/F-actin, soluble liver antigen, liver cytosol-1, M2-mitochondrial autoantibodies, and ANA associated with primary biliary cholangitis. The main differences in AMA detection were due to patients with autoantibodies against the non-dominant epitope of pyruvate dehydrogenase complex. Given that they are complementary, IFA and AgST should be performed in parallel. If there is high suspicion of AILD, AgST should always be performed.

Defective STAT5 Activation and Aberrant Expression of BCL6 in Naive CD4 T Cells Enhances Follicular Th Cell-like Differentiation in Patients with Granulomatosis with Polyangiitis.

Granulomatosis with polyangiitis (GPA) is a potentially fatal small vessel vasculitis of unknown etiology, characterized by anti-neutrophil cytoplasmic autoantibodies, chronic inflammation, and granulomatous tissue damage. T cell dysregulation, comprising decreased regulatory T cell function and increased circulating effector memory follicular Th cells (TFH), is strongly associated with disease pathogenesis, but the mechanisms driving these observations are unknown. We undertook transcriptomic and functional analysis of naive CD4 T cells from patients with GPA to identify underlying functional defects that could manifest in the pathogenic profiles observed in GPA. Gene expression studies revealed a dysregulation of the IL-2 receptor β/JAK-STAT signaling pathway and higher expression of BCL6 and BCL6-regulated genes in GPA naive CD4 T cells. IL-2-induced STAT5 activation in GPA naive CD4 T cells was decreased, whereas STAT3 activation by IL-6 and IL-2 was unperturbed. Consistently, BCL6 expression was sustained following T cell activation of GPA naive CD4 T cells and in vitro TFH differentiation of these cells resulted in significant increases in the production TFH-related cytokines IL-21 and IL-6. Thus, naive CD4 T cells are dysregulated in patients with GPA, resulting from an imbalance in signaling equilibrium and transcriptional changes that drives the skewed pathogenic CD4 effector immune response in GPA.

POS-444 EFFECT OF AVACOPAN, A SELECTIVE C5A RECEPTOR INHIBITOR, ON KIDNEY FUNCTION IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIS

Patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis and renal disease have a poor prognosis. The effect of avacopan, an oral C5a receptor inhibitor, on renal function is described. The ADVOCATE Phase 3 trial randomized patients to receive avacopan or prednisone taper on a background of either cyclophosphamide (followed by azathioprine) or rituximab. Primary endpoints were remission at Week 26 and sustained remission at Week 52. Secondary objectives included evaluation of kidney function. At Week 52, the difference in eGFR recovery in patients with eGFR <60 mL/min/1.73 m2and/or urinary abnormalities at baseline between avacopan and prednisone treatment groups was 5.5 mL/min/1.73 m2(95% CI [1.4, 9.6], p<0.01) (Figure 1A ). Improvement in eGFR with avacopan was most prominent in patients with eGFR <30 mL/min/1.73 m2at baseline, when by week 52, the least squares mean (LSM) increase in eGFR was 13.7 (avacopan group) vs. 8.2 mL/min/1.73 m2(prednisone group) (p<0.01) (Figure 1B) . Among patients with CKD Stage 4 at baseline: in the avacopan group (n=52), 26 (50%) improved 1 stage and 3 (5.8%) improved 2 stages; in the prednisone group (n=48), 21 (44%) improved 1 stage and 1 (2.1%) improved 2 stages (p=0.32). Avacopan was also associated with more rapid reduction in proteinuria and hematuria. Urinary albumin:creatinine ratio improved 40% within the first 4 weeks of treatment with avacopan vs. no change in the prednisone group (difference -40, 95% CI [-53, -22]). Figure 1. Change in Renal Function Through Week 52 In ADVOCATE, patients with ANCA-associated vasculitis in the avacopan group had greater recovery of kidney function compared to patients in the prednisone group, especially among patients with CKD Stage 4 and those with eGFR <60 mL/min/1.73 m2and/or urinary abnormalities at baseline.

Clinical significance and role of CXCL16 in anti-neutrophil cytoplasmic autoantibody-associated vasculitis

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a group of potentially life-threatening autoimmune diseases. The kidney and lung are the most common and most severely affected organs. Previous studies have shown that the chemokine ligand CXCL16 and its receptor CXCR6 play an important role in kidney disease. However, whether CXCL16/CXCR6 is involved in the pathogenesis of AAV remains elusive. In this study, the levels of CXCL16 and its specific receptor CXCR6 were investigated. According to kidney outcome, patients were divided into two groups, specifically one with high CXCL16 levels and one with low CXCL16 levels, by cut-off values using receiver operating characteristic (ROC) curves. The clinical parameters and histological features were further compared between the two groups. The ability of CXCL16 to induce neutrophil chemotaxis was analysed using a Transwell migration assay in a coculture system of conditional immortalized human glomerular endothelial cells (ciGEnCs) and neutrophils. We observed that the levels of CXCL16 were significantly increased in the circulation, along with the expression in renal tissue of AAV patients compared to healthy controls (HCs). CXCR6 expression on neutrophils was significantly higher in patients with AAV than in HCs. There were positive correlations between the levels of CXCL16 and serum creatinine, IL-6, CRP, and TNF-α and negative correlations with eGFR. The serum levels of CXCL16 could act as a predictive biomarker of renal outcome in AAV. CXCL16 secretion was upregulated in ciGEnCs treated with AAV serum. CXCL16 released from ciGEnCs contributed to neutrophil migration. Furthermore, neutrophil migration was attenuated by silencing CXCL16 expression via transfection with short hairpin RNA (shRNA) sequences and lentivirus. Taken together, these data suggest that the inhibition of the CXCL16/CXCR6 axis may provide new therapeutic strategies targeting AAV.

Competitively disrupting the neutrophil-specific receptor–autoantigen CD177:proteinase 3 membrane complex reduces anti-PR3 antibody-induced neutrophil activation

CD177 is a neutrophil-specific receptor presenting the proteinase 3 (PR3) autoantigen on the neutrophil surface. CD177 expression is restricted to a neutrophil subset, resulting in CD177pos/mPR3high and CD177neg/mPR3low populations. The CD177pos/mPR3high subset has implications for antineutrophil cytoplasmic autoantibody (ANCA)–associated autoimmune vasculitis, wherein patients harbor PR3-specific ANCAs that activate neutrophils for degranulation. Here, we generated high-affinity anti-CD177 monoclonal antibodies, some of which interfered with PR3 binding to CD177 (PR3 “blockers”) as determined by surface plasmon resonance spectroscopy and used them to test the effect of competing PR3 from the surface of CD177pos neutrophils. Because intact anti-CD177 antibodies also caused neutrophil activation, we prepared nonactivating Fab fragments of a PR3 blocker and nonblocker that bound specifically to CD177pos neutrophils. We observed that Fab blocker clone 40, but not nonblocker clone 80, dose-dependently reduced anti-PR3 antibody binding to CD177pos neutrophils. Importantly, preincubation with clone 40 significantly reduced respiratory burst in primed neutrophils challenged with either monoclonal antibodies to PR3 or PR3–ANCA immunoglobulin G from ANCA-associated autoimmune vasculitis patients. After separating the two CD177/mPR3 neutrophil subsets from individual donors by magnetic sorting, we found that PR3–ANCAs provoked significantly more superoxide production in CD177pos/mPR3high than in CD177neg/mPR3low neutrophils, and that anti-CD177 Fab clone 40 reduced the superoxide production of CD177pos cells to the level of the CD177neg cells. Our data demonstrate the importance of the CD177:PR3 membrane complex in maintaining a high ANCA epitope density and thereby underscore the contribution of CD177 to the severity of PR3–ANCA diseases.

The frequency of Treg subsets distinguishes disease activity in ANCA vasculitis.

T regulatory cells (Tregs) are a heterogeneous group of immunoregulatory cells that dampen self-harming immune responses and prevent the development of autoimmune diseases. In anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, Tregs possess diminished suppressive capacity, which has been attributed to the expression of a FOXP3 splice-variant lacking exon 2 in T cells (FOXP3Δ2 CD4+ T cells). However, the suppressive capacity of Tregs varies between subsets. We evaluated the frequency of Treg subsets in ANCA vasculitis as a potential explanation for diminished suppressive capacity. We developed a custom mass cytometry panel and performed deep immune profiling of Tregs in healthy controls, patients with active disease and in remission. Using these data, we performed multidimensional reduction and discriminant analysis to identify associations between Treg subsets and disease activity. Total Tregs were expanded in ANCA vasculitis, which was associated with remission and the administration of rituximab and/or prednisone. The frequency of FOXP3Δ2 CD4+ T cells did not distinguish disease activity and this population had high expression levels of CD127 and lacked both CD25 and Helios, suggesting that they are not conventional Tregs. The frequency of CXCR3+, CD103+ and CCR7+ Tregs distinguished disease activity, and the combination of the frequency of these three Treg subsets segregated active patients from patients in remission and healthy controls. From these three subsets, the frequency of CXCR3+ Tregs distinguished patients with active disease with renal involvement. Treg heterogeneity can discriminate disease activity and should be explored as a biomarker of disease activity in ANCA vasculitis.

Analysis of rs1864182 and rs1864183 variants in ATG10 gene and antineutrophil cytoplasmic autoantibody‐associated vasculitis in Chinese Guangxi population

ObjectivesTo investigate the association of autophagy‐associated gene 10 (ATG10) gene polymorphisms (rs1864182 and rs1864183) with antineutrophil cytoplasmic autoantibody (ANCA)‐associated vasculitis (AAV) in Chinese Guangxi population.MethodsThe single nucleotide polymorphisms (SNPs) of ATG10 rs1864182 and rs1864183 in 395 participants (195 AAVs and 200 healthy controls) were genotyped. Generalized multiple dimensionality reduction (GMDR) was used to analyze the SNP‐SNP interactions among two SNPs of ATG10 gene and other SNPs of autophagy gene previously studied by our research team.ResultsIn this study, we found that the two ATG10 SNPs were not associated with AAV risk in Chinese Guangxi population. However, there were statistically significant differences in the incidence of hemoptysis, hematuria, and proteinuria among the three genotypes of ATG10 rs1864182 and rs1864183 (p < 0.05). Moreover, permutation test of GMDR suggested that immunity‐related GTPase M(IRGM) rs4958847, autophagy‐associated gene 7 (ATG7) rs6442260, ATG7 rs2594966, ATG10 rs1864183, protein kinase B(AKT2) rs3730051, and AKT2 rs11552192 might interact with each other in the process of developing AAV (p < 0.05).ConclusionsOur results indicated that there existed no association between ATG10 SNPs and AAV, and SNP‐SNP interactions among IRGM rs4958847, ATG7 rs6442260, ATG7 rs2594966, ATG10 rs1864183, AKT2 rs3730051, and AKT2 rs11552192 may confer AAV risk in the Chinese Guangxi population.

CNS limited ANCA-associated vasculitis presenting as an isolated intraparenchymal mass

The authors report a 34-year-old male with antineutrophil cytoplasmic autoantibody (ANCA) associated vasculitis (AAV) which only involved the central nervous system and presented with an isolated mass in the left parietal lobe. Constitutional symptoms were lacking and the only symptom was progressive right-sided hemiparesis. Pathology suggested necrotizing vasculitis without eosinophils and granulomas. Cytoplasmic ANCA was elevated to 103.9 IU/ml (>5 times the upper limit) in serum. He obtained a regression following treatment of cyclophosphamide and steroids. Prompt diagnosis of AAV is essential since early and aggressive initiation of immunosuppressive therapy can avoid further neurological sequelae.

SARS-CoV-2 Vaccine Response in Patients With Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

The development of COVID-19 vaccines and mass vaccination is a landmark achievement of modern medicine. Management of patients with antineutrophil cytoplasmic autoantibodies–associated vasculitis (AAV) during the pandemic has been challenging. Immunosuppressive medications to control vasculitis are associated with severe COVID-19 infection and may impair immune response to the vaccine.

Pulmonary Vasculitides: A Radiological Review Emphasizing Parenchymal HRCT Features.

Vasculitides represent a heterogeneous group of immune-mediated disorders, characterized by a systemic inflammatory destructive process of the blood vessels resulting either in ischemia or hemorrhage. The organ involved and vessel size influence the pattern of presentation of the pathology. The lung is commonly involved in systemic vasculitides, with heterogeneous clinical, radiological, and histopathological presentations. Primary vasculitides most commonly associated with lung parenchymal involvement include small-vessel antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides, such as granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA). Several studies have reported cases of interstitial lung diseases (ILDs) associated with systemic vasculitis, particularly those positive for ANCA associated vasculitis/vasculitidis: AAV. We have selected from our case series different radiological features of pulmonary vasculitis (i.e., solitary or multiple nodules, cavitary lesions, nodules with centrilobular or peribronchial distribution, airspace consolidations, “crazy paving” appearance, interstitial disease), including cases with interstitial lung alterations. Therefore, the aim of this review is to describe the typical clinical manifestations of vasculitides and their main radiologic features (especially AAV).