Influence of the IL17A locus in giant cell arteritis susceptibility

Objective: Different lines of evidence have highlighted the role of IL-17A in the inflammatory process occurring in giant cell arteritis (GCA). The aim of the present study was to assess whether the IL17A locus influences GCA susceptibility and its clinical subphenotypes. Methods: We carried out a large meta-analysis including a total of 1266 biopsy-proven GCA patients and 3779 healthy controls from four European populations (Spain, Italy, Germany and Norway). Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) were selected by tagging and genotyped using TaqMan assays. Allelic combination and dependency tests were also performed. Results: In the pooled analysis, two of the five analysed polymorphisms showed evidence of association with GCA (rs2275913: PMH=1.85E−03, OR=1.17 (1.06-1.29); rs7747909: PMH=8.49E-03, OR=1.15 (1.04-1.27)). A clear trend of association was also found for the rs4711998 variant (PMH=0.059, OR=1.11 (1.00-1.23)). An independent effect of rs2275913 and rs4711998 was evident by conditional regression analysis. In addition, the haplotype harbouring the risk alleles better explained the observed association than the polymorphisms independently (likelihood p value <10−05). Conclusions: Polymorphisms within the IL17A locus show a novel association with GCA. This finding supports the relevant role of the Th17 cells in this vasculitis pathophysiology

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis

Objective: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). Methods: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. Results: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). Conclusions: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA

Conditions in subjects with rheumatic diseases: pulmonary manifestations of vasculitides

Pulmonary involvement is a common complication of vasculitides, especially small vessel vasculitides. This review provides an overview of vasculitic manifestations of the lung as well as of other organs involved in vasculitides. Furthermore, it provides the diagnostic procedures required to asses a patient with vasculitic lung involvement and gives an overview of current treatment strategies

Presence of Antibodies Binding to Negative Elongation Factor E in Sarcoidosis.

Sarcoidosis is characterized by multiorgan involvement and granulomatous inflammation. Its origin is unknown and the potential role of autoimmunity has not been sufficiently determined. We investigated the presence of autoantibodies in sarcoidosis using protein array technology. The derivation cohort consisted of patients with sarcoidosis (n = 25) and controls including autoimmune disease and blood donors (n = 246). In addition, we tested a validation cohort including pulmonary sarcoidosis patients (n = 58) and healthy controls (n = 13). Initially, sera of three patients with sarcoidosis were screened using a protein array with 28.000 proteins against controls. Thereby we identified the Negative Elongation Factor E (NELF-E) as an autoantigen. With confirmatory Enzyme-linked Immunosorbent Assay (ELISA)testing, 29/82 patients (35%) with sarcoidosis had antibodies against NELF-E of the Immunoglobulin (Ig) G type, whereas 18/253 (7%) sera of the controls were positive for NELF-E. Clinically, there was an association of the frequency of NELF-E antibody detection with lung parenchymal involvement and corresponding x-ray types. NELF-E autoantibodies are associated with sarcoidosis and should be further investigated

T Cells in Vascular Inflammatory Diseases

Inflammation of the human vasculature is a manifestation of many different diseases ranging from systemic autoimmune diseases to chronic inflammatory diseases, in which multiple types of immune cells are involved. For both autoimmune diseases and chronic inflammatory diseases several observations support a key role for T lymphocytes in these disease pathologies, but the underlying mechanisms are poorly understood. Previous studies in several autoimmune diseases have demonstrated a significant role for a specific subset of CD4(+) T cells termed effector memory T (T-EM cells. This expanded population of T-EM cells may contribute to tissue injury and disease progression. These cells exert multiple pro-inflammatory functions through the release of effector cytokines. Many of these cytokines have been detected in the inflammatory lesions and participate in the vasculitic reaction, contributing to recruitment of macrophages, neutrophils, dendritic cells, natural killer cells, B cells, and T cells. In addition, functional impairment of regulatory T cells paralyzes anti-inflammatory effects in vasculitic disorders. Interestingly, activation of T-EM cells is uniquely dependent on the voltage-gated potassium Kv1.3 channel providing an anchor for specific drug targeting. In this review, we focus on the CD4+ T cells in the context of vascular inflammation and describe the evidence supporting the role of different T cell subsets in vascular inflammation. Selective targeting of pathogenic T-EM cells might enable a more tailored therapeutic approach that avoids unwanted adverse side effects of generalized immunosuppression by modulating the effector functions of T cell responses to inhibit the development of vascular inflammation

Mepolizumab For The Treatment Of Patients With Eosinophilic Granulomatosis With Polyangiitis: A Phase Iii Randomized, Placebo-Controlled Trial

Mepolizumab For The Treatment Of Patients With Eosinophilic Granulomatosis With Polyangiitis: A Phase Iii Randomized, Placebo-Controlled Tria

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+\u2009ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+\u2009ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA

Apoptotic Effects of Antilymphocyte Globulins on Human Pro-inflammatory CD4+CD28− T-cells

BACKGROUND: Pro-inflammatory, cytotoxic CD4(+)CD28(-) T-cells with known defects in apoptosis have been investigated as markers of premature immuno-senescence in various immune-mediated diseases. In this study we evaluated the influence of polyclonal antilymphocyte globulins (ATG-Fresenius, ATG-F) on CD4(+)CD28(-) T-cells in vivo and in vitro. PRINCIPAL FINDINGS: Surface and intracellular three colour fluorescence activated cell sorting analyses of peripheral blood mononuclear cells from 16 consecutive transplant recipients and short-term cell lines were performed. In vivo, peripheral levels of CD3(+)CD4(+)CD28(-) T-cells decreased from 3.7 ± 7.1% before to 0 ± 0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9 ± 2.9% vs. 3.9 ± 3.0%). In vitro, ATG-F induced apoptosis even in CD4(+)CD28(-) T-cells, which was 4.3-times higher than in CD4(+)CD28(+) T-cells. ATG-F evoked apoptosis was partially reversed by the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and prednisolon-21-hydrogensuccinate. ATG-F triggered CD25 expression and production of pro-inflammatory cytokines, and induced down-regulation of the type 1 chemokine receptors CXCR-3, CCR-5, CX3CR-1 and the central memory adhesion molecule CD62L predominately in CD4(+)CD28(-) T-cells. CONCLUSION: In summary, in vivo depletion of peripheral CD3(+)CD4(+)CD28(-) T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis. CD25 expression and chemokine receptor down-regulation in CD4(+)CD28(-) T-cells only partly explain the underlying mechanism

A candidate gene approach identifies an IL33 genetic variant as a novel genetic risk factor for GCA

INTRODUCTION: Increased expression of IL-33 and its receptor ST2, encoded by the IL1RL1 gene, has been detected in the inflamed arteries of giant cell arteritis (GCA) patients. The aim of the present study was to investigate for the first time the potential influence of the IL33 and IL1RL1 loci on GCA predisposition. METHODS: A total of 1,363 biopsy-proven GCA patients and 3,908 healthy controls from four European cohorts (Spain, Italy, Germany and Norway) were combined in a meta-analysis. Six genetic variants: rs3939286, rs7025417 and rs7044343, within the IL33 gene, and rs2058660, rs2310173 and rs13015714, within the IL1RL1 gene, previously associated with immune-related diseases, were genotyped using predesigned TaqMan assays. RESULTS: A consistent association between the rs7025417 polymorphism and GCA was evident in the overall meta-analysis, under both allele (P(MH) = 0.041, OR = 0.88, CI 95% 0.78-0.99) and recessive (P(MH) = 3.40E-03, OR = 0.53, CI 95% 0.35-0.80) models. No statistically significant differences between allele or genotype frequencies for the other IL33 and IL1RL1 genetic variants were detected in this pooled analysis. CONCLUSIONS: Our results clearly evidenced the implication of the IL33 rs7025417 polymorphism in the genetic network underlying GCA