Showing papers by "Corinne Miceli-Richard published in 2017"

Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.

Abstract: Sjogren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmo ...

Characterization of CD4 T Cell Epitopes of Infliximab and Rituximab Identified from Healthy Donors.

Abstract: The chimeric antibodies anti-CD20 rituximab (Rtx) and anti-TNF infliximab (Ifx) induce anti-drug antibodies (ADAs) in many patients with inflammatory diseases. Because of the key role of CD4 T lymphocytes in the initiation of antibody responses, we localized the CD4 T cell epitopes of Rtx and Ifx. With the perspective to anticipate immunogenicity of therapeutic antibodies, identification of the CD4 T cell epitopes was performed using cells collected in healthy donors. Nine T cell epitopes were identified in the variable chains of both antibodies by deriving CD4 T cell lines raised against either Rtx or Ifx. The T cell epitopes often exhibited a good affinity for HLA-DR molecules and were part of the peptides identified by MHC-Associated Peptide Proteomics (MAPPs) assay from HLA-DR molecules of dendritic cells loaded with the antibodies. Two third of the T cell epitopes identified from the healthy donors stimulated PBMCs from patients having developed ADAs against Rtx or Ifx and promoted the secretion of a diversity of cytokines. These data emphasize the predictive value of evaluating the T cell repertoire of healthy donors and the composition of peptides bound to HLA-DR of DCs to anticipate and prevent immunogenicity of therapeutic antibodies.

Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjögren's Syndrome

Abstract: Background. Sjogren's syndrome and systemic lupus erythematosus (SLE) are related by clinical and serological manifestations as well as genetic risks. Both diseases are more commonly found in women compared to men at a ratio of about 10 to 1. Common X chromosome aneuploidies, 47,XXY and 47,XXX, are enriched among men and women, respectively, in either disease suggesting a dose effect on the X chromosome. Methods. We examined cohorts of Sjogren's syndrome or SLE patients with intensity plots of X chromosome single nucleotide polymorphism (SNP) alleles along with karyotype of selected subjects. Results. Among ∼2500 women with SLE we found three patients with a triple mosaic consisting of 45,X/46,XX/47,XXX. Among ∼2100 women with Sjogren's syndrome, one patient had 45,X/46,XX/47,XXX with a triplication of the distal p arm of the X chromosome in the 47,XXX cells. Neither the triple mosaic nor the partial triplication were found among controls. In another Sjogren's cohort, we found a mother-daughter pair with partial triplication of this same region of the X chromosome. The triple mosaic occurs in approximately 1 in 25,000 to 50,000 live female births, while partial triplications such are even rarer. Conclusions. Very rare X chromosome abnormalities are present among patients with either Sjogren's or SLE, and may inform the location of a gene(s) that mediate an X dose effect as well as critical cell types in which such effect is operative. This article is protected by copyright. All rights reserved.

Role of the IL-12/IL-35 balance in patients with Sjögren syndrome

Abstract: Background An interferon signature is involved in the pathogenesis of primary Sjogren syndrome (pSS), but whether the signature is type 1 or type 2 remains controversial. Mouse models and genetic studies suggest the involvement of T H 1 and type 2 interferon pathways. Likewise, polymorphisms of the IL-12A gene ( IL12A ), which encodes for IL-12p35, have been associated with pSS. The IL-12p35 subunit is shared by 2 heterodimers: IL-12 and IL-35. Objective We sought to confirm genetic association of the IL12A polymorphism and pSS and elucidate involvement of the IL-12/IL-35 balance in patients with pSS by using functional studies. Methods The genetic study involved 673 patients with pSS from 2 French pSS cohorts and 585 healthy French control subjects. Functional studies were performed on sorted monocytes, irrespective of whether they were stimulated. IL12A mRNA expression and IL-12 and IL-35 protein levels were assessed by using quantitative RT-PCR and ELISA and a multiplex kit for IL-35 and IL-12, respectively. Results We confirmed association of the IL12A rs485497 polymorphism and pSS and found an increased serum protein level of IL-12p70 in patients with pSS carrying the risk allele ( P = .016). Serum levels of IL-12p70 were greater in patients than control subjects ( P = .0001), especially in patients with more active disease ( P = .05); conversely, IL-35 levels were decreased in patients ( P = .0001), especially in patients with more active disease ( P = .05). In blood cellular subsets both IL12p35 and EBV-induced gene protein 3 (EBI3) mRNAs were detected only in B cells, with a trend toward a lower level among patients with pSS. Conclusion Our findings emphasize involvement of the IL-12/IL-35 balance in the pathogenesis of pSS. Serum IL-35 levels were associated with low disease activity, in contrast with serum IL-12p70 levels, which were associated with more active disease.

Takayasu Arteritis and Spondyloarthritis: Coincidence or Association? A Study of 14 Cases.

Abstract: Objective. Spondyloarthritis (SpA) and Takayasu arteritis (TA) are 2 chronic inflammatory diseases; their coexistence in a single patient is uncommon. The aims of our study were to describe clinical features of patients having SpA associated with TA and to identify some characteristics of the types of patients with SpA associated with TA. We also analyzed treatments used in this context. Methods. This French multicenter retrospective survey called for observations on behalf of the Club Rhumatismes et Inflammations, with a standardized questionnaire established by the investigators. Results. We included 14 patients (women: 10/14; median age at SpA diagnosis: 43.5 yrs, ranging from 19 to 63). Subtypes of SpA were ankylosing spondylitis (n = 11), psoriatic arthritis (n = 2), and synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (n = 1). HLA-B27 was positive in 3 cases, negative in 9, and unknown in 2. SpA was diagnosed before TA in 13 cases. Imaging findings compatible with the diagnosis of TA were found with computed tomography (11/14) and/or Doppler ultrasound (10/14). Laboratory tests showed increased acute-phase reactants in all cases (C-reactive protein ≥ 25 mg/l in 71% of the cases). All patients except 1 received corticosteroids and 7 were treated with anti–tumor necrosis factor (anti-TNF). Conclusion. Association of SpA and TA is rare but probably not coincidental. Peripheral pulse palpation and vascular auscultation should be systematic and are the first indicators of TA in patients with SpA. Moreover, increased acute-phase reactants during SpA followup should lead to search for TA. Finally, there are therapeutic implications because anti-TNF are efficient in SpA and might be efficient in TA.

Brief Report: The Role of Rare Protein-Coding Variants in Anti-Tumor Necrosis Factor Treatment Response in Rheumatoid Arthritis.

Abstract: Objective Many rheumatoid arthritis (RA) patients have their disease controlled with anti-tumor necrosis factor alpha (anti-TNF) biologic therapies However, a significant number of RA patients fail to respond to anti-TNF therapy Here, we hypothesized that rare and low-frequency variants might influence anti-TNF treatment response Methods We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry treated with anti-TNF medications After quality control, we included 690 genes in the analysis We applied single variants association and gene-based association tests to identify variants associated with anti-TNF treatment response We also performed gene set analyses of 27 TNF pathway genes, considering TNF's key mechanistic role Results We identified 14,420 functional variants, of which 6,934 were predicted as non-synonymous where 2,136 were further predicted to be damaging Despite being a well-powered study, no single variant or gene showed study-wide significant association with change in disease activity outcome or EULAR response outcome Intriguingly, we observed 3 genes, out of 27 with nominal signals of association (P<005), that were involved in the TNF signaling pathway However, when we performed a rigorous gene set enrichment analysis based on association P values ranking, we observed no evidence of enrichment of association at genes involved in the TNF pathway (Penrichment=015, based on phenotype permutations) Conclusions Our study suggests that rare and low-frequency protein-coding variants in TNF signaling pathway genes or other genes do not contribute substantially to anti-TNF treatment response in RA patients This article is protected by copyright All rights reserved

FRI0180 Multiple sclerosis risk-alleles study in patients with demyelinating side effects on anti tnf alpha therapy

Abstract: Background Tumor Necrosis Factor alpha (TNFα) is a key cytokine in inflammatory rheumatic diseases. TNF inhibitors (TNFi) has revolutionized treatment of rheumatic diseases, but may cause flares of multiple sclerosis (MS). Two Single Nucleotide Polymorphisms, (SNPs) rs1800693 and rs4149584, located within TNF receptor superfamilly 1 (TNFRSF1A) locus have been shown to increase the risk of developing MS [1]. The rs1800693*G allele leads to a dysfunctional TNFα soluble receptor that inhibits TNFα signaling while rs4149584 is involved in TNF receptor associated periodic syndrome. Objectives The aim of this study was to look for a possible the association between TNFRSF1A polymorphisms and demyelinating complications occurring during TNFi therapy. Methods Patients who presented with a demyelinating disorder (central or peripheral involvement) while treated with TNFi (cases), were recruited between March 2013 and December 2015, through the physicians involved in the CRI (“Club Rhumatismes et Inflammation”) a nationwide network of the French Society of Rheumatology. Rheumatoid arthritis patients treated with TNFi, from the French ReAct cohort, and who did not develop demyelinating complication constituted the control population (n=294). The frequency of rs1800693 and rs4149584 TNFRSF1A SNPs were compared between cases and controls. Results Twenty-four cases with demyelinating disorders, recruited from 11 centers with a median age of 39.7 years (range 30.4–75.8); of which 16 (67%) were females were included in the study. Neurological symptoms occurred after a median of 18.3 (1–66) months of anti TNFi; 15 (62.5%) had central neurologic involvement and 9 (37.5%) had peripheral involvement. The median follow-up was 26 (4–54) Months. No significant difference in the frequency of the rs1800693 MS risk-alleles (39,5% for cases vs 38,6% for controls) was observed. Similarly no difference was observed between cases (2%) and controls (4%) for rs4149584. Conclusions This study was unable to show an association between MS-associated SNPs within TNFRSF1A locus and the occurrence of demyelination while taking TNFi, suggesting that demyelination might be linked to other genetic factors or other pathways. References De Jager PL, Jia X, Wang J, et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 2009;41:776–82. doi:10.1038/ng.401. Disclosure of Interest None declared