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Journal of Autoimmunity

Srinivasa Reddy Bonam, Fengjuan Wang, Sylviane Muller
Nowadays, pharmacologic treatments of autoinflammatory diseases are largely palliative rather than curative. Most of them result in non-specific immunosuppression, which can be associated with broad disruption of natural and induced immunity with significant and sometimes serious unwanted injuries. Among the novel strategies that are under development, tools that modulate the immune system to restore normal tolerance mechanisms are central. In these approaches, peptide therapeutics constitute a class of agents that display many physicochemical advantages...
September 12, 2018: Journal of Autoimmunity
Lenche Chakievska, Maike M Holtsche, Axel Künstner, Stephanie Goletz, Britt-Sabina Petersen, Diamant Thaci, Saleh M Ibrahim, Ralf J Ludwig, Andre Franke, Christian D Sadik, Detlef Zillikens, Christoph Hölscher, Hauke Busch, Enno Schmidt
IL-17A has been identified as key regulatory molecule in several autoimmune and chronic inflammatory diseases followed by the successful use of anti-IL-17 therapy, e.g. in ankylosing spondylitis and psoriasis. Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease with a high need for more specific, effective and safe treatment options. The aim of this study was to clarify the pathophysiological importance of IL-17A in BP. We found elevated numbers of IL-17A+ CD4+ lymphocytes in the peripheral blood of BP patients and identified CD3+ cells as major source of IL-17A in early BP skin lesions...
September 12, 2018: Journal of Autoimmunity
Gerardo Di Scala, Alessandra Bettiol, Rafaela Diana Cojan, Martina Finocchi, Elena Silvestri, Giacomo Emmi
OBJECTIVE: To evaluate the efficacy and safety of secukinumab in Behçet's patients with active mucocutaneous and articular manifestations refractory to previous treatments. METHODS: We retrospectively evaluated 5 patients treated with the IL17-inhibitor secukinumab and diagnosed with Behçet according to ISG/ICBD criteria. All patients had active mucocutaneous and articular manifestations refractory to colchicine, conventional DMARDs and at least one anti-TNFα agent...
September 11, 2018: Journal of Autoimmunity
Jacqueline Thiel, Christina Alter, Sina Luppus, Anja Eckstein, Susanne Tan, Dagmar Führer, Eva Pastille, Astrid M Westendorf, Jan Buer, Wiebke Hansen
MircoRNAs (miRs) are small molecules that regulate gene expression at the posttranscriptional level. They have been proposed to be involved in the regulation of several immune responses including autoimmunity. Here, we identified miR-183 and miR-96 to be highly expressed in CD4+ T cells from peripheral blood of Graves' orbitopathy (GO) patients as well as in human and murine T cells upon activation in vitro. By using Luciferase-based binding assays, we identified EGR-1 as target for miR-183 and miR-96. Overexpression of miR-183 and miR-96 in murine CD4+ T cells by retroviral gene transfer resulted in decreased EGR-1 and PTEN expression, elevated Akt phosphorylation and enhanced proliferation...
September 7, 2018: Journal of Autoimmunity
Sarah M Wade, Michelle Trenkmann, Trudy McGarry, Mary Canavan, Viviana Marzaioli, Siobhan C Wade, Douglas J Veale, Ursula Fearon
OBJECTIVES: To investigate the functional role of miR-23a in synovial fibroblasts (SFC) activation in psoriatic arthritis (PsA). METHODS: Differential expression of the miR-23a-27a-24-2 cluster was identified by real-time quantitative PCR in PsA synovial tissue and peripheral blood mononuclear cells (PBMC) compared to osteoarthritis (OA) and correlated with disease activity. For regulation experiments, PsA synovial fibroblasts (SFC) were cultured with Toll-like receptor (TLR) ligands and pro-inflammatory cytokines...
September 1, 2018: Journal of Autoimmunity
Prabhakaran Kumar, Palash Bhattacharya, Bellur S Prabhakar
The immune system ensures optimum T-effector (Teff) immune responses against invading microbes and tumor antigens while preventing inappropriate autoimmune responses against self-antigens with the help of T-regulatory (Treg) cells. Thus, Treg and Teff cells help maintain immune homeostasis through mutual regulation. While Tregs can contribute to tumor immune evasion by suppressing anti-tumor Teff response, loss of Treg function can result in Teff responses against self-antigens leading to autoimmune disease...
August 30, 2018: Journal of Autoimmunity
Elise V Mike, Hadijat M Makinde, Maria Gulinello, Kamala Vanarsa, Leal Herlitz, Gaurav Gadhvi, Deborah R Winter, Chandra Mohan, John G Hanly, C C Mok, Carla M Cuda, Chaim Putterman
Neuropsychiatric manifestations in lupus (NPSLE) affect ∼20-40% of patients. In the central nervous system, lipocalin-2 (LCN2) can promote injury through mechanisms directly linked to NPSLE, including brain barrier disruption, neurotoxicity, and glial activation. Since LCN2 is elevated in lupus and has been implicated in neuroinflammation, we investigated whether LCN2 is required for the pathogenesis of NPSLE. Here, we investigated the effects of LCN2 deficiency on the development of neurobehavioral deficits in the B6...
August 30, 2018: Journal of Autoimmunity
Inken Wohlers, Lars Bertram, Christina M Lill
Genome-wide association studies (GWAS) have identified a large number of genetic risk loci for autoimmune diseases. However, the functional variants underlying these disease associations remain largely unknown. There is evidence that microRNA-mediated regulation may play an important role in this context. Therefore, we assessed whether autoimmune disease loci unfold their effects via altering microRNA expression in relevant immune cells. To this end, we performed comprehensive data integration of many large and publicly available datasets to combine information on autoimmune disease risk loci with RNA-Seq-based microRNA expression data...
August 21, 2018: Journal of Autoimmunity
Margarita Dominguez-Villar, Khadir Raddassi, Ann Caroline Danielsen, Joseph Guarnaccia, David A Hafler
Fingolimod is an approved therapeutic option for patients with relapsing-remitting multiple sclerosis that primarily functions by sequestering T cells in lymph nodes inhibiting their egress to the central nervous system. However, recent data suggests that Fingolimod may also directly affect the immune cell function. Here we examined the in vivo effects of Fingolimod in modulating the phenotype and function of T cell and Foxp3 regulatory T cell populations in patients with multiple sclerosis under Fingolimod treatment...
August 16, 2018: Journal of Autoimmunity
Li Zhang, Tomasz Sosinowski, R Aaron, Joseph Ray Cepeda, Nitin S Sekhar, Sean M Hartig, Dongmei Miao, Liping Yu, Massimo Pietropaolo, Howard W Davidson
A primary initiating epitope in the NOD mouse model of Type 1 Diabetes (T1D) lies between residues 9 and 23 of the insulin B chain. The B:9-23 peptide can bind to the NOD MHC class II molecule (I-Ag7 ) in multiple registers, but only one, (register 3, R3), creates complexes able to stimulate the majority of pathogenic B:9-23-specific CD4+ T cells. Previously we generated a monoclonal antibody (mAb287) that targets this critical I-Ag7 -B:9-23(R3) complex. When given weekly to pre-diabetic mice at either early or late stages of disease, mAb287 was able to delay or prevent T1D in the treated animals...
August 16, 2018: Journal of Autoimmunity
Adrien Mirouse, Lucie Biard, Cloé Comarmond, Marc Lambert, Arsène Mekinian, Yasmina Ferfar, Jean-Emmanuel Kahn, Ygal Benhamou, Laurent Chiche, Fabien Koskas, Philippe Cluzel, Eric Hachulla, Emmanuel Messas, Patrice Cacoub, Tristan Mirault, Matthieu Resche-Rigon, David Saadoun
OBJECTIVE: To report the long term mortality in Takayasu arteritis (TA) and to identify prognosis factors. METHODS: We analyzed the causes of death and the factors associated with mortality in a cohort of 318 patients [median age at diagnosis was 36 [25-47] years and 276 (86%) patients were women] fulfilling American College of Rheumatology and/or Ishikawa criteria of TA. A prognostic score for death and vascular complications was elaborated based on a multivariate model...
August 16, 2018: Journal of Autoimmunity
Evaggelia Liaskou, Samita R Patel, Gwilym Webb, Danai Bagkou Dimakou, Sarah Akiror, Mahesh Krishna, George Mells, Dave E Jones, Simon J Bowman, Francesca Barone, Benjamin A Fisher, Gideon M Hirschfield
IL-12 is a pro-inflammatory cytokine that induces the production of interferon-γ (IFNγ) and favours the differentiation of T helper 1 (Th1) cells. In the presence of IL-12 human Treg cells acquire a Th1-like phenotype with reduced suppressive activity in vitro. Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterised by high Th1 and Th17 infiltrating cells, reduced frequencies of Treg cells, and a genetic association with IL-12 signalling. Herein, we sought to evaluate the IL-12 signalling pathway in PBC pathology, by studying human samples from patients with PBC, alongside those with primary Sjögren's syndrome (pSS)(autoimmune disease with IL-12 signalling gene association), primary sclerosing cholangitis (PSC) (cholestatic liver disease without IL-12 gene association) and healthy individuals...
August 14, 2018: Journal of Autoimmunity
Angela Lombardi, Effie Tsomos, Sara S Hammerstad, Yaron Tomer
IFNα is a cytokine essential to a vast array of immunologic processes. Its induction early in the innate immune response provides a priming mechanism that orchestrates numerous subsequent pathways in innate and adaptive immunity. Despite its beneficial effects in viral infections IFNα has been reported to be associated with several autoimmune diseases including autoimmune thyroid disease, systemic lupus erythematosus, rheumatoid arthritis, primary biliary cholangitis, and recently emerged as a major cytokine that triggers Type 1 Diabetes...
August 14, 2018: Journal of Autoimmunity
Dan Lu, Jia Song, Yizhe Sun, Fang Qi, Liang Liu, Yan Jin, Michael A McNutt, Yuxin Yin
Dysregulation of innate immunity accompanied by excessive interferon production contributes to autoimmune disease. However, the mechanism by which the immune response is modulated in autoimmune disorders is largely unknown. Here we identified loss-of-function mutations of OTUD1 associated with multiple autoimmune diseases. Under inflammatory conditions, inducible OTUD1 acts as an immune checkpoint and blocks RIG-I-like receptors signaling. As a deubiquitinase, OTUD1 directly interacts with transcription factor IRF3 and removes the K63-linked poly-ubiquitin chains on IRF3 Lysine 98, which inhibits IRF3 nuclear translocation and transcriptional activity...
August 9, 2018: Journal of Autoimmunity
Anyan Xie, René J Robles, Samiran Mukherjee, Haohai Zhang, Linda Feldbrügge, Eva Csizmadia, Yan Wu, Keiichi Enjyoji, Alan C Moss, Leo E Otterbein, Francisco J Quintana, Simon C Robson, Maria Serena Longhi
In Crohn's disease, pathogenic Th17-cells express low levels of CD39 ectonucleotidase and are refractory to the immunosuppressive effects of unconjugated bilirubin (UCB), an endogenous ligand for aryl-hydrocarbon-receptor (AhR). This resistance to AhR ligation might be associated with alterations in responses to hypoxia. Limited exposure to hypoxia appears beneficial in acute tissue injury. However, in protracted inflammation, hypoxemia may paradoxically result in Th17-cell activation. We report here that in vitro exposure of Th17-cells from Crohn's disease patients to hypoxia limits responsiveness to AhR stimulation by UCB, as reflected by lower CD39 levels...
August 8, 2018: Journal of Autoimmunity
Xuan-Hung Nguyen, Yves Dauvilliers, Clémence Quériault, Corine Perals, Raphaelle Romieu-Mourez, Pierre-Emmanuel Paulet, Raphaël Bernard-Valnet, Nicolas Fazilleau, Roland Liblau
Despite genetic and epidemiological evidence strongly supporting an autoimmune basis for narcolepsy type 1, the mechanisms involved have remained largely unknown. Here, we aimed to investigate whether the frequency and function of circulating follicular helper and follicular regulatory T cells are altered in narcolepsy type 1. Peripheral blood mononuclear cells were collected from 32 patients with narcolepsy type 1, including 11 who developed disease after Pandemrix® vaccination, and 32 age-, sex-, and HLA-DQB1*06:02-matched healthy individuals...
August 6, 2018: Journal of Autoimmunity
Pavanish Kumar, Leong Jing Yao, Suzan Saidin, Bhairav Paleja, Jorg van Loosdregt, Camillus Chua, Thaschawee Arkachaisri, Alessandro Consolaro, Marco Gattorno, Alberto Martini, Ken D Pischel, Gary W Williams, Martin Lotz, Salvatore Albani
T-cell resilience is critical to the immune pathogenesis of human autoimmune arthritis. Autophagy is essential for memory T cell generation and associated with pathogenesis in rheumatoid arthritis (RA). Our aim here was to delineate the role and molecular mechanism of autophagy in resilience and persistence of pathogenic T cells from autoimmune arthritis. We demonstrated "Autophagic memory" as elevated autophagy levels in CD4+ memory T cells compared to CD4+ naive T cells and in Jurkat Human T cell line trained with starvation stress...
August 1, 2018: Journal of Autoimmunity
Imanol M Laza, Nerea G Ventades, Montserrat Hervella, Concepción de-la-Rúa
Genetic investigations on ancient human remains affected by rheumatological pathologies are a research field of particular interest for identifying the pathogenesis of diseases, especially those having an autoimmune background such as spondyloarthopaties (SpA). Reliable studies concerning this topic require collaboration between multiple disciplines, usually starting from paleopathologic observations up to molecular genetic screening. Here, we focused our investigation in a medieval necropolis in the Basque Country (13th-15th century, N = 163), which presents a high frequency of joint pathologies through two approaches: on the one hand, the analysis of joint manifestations for the differential diagnosis of the SpA and, on the other hand, the determination of the alleles of the HLA-B gene...
July 28, 2018: Journal of Autoimmunity
A Maciejewski-Duval, C Comarmond, A Leroyer, M Zaidan, A Le Joncour, A C Desbois, J P Fouret, F Koskas, P Cluzel, M Garrido, P Cacoub, D Saadoun
BACKGROUND: Mammalian target of rapamycin complex 1 (mTORC 1) drives the proinflammatory expansion of T helper (TH) type 1, TH17 cells and controls fibroblast proliferation, typical features of large vessel vasculitis (LVV) pathogenesis. Molecular pathways involved in arterial lesions of LVV are unknown. METHODS: We evaluate mTORC pathway activation in vascular aorta lesions and in T cell homeostasis of patients with LVV. RESULTS: Proliferation of both endothelial cells and vascular smooth-muscle cells was shown in vascular lesions in LVV...
July 27, 2018: Journal of Autoimmunity
Sonja M Lacher, Christoph Thurm, Ute Distler, Alma N Mohebiany, Nicole Israel, Maja Kitic, Anna Ebering, Yilang Tang, Matthias Klein, Guido H Wabnitz, Florian Wanke, Yvonne Samstag, Tobias Bopp, Florian C Kurschus, Luca Simeoni, Stefan Tenzer, Ari Waisman
NF-κB inducing kinase (NIK) is the key protein of the non-canonical NF-κB pathway and is important for the development of lymph nodes and other secondary immune organs. We elucidated the specific role of NIK in T cells using T-cell specific NIK-deficient (NIKΔT ) mice. Despite showing normal development of lymphoid organs, NIKΔT mice were resistant to induction of CNS autoimmunity. T cells from NIKΔT mice were deficient in late priming, failed to up-regulate T-bet and to transmigrate into the CNS. Proteomic analysis of activated NIK-/- T cells showed de-regulated expression of proteins involved in the formation of the immunological synapse: in particular, proteins involved in cytoskeleton dynamics...
July 27, 2018: Journal of Autoimmunity
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