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The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus.
CONCLUSIONS: This study provides novel insights into clinical beneficence of reducing excessive NET formation in SLE by therapeutic targeting ANA production with RTX + BLM. Altogether putting forward a new treatment concept that specifically ameliorates underlying SLE pathophysiology. TRIAL REGISTRATION: ClinicalTrials.gov NCT02284984. PMID: 29636274 [PubMed - as supplied by publisher] (Source: Journal of Autoimmunity)
Source: Journal of Autoimmunity - April 7, 2018 Category: Allergy & Immunology Authors: Kraaij T, Kamerling SWA, de Rooij ENM, van Daele PLA, Bredewold OW, Bakker JA, Bajema IM, Scherer HU, Toes REM, Huizinga TJW, Rabelink TJ, van Kooten C, Teng YKO Tags: J Autoimmun Source Type: research

Mechanisms of neuropsychiatric lupus: The relative roles of the blood-cerebrospinal fluid barrier versus blood-brain barrier.
Abstract The pathogenesis of neuropsychiatric lupus (NPSLE) is believed to include the entry of circulating neuropathic antibodies to the brain via a pathologically permeable blood-brain barrier (BBB). Nevertheless, direct evidence of BBB pathology or mechanisms underlying BBB dysfunction is missing. Here, we examined BBB integrity in an established NPSLE mouse model (MRL/faslpr/lpr). Surprisingly, challenging the barrier with various exogenous tracers demonstrated insignificant changes in BBB permeability. Furthermore, electron microscopy showed no ultrastructure changes supporting hyper-permeability. However, we...
Source: Journal of Autoimmunity - April 4, 2018 Category: Allergy & Immunology Authors: Gelb S, Stock AD, Anzi S, Putterman C, Ben-Zvi A Tags: J Autoimmun Source Type: research

Gain of function mutation and inflammasome driven diseases in human and mouse models.
fel B Abstract Activation of the NLRP3 inflammasome, a multiprotein complex, leading to caspase activation with production of proinflammatory IL-1β represents a major pathway of inflammation. Recent, studies in mice and human patients uncovered several gain-of- function (GOF) mutations in inflammasome sensor proteins that allow inflammasome assembly in the absence of cognate ligands to trigger autoinflammatory syndromes. Cryopyrin-associated periodic syndromes (CAPS) are rare autoinflammatory diseases, comprising a broad disease spectrum with varying severity. CAPS are associated with GOF mutations in the NLR...
Source: Journal of Autoimmunity - March 30, 2018 Category: Allergy & Immunology Authors: Cordero MD, Alcocer-Gómez E, Ryffel B Tags: J Autoimmun Source Type: research

Autoantibodies targeting TLR and SMAD pathways define new subgroups in systemic lupus erythematosus.
Abstract OBJECTIVES: The molecular targets of the vast majority of autoantibodies in systemic lupus erythematosus (SLE) are unknown. We set out to identify novel autoantibodies in SLE to improve diagnosis and identify subgroups of SLE individuals. METHODS: A baculovirus-insect cell expression system was used to create an advanced protein microarray with 1543 full-length human proteins expressed with a biotin carboxyl carrier protein (BCCP) folding tag, to enrich for correctly folded proteins. Sera from a discovery cohort of UK and US SLE individuals (n = 186) and age/ethnicity matched controls (n = 18...
Source: Journal of Autoimmunity - March 22, 2018 Category: Allergy & Immunology Authors: Lewis MJ, McAndrew MB, Wheeler C, Workman N, Agashe P, Koopmann J, Uddin E, Morris DL, Zou L, Stark R, Anson J, Cope AP, Vyse TJ Tags: J Autoimmun Source Type: research

Systemic activation of NLRP3 inflammasome in patients with severe primary Sj ögren's syndrome fueled by inflammagenic DNA accumulations.
Systemic activation of NLRP3 inflammasome in patients with severe primary Sjögren's syndrome fueled by inflammagenic DNA accumulations. J Autoimmun. 2018 Mar 15;: Authors: Vakrakou AG, Boiu S, Ziakas PD, Xingi E, Boleti H, Manoussakis MN Abstract Sjögren's syndrome (SS) patients manifest high cell-free DNA (cf-DNA) levels in serum, associated with impaired DNaseI activity. Undegraded DNA may accumulate in tissues and act as an inflammasome-activating signal. Herein, we investigated the occurrence of aberrant DNA build-up in various biologic compartments of SS patients and its correlation wit...
Source: Journal of Autoimmunity - March 15, 2018 Category: Allergy & Immunology Authors: Vakrakou AG, Boiu S, Ziakas PD, Xingi E, Boleti H, Manoussakis MN Tags: J Autoimmun Source Type: research

LINE1 contributes to autoimmunity through both RIG-I- and MDA5-mediated RNA sensing pathways.
In this study, we report that endogenous LINE1 components trigger IFNβ production in multiple human cell types, including those defective for cGAS/STING-mediated DNA sensing. In these cells, LINE1 DNA synthesis and retrotransposition were not required for LINE1-triggered immune activation, but RNA sensing pathways were essential. LINE1-triggered immune activation could be suppressed by diverse LINE1 inhibitors, including AGS-associated proteins targeting LINE1 RNA or proteins. However, AGS-associated ADAR1 or TREX1 mutants were defective in suppressing LINE1 retrotransposition or LINE1-triggered immune activation. The...
Source: Journal of Autoimmunity - March 7, 2018 Category: Allergy & Immunology Authors: Zhao K, Du J, Peng Y, Li P, Wang S, Wang Y, Hou J, Kang J, Zheng W, Hua S, Yu XF Tags: J Autoimmun Source Type: research

Engrafting human regulatory T cells with a flexible modular chimeric antigen receptor technology.
mann MP Abstract As regulatory T cells (Tregs) play a fundamental role in immune homeostasis their adoptive transfer emerged as a promising treatment strategy for inflammation-related diseases. Preclinical animal models underline the superiority of antigen-specific Tregs compared to polyclonal cells. Here, we applied a modular chimeric antigen receptor (CAR) technology called UniCAR for generation of antigen-specific human Tregs. In contrast to conventional CARs, UniCAR-endowed Tregs are indirectly linked to their target cells via a separate targeting module (TM). Thus, transduced Tregs can be applied universally ...
Source: Journal of Autoimmunity - March 1, 2018 Category: Allergy & Immunology Authors: Koristka S, Kegler A, Bergmann R, Arndt C, Feldmann A, Albert S, Cartellieri M, Ehninger A, Ehninger G, Middeke JM, Bornhäuser M, Schmitz M, Pietzsch J, Akgün K, Ziemssen T, Steinbach J, Bachmann MP Tags: J Autoimmun Source Type: research

Origins and specificity of auto-antibodies in Sm+ SLE patients.
Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease accompanied by production of autoantibodies directed to a variety of self-proteins and nucleic acids. The genetic basis of SLE is also complex with at least 40 susceptibility loci identified. This complexity suggests that there are a variety of SLE manifestations; nevertheless, SLE is treated as a single disease clinically. One unique SLE target is the Smith antigen (Sm), a nuclear ribonucleoprotein complex. Sm response occurs in 25% of patients with SLE. To simplify analysis of the disease and its associated autoantibody repertoire, we fo...
Source: Journal of Autoimmunity - March 1, 2018 Category: Allergy & Immunology Authors: Kalinina O, Louzoun Y, Wang Y, Utset T, Weigert M Tags: J Autoimmun Source Type: research

Rescue of autophagy and lysosome defects in salivary glands of MRL/lpr mice by a therapeutic phosphopeptide.
Abstract Sjögren's syndrome is a multifactorial systemic autoimmune disorder characterized by lymphocytic infiltrates in exocrine organs. Patients present with sicca symptoms, such as extensive dry eyes and dry mouth, and parotid enlargement. Other serious complications include profound fatigue, chronic pain, major organ involvement, neuropathies and lymphomas. Current treatments only focus on relieving symptoms and do not target the origin of the disease, which is largely unknown. The question we addressed here was whether some defects exist in autophagy processes in Sjögren's syndrome and if they can b...
Source: Journal of Autoimmunity - February 24, 2018 Category: Allergy & Immunology Authors: Li B, Wang F, Schall N, Muller S Tags: J Autoimmun Source Type: research

Targeting CD6 for the treatment of experimental autoimmune uveitis.
CONCLUSIONS: Together, these data strongly suggest that CD6 plays a previously unknown, but pivotal role in autoimmune uveitis, and may be a promising new treatment target for this blinding disease. In addition, the newly developed mouse anti-mouse/human CD6 mAbs could be valuable tools for testing CD6-targeted therapies in other mouse models of human diseases. PMID: 29472120 [PubMed - as supplied by publisher] (Source: Journal of Autoimmunity)
Source: Journal of Autoimmunity - February 19, 2018 Category: Allergy & Immunology Authors: Zhang L, Li Y, Qiu W, Bell BA, Dvorina N, Baldwin WM, Singer N, Kern T, Caspi RR, Fox DA, Lin F Tags: J Autoimmun Source Type: research

Beyond thrombosis: Anti- β2GPI domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome.
Beyond thrombosis: Anti-β2GPI domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome. J Autoimmun. 2018 Feb 14;: Authors: Chighizola CB, Pregnolato F, Andreoli L, Bodio C, Cesana L, Comerio C, Gerosa M, Grossi C, Kumar R, Lazzaroni MG, Mahler M, Mattia E, Nalli C, Norman GL, Raimondo MG, Ruffatti A, Tonello M, Trespidi L, Tincani A, Borghi MO, Meroni PL Abstract Antibodies against β2 glycoprotein I (anti-β2GPI) have been identified as the main pathogenic autoantibody subset in anti-phospholipid syndrome (APS); the most relevant epitope is a cryptic and confo...
Source: Journal of Autoimmunity - February 14, 2018 Category: Allergy & Immunology Authors: Chighizola CB, Pregnolato F, Andreoli L, Bodio C, Cesana L, Comerio C, Gerosa M, Grossi C, Kumar R, Lazzaroni MG, Mahler M, Mattia E, Nalli C, Norman GL, Raimondo MG, Ruffatti A, Tonello M, Trespidi L, Tincani A, Borghi MO, Meroni PL Tags: J Autoimmun Source Type: research

The treatment of anti-phospholipid syndrome: A comprehensive clinical approach.
Abstract Anti-phospholipid syndrome (APS) is an acquired pro-thrombotic autoimmune disease that predisposes to thrombotic events and/or obstetric complications, in the persistent presence of anti-phospholipid antibodies (aPL). Life long moderate-intensity anticoagulation is the option of choice for aPL-positive patients with a previous thrombosis; critical issues concern the management of those with a history of arterial event due to the high rate of recurrence. Alternatives comprise anti-platelet agents and high-intensity anticoagulation. Low dose aspirin (LDASA) and low molecular weight heparin provide the mains...
Source: Journal of Autoimmunity - February 12, 2018 Category: Allergy & Immunology Authors: Chighizola CB, Andreoli L, Gerosa M, Tincani A, Ruffatti A, Meroni PL Tags: J Autoimmun Source Type: research

Low CD25 on autoreactive Tregs impairs tolerance via low dose IL-2 and antigen delivery.
Abstract Dendritic cell (DC)-mediated T cell tolerance deficiencies contribute to the pathogenesis of autoimmune diseases such as type 1 diabetes. Delivering self-antigen to dendritic-cell inhibitory receptor-2 (DCIR2)+ DCs can delay but not completely block diabetes development in NOD mice. These DCIR2-targeting antibodies induce tolerance via deletion and anergy, but do not increase islet-specific Tregs. Because low-dose IL-2 (LD-IL-2) administration can preferentially expand Tregs, we tested whether delivering islet-antigen to tolerogenic DCIR2+ DCs along with LD-IL-2 would boost islet-specific Tregs and furthe...
Source: Journal of Autoimmunity - February 10, 2018 Category: Allergy & Immunology Authors: Hotta-Iwamura C, Benck C, Coley WD, Liu Y, Zhao Y, Quiel JA, Tarbell KV Tags: J Autoimmun Source Type: research

The immunobiology of mucosal-associated invariant T cell (MAIT) function in primary biliary cholangitis: Regulation by cholic acid-induced Interleukin-7.
Abstract Mucosal-associated invariant T (MAIT) cells are novel innate-like T cells constituting a significant proportion of circulating and hepatic T cells. Herein, we extensively examine the phenotypical and functional alterations of MAIT cells and their regulation in a cohort of 56 patients with Primary Biliary Cholangitis (PBC) and 53 healthy controls (HC). Additionally alterations of MAIT cells were assessed before and after UDCA treatment. Finally the localization of MAIT cell in liver was examined using specific tetramer staining and the underlying mechanisms of these alterations in PBC were explored. Our da...
Source: Journal of Autoimmunity - February 8, 2018 Category: Allergy & Immunology Authors: Jiang X, Lian M, Li Y, Zhang W, Wang Q, Wei Y, Zhang J, Chen W, Xiao X, Miao Q, Bian Z, Qiu D, Fang J, Ansari AA, Leung PSC, Coppel RL, Tang R, Gershwin ME, Ma X Tags: J Autoimmun Source Type: research

TGF- β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis.
TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis. J Autoimmun. 2018 Feb 06;: Authors: Peres RS, Donate PB, Talbot J, Cecilio NT, Lobo PR, Machado CC, Lima KWA, Oliveira RD, Carregaro V, Nakaya HI, Cunha TM, Alves-Filho JC, Liew FY, Louzada-Junior P, Cunha FQ Abstract Rheumatoid arthritis (RA) is an autoimmune arthropathy characterized by chronic articular inflammation. Methotrexate (MTX) remains the first-line therapy for RA and its anti-inflammatory effect is associated with the maintenance of high levels of extrac...
Source: Journal of Autoimmunity - February 6, 2018 Category: Allergy & Immunology Authors: Peres RS, Donate PB, Talbot J, Cecilio NT, Lobo PR, Machado CC, Lima KWA, Oliveira RD, Carregaro V, Nakaya HI, Cunha TM, Alves-Filho JC, Liew FY, Louzada-Junior P, Cunha FQ Tags: J Autoimmun Source Type: research

T cells are influenced by a long non-coding RNA in the autoimmune associated PTPN2 locus.
Padyukov L Abstract Non-coding SNPs in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) locus have been linked with several autoimmune diseases, including rheumatoid arthritis, type I diabetes, and inflammatory bowel disease. However, the functional consequences of these SNPs are poorly characterized. Herein, we show in blood cells that SNPs in the PTPN2 locus are highly correlated with DNA methylation levels at four CpG sites downstream of PTPN2 and expression levels of the long non-coding RNA (lncRNA) LINC01882 downstream of these CpG sites. We observed that LINC01882 is mainly expressed in T cells ...
Source: Journal of Autoimmunity - February 2, 2018 Category: Allergy & Immunology Authors: Houtman M, Shchetynsky K, Chemin K, Hensvold AH, Ramsköld D, Tandre K, Eloranta ML, Rönnblom L, Uebe S, Catrina AI, Malmström V, Padyukov L Tags: J Autoimmun Source Type: research

Predicting progression to diabetes in islet autoantibody positive children.
The objective of this study was to explore less costly and less time-consuming options. All children being prospectively followed by the Diabetes Autoimmunity Study in the Young (DAISY) who had a complete baseline OGTT and at least one confirmed islet autoantibody (Ab+) were included in this study (n = 68). Of 68 Ab+ subjects with a baseline OGTT, 25 developed diabetes after a mean follow-up 5.7 yrs, at a mean age of 12.4 yrs. Univariate proportional hazards (PH) models suggested that age at seroconversion, number of Ab+, IA-2A levels, HbA1c and metabolic variables from the OGTT predicted progressi...
Source: Journal of Autoimmunity - January 27, 2018 Category: Allergy & Immunology Authors: Steck AK, Dong F, Frohnert BI, Waugh K, Hoffman M, Norris JM, Rewers MJ Tags: J Autoimmun Source Type: research

Th17  cells, γδ T cells and their interplay in EAE and multiple sclerosis.
Th17 cells, γδ T cells and their interplay in EAE and multiple sclerosis. J Autoimmun. 2018 Jan 21;: Authors: McGinley AM, Edwards SC, Raverdeau M, Mills KHG Abstract Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) that shares many features with the human disease. This review will focus on the role of IL-17-secreting CD4 and γδ T cells in EAE and MS, the plasticity of Th17 cells in vivo and the application of these findings to the understating of the pathogenesis and the development of new treatments for MS. There is convin...
Source: Journal of Autoimmunity - January 21, 2018 Category: Allergy & Immunology Authors: McGinley AM, Edwards SC, Raverdeau M, Mills KHG Tags: J Autoimmun Source Type: research

Treg-specific deletion of NKAP results in severe, systemic autoimmunity due to peripheral loss of Tregs.
Abstract Regulatory T cells are critical for the generation and maintenance of peripheral tolerance. Conditional deletion of the transcriptional repressor NKAP in Tregs using Foxp3-YFP-cre NKAP conditional knockout mice causes aggressive autoimmunity characterized by thymic atrophy, lymphadenopathy, peripheral T cell activation, generation of autoantibodies, immune infiltration into several organs, and crusty skin at 3 weeks of age, similar to that of "scurfy" Foxp3-mutant mice. While Treg development in the thymus proceeds normally in the absence of NKAP, there is a severe loss of thymically-derived Tre...
Source: Journal of Autoimmunity - January 20, 2018 Category: Allergy & Immunology Authors: Dash B, Shapiro MJ, Chung JY, Romero Arocha S, Shapiro VS Tags: J Autoimmun Source Type: research

Current concerns and perspectives on Zika virus co-infection with arboviruses and HIV.
Abstract Dissemination of vector-borne viruses, such as Zika virus (ZIKV), in tropical and sub-tropical regions has a complicated impact on the immunopathogenesis of other endemic viruses such as dengue virus (DENV), chikungunya virus (CHIKV) and human immunodeficiency virus (HIV). The consequences of the possible co-infections with these viruses have specifically shown significant impact on the treatment and vaccination strategies. ZIKV is a mosquito-borne flavivirus from African and Asian lineages that causes neurological complications in infected humans. Many of DENV and CHIKV endemic regions have been experien...
Source: Journal of Autoimmunity - January 16, 2018 Category: Allergy & Immunology Authors: Rothan HA, Bidokhti MRM, Byrareddy SN Tags: J Autoimmun Source Type: research

Expression level of risk genes of MHC class II is a susceptibility factor for autoimmunity: New insights.
Abstract To date, the study of the impact of major hystocompatibility complex on autoimmunity has been prevalently focused on structural diversity of MHC molecules in binding and presentation of (auto)antigens to cognate T cells. Recently, a number of experimental evidences suggested new points of view to investigate the complex relationships between MHC gene expression and the individual predisposition to autoimmune diseases. Irrespective of the nature of the antigen, a threshold of MHC-peptide complexes needs to be reached, as well as a threshold of T cell receptors engaged is required, for the activation and pr...
Source: Journal of Autoimmunity - January 10, 2018 Category: Allergy & Immunology Authors: Gianfran C, Pisapia L, Picascia S, Strazzullo M, Del Pozzo G Tags: J Autoimmun Source Type: research

Th17-lineage cells in pulmonary sarcoidosis and L öfgren's syndrome: Friend or foe?
Th17-lineage cells in pulmonary sarcoidosis and Löfgren's syndrome: Friend or foe? J Autoimmun. 2018 Jan 05;: Authors: Miedema JR, Kaiser Y, Broos CE, Wijsenbeek MS, Grunewald J, Kool M Abstract Sarcoidosis, a multisystem granulomatous disorder, has historically been classified as Th1-driven disease. However, increasing data demonstrate a key role of Th17-cell plasticity in granuloma formation and maintenance. In Löfgren's syndrome (LS), an acute and distinct phenotype of sarcoidosis with a favorable outcome, differences in Th17-lineage cell subsets, cytokine expression and T-cell suppressiv...
Source: Journal of Autoimmunity - January 5, 2018 Category: Allergy & Immunology Authors: Miedema JR, Kaiser Y, Broos CE, Wijsenbeek MS, Grunewald J, Kool M Tags: J Autoimmun Source Type: research

Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.
In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip. Cox proportional hazards analyses were performed to discover the SNPs associated with the risk for IA, T1D, or both. Three regions were associated with the risk of developing any persistent confirmed islet autoantibody: one known region near SH2B3 (HR = 1.35, p = 3.58 × 10-7) with Bonferroni-corrected significance and another known region near PTPN22 (HR = 1.46, p = 2.17 × 10-6) and one n...
Source: Journal of Autoimmunity - January 5, 2018 Category: Allergy & Immunology Authors: Sharma A, Liu X, Hadley D, Hagopian W, Chen WM, Onengut-Gumuscu S, Törn C, Steck AK, Frohnert BI, Rewers M, Ziegler AG, Lernmark Å, Toppari J, Krischer JP, Akolkar B, Rich SS, She JX, TEDDY Study Group Tags: J Autoimmun Source Type: research

CD8+ T cells and IFN- γ induce autoimmune myelofibrosis in mice.
In conclusion, our results demonstrate that CD8+ T cells and IFN-γ are associated with autoimmune myelofibrosis, a finding that may allow targeting of CD8+ T cells and IFN-γ as a therapeutic targets. PMID: 29307587 [PubMed - as supplied by publisher] (Source: Journal of Autoimmunity)
Source: Journal of Autoimmunity - January 4, 2018 Category: Allergy & Immunology Authors: Yao Y, Li L, Yang SH, Gao CY, Liao LH, Xie YQ, Yin XY, Yang YQ, Fei YY, Lian ZX Tags: J Autoimmun Source Type: research

Autoantibodies against podocytic UCHL1 are associated with idiopathic nephrotic syndrome relapses and induce proteinuria in mice.
es G Abstract Idiopathic steroid sensitive nephrotic syndrome (INS), the most frequent childhood nephropathy, is thought to be mediated by a circulating soluble factor that reversibly affects the renal protein sieving. The efficiency of rituximab therapy recently highlighted the involvement of B cells. Here we studied the involvement of a specific immunoglobulin G (IgG) in the disease. After plasma fractionation by size exclusion chromatography, a detachment of cultured podocyte was observed with one IgG-containing fraction from 47% patients in relapse, 9% of patients in remission and 0% of controls. Podocyte prot...
Source: Journal of Autoimmunity - January 4, 2018 Category: Allergy & Immunology Authors: Jamin A, Berthelot L, Couderc A, Chemouny JM, Boedec E, Dehoux L, Abbad L, Dossier C, Daugas E, Monteiro RC, Deschênes G Tags: J Autoimmun Source Type: research

Pathogenic IgG4 autoantibodies from endemic pemphigus foliaceus recognize a desmoglein-1 conformational epitope.
Abstract Fogo Selvagem (FS), the endemic form of pemphigus foliaceus, is mediated by pathogenic IgG4 autoantibodies against the amino-terminal extracellular cadherin domain of the desmosomal cadherin desmoglein 1 (Dsg1). Here we define the detailed epitopes of these pathogenic antibodies. Proteolytic footprinting showed that IgG4 from 95% of FS donor sera (19/20) recognized a 16-residue peptide (A129LNSMGQDLERPLELR144) from the EC1 domain of Dsg1 that overlaps the binding site for an adhesive-partner desmosomal cadherin molecule. Mutation of Dsg1 residues M133 and Q135 reduced the binding of FS IgG4 autoantibodies...
Source: Journal of Autoimmunity - January 4, 2018 Category: Allergy & Immunology Authors: Evangelista F, Roth AJ, Prisayanh P, Temple BR, Li N, Qian Y, Culton DA, Liu Z, Harrison OJ, Brasch J, Honig B, Shapiro L, Diaz LA Tags: J Autoimmun Source Type: research

Th17 plasticity and its relevance to inflammatory bowel disease.
Abstract It is now clear that previously polarized T cells possess the ability to change their phenotype and repolarize towards different fates. This intrinsic flexibility is commonly referred to as plasticity and is influenced by the cytokine milieu, microbial products and products of metabolism which, in turn, regulate transcription factors and epigenetic machinery in the intestinal lamina propria. The intestinal immune system faces a particularly difficult challenge. It serves to protect the largest mucosal surface against infection and injury while maintaining a state of tolerance towards dietary antigens and ...
Source: Journal of Autoimmunity - December 28, 2017 Category: Allergy & Immunology Authors: Ueno A, Jeffery L, Kobayashi T, Hibi T, Ghosh S, Jijon H Tags: J Autoimmun Source Type: research

A cellular and molecular view of T helper 17  cell plasticity in autoimmunity.
A cellular and molecular view of T helper 17 cell plasticity in autoimmunity. J Autoimmun. 2017 Dec 21;: Authors: Stadhouders R, Lubberts E, Hendriks RW Abstract Since the original identification of the T helper 17 (Th17) subset in 2005, it has become evident that these cells do not only contribute to host defence against pathogens, such as bacteria and fungi, but that they are also critically involved in the pathogenesis of many autoimmune diseases. In contrast to the classic Th1 and Th2 cells, which represent rather stably polarized subsets, Th17 cells display remarkable heterogeneity and ...
Source: Journal of Autoimmunity - December 21, 2017 Category: Allergy & Immunology Authors: Stadhouders R, Lubberts E, Hendriks RW Tags: J Autoimmun Source Type: research

Plasticity and heterogeneity of Th17 in immune-mediated kidney diseases.
Abstract Anti-neutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis, anti-glomerular basement membrane (GBM) glomerulonephritis and lupus nephritis are the most common causes of rapid progressive glomerulonephritis (RPGN) in the Western world. These aggressive forms of autoimmune kidney diseases significantly contribute to end-stage renal disease and are associated with high morbidity and mortality. Moreover, patients show significant heterogeneity with respect to clinical outcome and response to therapy. T cell infiltration is a morphological hallmark of RPGN and it is a critical driver of kidney...
Source: Journal of Autoimmunity - December 21, 2017 Category: Allergy & Immunology Authors: Krebs CF, Panzer U Tags: J Autoimmun Source Type: research

Critical role of ROCK2 activity in facilitating mucosal CD4+ T cell activation in inflammatory bowel disease.
In this study, we demonstrated that the levels of ROCK2, but not ROCK1, activity were significantly upregulated in peripheral blood mononuclear cells (PBMC) and inflamed mucosa from IBD patients using a ROCK activity assay, and that ROCK2 activity in intestinal mucosa was positively correlated with disease severity. Stimulation with TNF markedly upregulated ROCK2 activity in IBD CD4+ T cells through NF-κB signaling. Blockade of ROCK2 activity using Slx-2119 significantly suppressed proinflammatory cytokines in inflamed mucosa from IBD patients including IFX-unresponsive CD patients, and inhibited IBD CD4+ T cells to ...
Source: Journal of Autoimmunity - December 19, 2017 Category: Allergy & Immunology Authors: Yang W, Zhou G, Yu T, Chen L, Yu L, Guo Y, Cong Y, Liu Z Tags: J Autoimmun Source Type: research

Tolerogenic Ag-PLG nanoparticles induce tregs to suppress activated diabetogenic CD4 and CD8 T cells.
Abstract Type 1 diabetes (T1D) is mediated by destruction of pancreatic β cells by autoantigen-specific CD4+ and CD8+ T cells, thus the ideal solution for T1D is the restoration of immune tolerance to β cell antigens. We demonstrate the ability of carboxylated 500 nm biodegradable poly(lactide-co-glycolide) (PLG) nanoparticles PLG nanoparticles (either surface coupled with or encapsulating the cognate diabetogenic peptides) to rapidly and efficiently restore tolerance in NOD.SCID recipients of both activated diabetogenic CD4+ BDC2.5 chromagranin A-specific and CD8+ NY8.3 islet-specific glucose-6-pho...
Source: Journal of Autoimmunity - December 16, 2017 Category: Allergy & Immunology Authors: Prasad S, Neef T, Xu D, Podojil JR, Getts DR, Shea LD, Miller SD Tags: J Autoimmun Source Type: research

Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumatoid arthritis.
Abstract T helper 17 (Th17) cells are important mediators of immune responses against extracellular bacteria and fungi, and as such play critical regulatory roles in maintaining mucosal homeostasis. Conversely, Th17 cells and their effector molecules interleukin 17A (IL-17A), IL-17F, interferon (IFN)γ, tumor necrosis factor (TNF)α, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are implicated in the pathology of rheumatoid arthritis (RA). Interactions between Th17 cells and other immune cells or stromal cells that are present in the synovial tissue during the earliest phases of the disea...
Source: Journal of Autoimmunity - December 15, 2017 Category: Allergy & Immunology Authors: van Hamburg JP, Tas SW Tags: J Autoimmun Source Type: research

Immune responses to peptides containing homocitrulline or citrulline in the DR4-transgenic mouse model of rheumatoid arthritis.
In conclusion, DR4tg mice immunized with HomoCitJED developed immune responses to CitJED, indicating cross-reactivity. CitJED immune responses were dependent on the SE. HomoCitJED responses occurred in the absence of the SE (B6 mice); however, they developed earlier in DR4tg SE-expressing mice. PMID: 29242008 [PubMed - as supplied by publisher] (Source: Journal of Autoimmunity)
Source: Journal of Autoimmunity - December 11, 2017 Category: Allergy & Immunology Authors: Lac P, Saunders S, Tutunea-Fatan E, Barra L, Bell DA, Cairns E Tags: J Autoimmun Source Type: research

Activation of thyroid antigen-reactive B cells in recent onset autoimmune thyroid disease patients.
In this study, we analyzed the phenotype of thyroid antigen-reactive B cells in the peripheral blood of recent onset and long standing AITD patients. We found that in recent onset patients thyroid antigen-reactive B cells in blood no longer appear anergic, rather they express CD86, a marker of activation. This likely reflects activation of these cells leading to their production of autoantibodies. Hence, this study reports the early loss of anergy in thyroid antigen-reactive B cells, an event that contributes to development of AITD. PMID: 29233566 [PubMed - as supplied by publisher] (Source: Journal of Autoimmunity)
Source: Journal of Autoimmunity - December 9, 2017 Category: Allergy & Immunology Authors: Smith MJ, Rihanek M, Coleman BM, Gottlieb PA, Sarapura VD, Cambier JC Tags: J Autoimmun Source Type: research

Allele-specific methylation of type 1 diabetes susceptibility genes.
Abstract The susceptibility to autoimmune diseases is influenced by genes encoding major histocompatibility complex (MHC) proteins. By examining the epigenetic methylation maps of cord blood samples, we found marked differences in the methylation status of CpG sites within the MHC genes (cis-metQTLs) between carriers of the type 1 diabetes risk haplotypes HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and HLA-DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8). These differences were found in children and adults, and were accompanied by reduced HLA-DR protein expression in immune cells with the HLA-DR3-DQ2 haplotype. Extensive cis-m...
Source: Journal of Autoimmunity - December 7, 2017 Category: Allergy & Immunology Authors: Kindt ASD, Fuerst RW, Knoop J, Laimighofer M, Telieps T, Hippich M, Woerheide MA, Wahl S, Wilson R, Sedlmeier EM, Hommel A, Todd JA, Krumsiek J, Ziegler AG, Bonifacio E Tags: J Autoimmun Source Type: research

Innately versatile: γδ17 T cells in inflammatory and autoimmune diseases.
Innately versatile: γδ17 T cells in inflammatory and autoimmune diseases. J Autoimmun. 2017 Dec 01;: Authors: Papotto PH, Reinhardt A, Prinz I, Silva-Santos B Abstract IL-17-producing γδ (γδ17) T cells form a versatile subset of cells that respond rapidly to innate stimuli and support the pro-inflammatory functions of different myeloid and lymphoid lineages, being particularly critical in the early stages of inflammatory and autoimmune responses. In mice, under homeostatic conditions, these innate-like lymphocytes are pre-programmed in the fetal thymus, through...
Source: Journal of Autoimmunity - December 1, 2017 Category: Allergy & Immunology Authors: Papotto PH, Reinhardt A, Prinz I, Silva-Santos B Tags: J Autoimmun Source Type: research

Th17  cells in primary Sjögren's syndrome: Pathogenicity and plasticity.
Th17 cells in primary Sjögren's syndrome: Pathogenicity and plasticity. J Autoimmun. 2017 Nov 27;: Authors: Verstappen GM, Corneth OBJ, Bootsma H, Kroese FGM Abstract Th17 cells play an important physiological role at mucosal barriers, and are involved in inflammatory responses to pathogens. Th17 cells and their signature cytokine IL-17 are also present in salivary gland lesions of primary Sjögren's syndrome (pSS) patients and can be elevated in their peripheral blood. In pSS patients, clear correlations between increased Th17 cell activity and symptoms of the disease hav...
Source: Journal of Autoimmunity - November 27, 2017 Category: Allergy & Immunology Authors: Verstappen GM, Corneth OBJ, Bootsma H, Kroese FGM Tags: J Autoimmun Source Type: research

Excessive interferon- α signaling in autoimmunity alters glycosphingolipid processing in B cells.
Excessive interferon-α signaling in autoimmunity alters glycosphingolipid processing in B cells. J Autoimmun. 2017 Nov 27;: Authors: Tan AH, Sanny A, Ng SW, Ho YS, Basri N, Lee AP, Lam KP Abstract Excessive interferon-α (IFN-α) production by innate immune cells is a hallmark of autoimmune diseases. What other cell type secretes IFN-α and how IFN-α affects immune cell metabolism and homeostasis in autoimmunity are largely unclear. Here, we report that autoimmune B cells, arising from two different B cell-specific genetic lesions in mice, secrete IFN-α. In addition, I...
Source: Journal of Autoimmunity - November 27, 2017 Category: Allergy & Immunology Authors: Tan AH, Sanny A, Ng SW, Ho YS, Basri N, Lee AP, Lam KP Tags: J Autoimmun Source Type: research

Tick-borne diseases and autoimmunity: A comprehensive review.
ya JM Abstract Tick-borne diseases (TBDs) are emerging and reemerging diseases transmitted by ticks, which portray wide heterogeneity and global distribution. TBDs may present acute clinical pictures that resemble those of autoimmune diseases (i.e., musculoskeletal symptoms, cutaneous involvement, neurologic impairment, renal failure, etc.), and in some cases infection is considered a triggering factor for autoimmunity (e.g., rheumatoid arthritis, autoimmune thyroid disease, vasculitides). The clinician should consider TBDs among the differential diagnoses when approaching autoimmune-like signs in areas of tick in...
Source: Journal of Autoimmunity - November 25, 2017 Category: Allergy & Immunology Authors: Rodríguez Y, Rojas M, Gershwin ME, Anaya JM Tags: J Autoimmun Source Type: research

Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in  vivo.
Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo. J Autoimmun. 2017 Nov 25;: Authors: Maschmeyer P, Petkau G, Siracusa F, Zimmermann J, Zügel F, Kühl AA, Lehmann K, Schimmelpfennig S, Weber M, Haftmann C, Riedel R, Bardua M, Heinz GA, Tran CL, Hoyer BF, Hiepe F, Herzog S, Wittmann J, Rajewsky N, Melchers FG, Chang HD, Radbruch A, Mashreghi MF Abstract In T lymphocytes, expression of miR-148a is induced by T-bet and Twist1, and is specific for pro-inflammatory Th1 cells. In these cells, miR-148a inhibits the expression of the pro-apoptotic pr...
Source: Journal of Autoimmunity - November 25, 2017 Category: Allergy & Immunology Authors: Maschmeyer P, Petkau G, Siracusa F, Zimmermann J, Zügel F, Kühl AA, Lehmann K, Schimmelpfennig S, Weber M, Haftmann C, Riedel R, Bardua M, Heinz GA, Tran CL, Hoyer BF, Hiepe F, Herzog S, Wittmann J, Rajewsky N, Melchers FG, Chang HD, Radbruch A, Mashreg Tags: J Autoimmun Source Type: research

Decrease of galectin-3 in keratinocytes: A potential diagnostic marker and a critical contributor to the pathogenesis of psoriasis.
We report here that epidermal galectin-3 expression is significantly downregulated in lesional skin, but not in non-lesional skin in psoriasis patients, nor in a group of diseases known as psoriasiform dermatitis clinically and histologically similar to psoriasis. The deficiency of epidermal galectin-3 is sufficient to promote development of psoriatic lesions, as evidenced by more severe skin inflammation in galectin-3 knockout (gal3(-/-)) mice, compared to wild-type mice, after imiquimod treatment, and in skin from gal3(-/-) mice grafted onto wildtype mice. The development of psoriatic-like lesions is attributable to 1) t...
Source: Journal of Autoimmunity - November 20, 2017 Category: Allergy & Immunology Authors: Shi ZR, Tan GZ, Cao CX, Han YF, Meng Z, Man XY, Jiang ZX, Zhang YP, Dang NN, Wei KH, Bu DF, Liu FT, Wang L Tags: J Autoimmun Source Type: research

Signaling via toll-like receptor 4 and CD40 in B cells plays a regulatory role in the pathogenesis of multiple sclerosis through interleukin-10 production.
CONCLUSIONS: Cross-talk between TLR4 and CD40 signaling plays a crucial role in regulating IL-10 production by B cells during MS relapses, which may promote recovery from relapse. CD40 signaling in B cells is involved in the response to interferon-β in MS. Collectively, TLR4 and CD40 signaling in B cells may provide a promising target for MS therapy. PMID: 29146546 [PubMed - as supplied by publisher] (Source: Journal of Autoimmunity)
Source: Journal of Autoimmunity - November 13, 2017 Category: Allergy & Immunology Authors: Okada Y, Ochi H, Fujii C, Hashi Y, Hamatani M, Ashida S, Kawamura K, Kusaka H, Matsumoto S, Nakagawa M, Mizuno T, Takahashi R, Kondo T Tags: J Autoimmun Source Type: research

A gene module associated with dysregulated TCR signaling pathways in CD4(+) T cell subsets in rheumatoid arthritis.
Abstract We analyzed the transcriptome of detailed CD4(+) T cell subsets including them after abatacept treatment, and examined the difference among CD4(+) T cell subsets and identified gene sets that are closely associated disease activity and abatacept treatment. Seven CD4(+) T cell subsets (naive, Th1, Th17, Th1/17, nonTh1/17, Tfh and Treg) were sorted from PBMCs taken from 10 RA patients and 10 healthy controls, and three RA patients donated samples before and 6 months after abatacept treatment. Paired-end RNA sequencing was performed using HiSeq 2500. A total of 149 samples except for 12 outliers were analyze...
Source: Journal of Autoimmunity - November 13, 2017 Category: Allergy & Immunology Authors: Sumitomo S, Nagafuchi Y, Tsuchida Y, Tsuchiya H, Ota M, Ishigaki K, Nakachi S, Kato R, Sakurai K, Hanata N, Tateishi S, Kanda H, Suzuki A, Kochi Y, Fujio K, Yamamoto K Tags: J Autoimmun Source Type: research

Dominant-negative loss of function arises from a second, more frequent variant within the SAND domain of autoimmune regulator (AIRE).
Abstract A genetic variant in the SAND domain of autoimmune regulator (AIRE), R247C, was identified in a patient with type I diabetes mellitus (T1DM) and his mother with rheumatoid arthritis. In vitro, the variant dominantly inhibited AIRE; however, typical features of Autoimmune Polyendocrinopathy Candidiasis and Ectodermal Dysplasia (APECED) were not seen in the subjects. Rather, early manifestation of autoimmunity appeared to be dependent on additional genetic factors. On a population level, diverse variants were identified in this region. Surprisingly, many likely pathogenic variants were seen disproporti...
Source: Journal of Autoimmunity - November 9, 2017 Category: Allergy & Immunology Authors: Abbott JK, Huoh YS, Reynolds PR, Yu L, Rewers M, Reddy M, Anderson MS, Hur S, Gelfand EW Tags: J Autoimmun Source Type: research

CCR6 signaling inhibits suppressor function of induced-Treg during gut inflammation.
In conclusion, we have identified a new role of CCR6 signaling in the differentiation of iTregs during inflammation and gut autoimmunity. PMID: 29126851 [PubMed - as supplied by publisher] (Source: Journal of Autoimmunity)
Source: Journal of Autoimmunity - November 7, 2017 Category: Allergy & Immunology Authors: Kulkarni N, Meitei HT, Sonar SA, Sharma PK, Mujeeb VR, Srivastava S, Boppana R, Lal G Tags: J Autoimmun Source Type: research

Autophagy dysfunction in autoinflammatory diseases.
Abstract Autoinflammatory diseases (AUIDs) are a genetically heterogeneous group of rheumatic diseases characterized by episodic inflammation linked with dysregulated innate immune responses. In this review, we summarize the molecular mechanisms altered by disease-associated variants in several AUIDs, including NOD2-associated diseases, TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), and highlight the roles dysregulated autophagy plays in disease pathogenesis. Autophagy is a conserved eukaryotic pathway for the ...
Source: Journal of Autoimmunity - November 3, 2017 Category: Allergy & Immunology Authors: Hua Y, Shen M, McDonald C, Yao Q Tags: J Autoimmun Source Type: research

CD39 and CD73 activity are protective in a mouse model of antiphospholipid antibody-induced miscarriages.
CONCLUSION: We demonstrate a protective role for CD39 in APS and provide rationale for both the development of endothelial cell-targeted soluble CD39 as a novel therapeutic for APS and analysis of perturbations in the purinergic pathway to explain human disease. PMID: 29103803 [PubMed - as supplied by publisher] (Source: Journal of Autoimmunity)
Source: Journal of Autoimmunity - November 2, 2017 Category: Allergy & Immunology Authors: Samudra AN, Dwyer KM, Selan C, Freddi S, Murray-Segal L, Nikpour M, Hickey MJ, Peter K, Robson SC, Sashindranath M, Cowan PJ, Nandurkar HH Tags: J Autoimmun Source Type: research

"NETtling" the host: Breaking of tolerance in chronic inflammation and chronic infection.
"NETtling" the host: Breaking of tolerance in chronic inflammation and chronic infection. J Autoimmun. 2017 Oct 31;: Authors: Skopelja-Gardner S, Jones JD, Rigby WFC Abstract How and why we break tolerance to self-proteins still remains a largely unanswered question. Neutrophils have been identified as a rich source of autoantigens in a wide array of autoimmune diseases that arise as a consequence of different environmental and genetic factors, e.g. rheumatoid arthritis (RA), lupus, vasculitis, cystic fibrosis (CF) etc. Specifically, neutrophil extracellular trap (NET) formation has been ide...
Source: Journal of Autoimmunity - October 31, 2017 Category: Allergy & Immunology Authors: Skopelja-Gardner S, Jones JD, Rigby WFC Tags: J Autoimmun Source Type: research

Wandering pathways in the regulation of innate immunity and inflammation.
Abstract Tumor-associated macrophages (TAM) have served as a paradigm of cancer-related inflammation. Moreover, investigations on TAM have led to the dissection of macrophage plasticity and polarization and to the discovery and analysis of molecular pathways of innate immunity, in particular cytokines, chemokines and PTX3 as a prototypic fluid phase pattern recognition molecule. Mechanisms of negative regulation are complex and include decoy receptors, receptor antagonists, anti-inflammatory cytokines and the signalling regulator IL-1R8. In this review, topics and open issues in relation to regulation of innate im...
Source: Journal of Autoimmunity - October 24, 2017 Category: Allergy & Immunology Authors: Mantovani A Tags: J Autoimmun Source Type: research

Defective regulation of L1 endogenous retroelements in primary Sjogren's syndrome and systemic lupus erythematosus: Role of methylating enzymes.
CONCLUSION: Our data support a contributory role of altered methylation mechanisms in the pathogenesis of systemic autoimmune disorders and related lymphoproliferative processes and suggest that LSH and DNMT3A should be investigated as candidate upstream mediators of decreased L1 promoter methylation and increased L1 expression. PMID: 29074164 [PubMed - as supplied by publisher] (Source: Journal of Autoimmunity)
Source: Journal of Autoimmunity - October 23, 2017 Category: Allergy & Immunology Authors: Mavragani CP, Nezos A, Sagalovskiy I, Seshan S, Kirou KA, Crow MK Tags: J Autoimmun Source Type: research