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  • The etiology of rheumatoid arthritis
    J. Autoimmun. (IF 7.543) Pub Date : 2020-01-22
    Hans Ulrich Scherer; Thomas Häupl; Gerd R. Burmester

    Rheumatoid arthritis is a heterogeneous disease, which can be, based on data combining genetic risk factors and autoantibodies, sub-classified into ACPA-positive and -negative RA. Presence of ACPA and RF as well as rising CRP-levels in some patients years before onset of clinical symptoms indicate that relevant immune responses for RA development are initiated very early. ACPA are highly specific for RA, whereas RF can also be found among healthy (elderly) individuals and patients with other autoimmune diseases or infection. The most important genetic risk factor for RA development, the shared epitope alleles, resides in the MHC class II region. Shared epitope alleles, however, only predispose to the development of ACPA-positive RA. Smoking is thus far the most important environmental risk factor associated with the development of RA. Studies on synovitis have shown the importance not only of adaptive but also of innate immune responses. In summary of the various results from immunological changes in blood and synovial tissue, the extension of the immune response from a diffuse myeloid to a lympho-myeloid inflammation appears to be associated with a more successful therapeutic response to biologics. With respect to advances in synovitis research, new targets for treatment against pathological subsets of immune cells or fibroblasts are already on the horizon. However, alternative strategies involving the microbiome may play an important role as well and research in this field is growing rapidly.

    更新日期:2020-01-22
  • Cepharanthine blocks TSH receptor peptide presentation by HLA-DR3: Therapeutic implications to Graves’ disease
    J. Autoimmun. (IF 7.543) Pub Date : 2020-01-21
    Cheuk Wun Li; Roman Osman; Francesca Menconi; Erlinda Concepcion; Yaron Tomer

    We have previously identified a signature HLA-DR3 pocket variant, designated HLA-DRβ1-Arg74 that confers a high risk for Graves' Disease (GD). In view of the key role of HLA-DRβ1-Arg74 in triggering GD we hypothesized that thyroid-stimulating hormone receptor (TSHR) peptides that bind to the HLA-DRβ1-Arg74 pocket with high affinity represent key pathogenic TSHR peptides triggering GD, and that blocking their presentation to CD4+ T-cells can be used as a novel therapeutic approach in GD. There were several previous attempts to identify the major pathogenic TSHR peptide utilizing different methodologies, however the results were inconsistent and inconclusive. Therefore, the aim of our study was to use TSHR peptide binding affinity to HLA-DRβ1-Arg74 as a method to identify the key pathogenic TSHR peptides that trigger GD. Using virtual screening and ELISA and cellular binding assays we identified 2 TSHR peptides that bound with high affinity to HLA-DRβ1-Arg74 - TSHR.132 and TSHR.197. Peptide immunization studies in humanized DR3 mice showed that only TSHR.132, but not TSHR.197, induced autoreactive T-cell proliferation and cytokine responses. Next, we induced experimental autoimmune Graves’ disease (EAGD) in a novel BALB/c-DR3 humanized mouse model we created and confirmed TSHR.132 as a major DRβ1-Arg74 binding peptide triggering GD in our mouse model. Furthermore, we demonstrated that Cepharanthine, a compound we have previously identified as DRβ1-Arg74 blocker, could block the presentation and T-cell responses to TSHR.132 in the EAGD model.

    更新日期:2020-01-22
  • EZH2 deficiency attenuates Treg differentiation in rheumatoid arthritis
    J. Autoimmun. (IF 7.543) Pub Date : 2020-01-15
    Xin-yue Xiao; Yue-ting Li; Xu Jiang; Xin Ji; Xin Lu; Bo Yang; Li-jun Wu; Xiao-han Wang; Jing-bo Guo; Li-dan Zhao; Yun-yun Fei; Hua-xia Yang; Wen Zhang; Feng-chun Zhang; Fu-lin Tang; Jian-min Zhang; Wei He; Hua Chen; Xuan Zhang

    The chromatin modifier enhancer of zeste homolog 2 (EZH2) methylates lysine 27 of histone H3 (H3K27) and regulates T cell differentiation. However, the potential role of EZH2 in the pathogenesis of rheumatoid arthritis (RA) remains elusive. We analyzed EZH2 expression in PBMC, CD4+ T cells, CD19+ B cell, and CD14+ monocytes from active treatment-naïve RA patients and healthy controls (HC). We also suppressed EZH2 expression using EZH2 inhibitor GSK126 and measured CD4+ T cell differentiation, proliferation and apoptosis. We further examined TGFβ-SMAD and RUNX1 signaling pathways in EZH2-suppressed CD4+ T cells. Finally, we explored the regulation mechanism of EZH2 by RA synovial fluid and fibroblast-like synoviocyte (FLS) by neutralizing key proinflammatory cytokines. EZH2 expression is lower in PBMC and CD4+ T cells from RA patients than those from HC. EZH2 inhibition suppressed regulatory T cells (Tregs) differentiation and FOXP3 transcription, and downregulated RUNX1 and upregulated SMAD7 expression in CD4+ T cells. RA synovial fluid and fibroblast-like synoviocytes suppressed EZH2 expression in CD4+ T cells, which was partially neutralized by anti-IL17 antibody. Taken together, EZH2 in CD4+ T cells from RA patients was attenuated, which suppressed FOXP3 transcription through downregulating RUNX1 and upregulating SMAD7 in CD4+ T cells, and ultimately suppressed Tregs differentiation. IL17 in RA synovial fluid might promote downregulation of EZH2 in CD4+ T cells. Defective EZH2 in CD4+ T cells might contribute to Treg deficiency in RA.

    更新日期:2020-01-15
  • Treatment of experimental autoimmune encephalomyelitis with engineered bi-specific Foxp3+ regulatory CD4+ T cells
    J. Autoimmun. (IF 7.543) Pub Date : 2020-01-13
    Manish Malviya; Abdelhadi Saoudi; Jan Bauer; Simon Fillatreau; Roland Liblau

    The use of autoantigen-specific regulatory T cells (Tregs) as a cellular therapy for autoimmune diseases is appealing. However, it is challenging to isolate and expand large quantity of Tregs expressing disease-relevant T-cell receptors (TCR). To overcome this problem, we used an approach aiming at redirecting the specificity of polyclonal Tregs through autoreactive TCR gene transfer technology. In this study, we examined whether Tregs engineered through retroviral transduction to express a TCR cross-reactive to two CNS autoantigens, myelin oligodendrocyte glycoprotein (MOG) and neurofilament-medium (NF-M), had a superior protective efficacy compared with Tregs expressing a MOG mono-specific TCR. We observed that engineered Tregs (engTregs) exhibited in vitro regulatory effects related to the antigenic specificity of the introduced TCR, and commensurate in potency with the avidity of the transduced TCR. In experimental autoimmune encephalomyelitis (EAE), adoptively transferred engTregs proliferated, and migrated to the CNS, while retaining FoxP3 expression. EngTregs expressing MOG/NF-M cross-reactive TCR had superior protective properties over engTregs expressing MOG-specific TCR in MOG-induced EAE. Remarkably, MOG/NF-M bi-specific TCR-engTregs also improved recovery from EAE induced by an unrelated CNS autoantigen, proteolipid protein (PLP). This study underlines the benefit of using TCRs cross-reacting towards multiple autoantigens, compared with mono-reactive TCR, for the generation of engTregs affording protection from autoimmune disease in adoptive cell therapy.

    更新日期:2020-01-13
  • Alveolar haemorrhage in ANCA-associated vasculitis: Long-term outcome and mortality predictors
    J. Autoimmun. (IF 7.543) Pub Date : 2020-01-09
    Luca Quartuccio; Milena Bond; Miriam Isola; Sara Monti; Mara Felicetti; Federica Furini; Stefano Murgia; Alvise Berti; Elena Silvestri; Giulia Pazzola; Enrica Bozzolo; Pietro Leccese; Bernd Raffeiner; Simone Parisi; Ilaria Leccese; Francesco Cianci; Silvano Bettio; Pierpaolo Sainaghi; Salvatore De Vita

    Introduction Alveolar haemorrhage (AH) is considered an important cause of morbidity and early mortality in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV). Objectives The aim of this study was to identify predictors of outcome in patients with AH-AAV and to evaluate outcome and causes of death in this subset. Materials and methods A multicenter retrospective study was conducted in 29 Italian Centers. Clinicians were asked to recruit all patients diagnosed with AAV-associated AH during the last 10 years, from 2007 to 2016. Univariate and multivariable analysis were performed. Results One-hundred and six patients were included (median age at onset of 55 years [IQR 42–67]). The majority were ANCA-positive (PR3 57.1%, MPO 33.7%) and 72.6% had also renal involvement. At presentation, anaemia was shown in 97 (92.4%) patients, hemoptysis in 54 (51.9%), respiratory failure in 68 (66.7%), of whom 48 (70.6%), requiring respiratory support. At the end of the 37 months [IQR 13–77] follow-up, 19/106 (17.9%) patients were dead. The main causes of death were active disease and infections. By stepwise regression analysis, age >65 years (HR 3.66 [95% CI 1.4–9.51], p = 0.008) and the need for respiratory support (HR 4.58 [95% CI 1.51–13.87], p = 0.007) at AH onset were confirmed to be predictive of mortality. Conclusions Predictors of outcome in AAV-AH were determined. Factors related to the patient's performance status and the severity of the lung involvement strongly influenced the outcome. Balancing harms and benefits for the individual patient in induction and maintenance treatment strategies is crucial.

    更新日期:2020-01-09
  • Treat to target in axial spondyloarthritis: From its concept to its implementation
    J. Autoimmun. (IF 7.543) Pub Date : 2020-01-08
    Maxime Dougados

    Treat to target is defined by a process defining a level of a relevant outcome of the disease to be reached in order to prevent subsequent disability The benefit of a Treat to Target strategy has been clearly demonstrated in chronic diseases such as diabetes and hypertension. A better knowledge of the natural history of chronic inflammatory rheumatic diseases including axial spondyloarthritis has emphasized the deleterious long term effect of a sustained inflammation, usually evaluated by disease activity markers. The Treat to Treat strategy in axial spondyloarthritis has emerged since the possibility of getting treatments not only capable to improve the current symptomatic situation of the patient but also to prevent further deleterious irreversible hard endpoints such as disability due to structural damage or important comorbidities such as renal failure or cardiovascular diseases. This is particularly the case for the “conventional” biologics (e.g. TNF blockers) with an experience in daily practice for at least two decades but also for more recent biologics (e.g. anti IL17 inhibitors) and for some promising targeted synthetic Disease Modifying AntiRheumatics Drugs (e.g. JAK kinase inhibitors) moreover, a part from the abrogation of inflammation, other targets can be considered such as smoking cessation, NSAID intake reduction or treatment of predisposing factors of cardiovascular diseases (e. g. hypertension, …). A Treat to Target strategy in axial spondyloarthritis has to consider the following different components:the stages of the disease, the risks of the disease, the reversible predisposing factors of the risks of the disease, the optimal threshold of the outcome measures evaluating the predisposing factors (TARGET), the time to reach the target and the necessity to maintain this success (sustainability). Moreover, the different methods/initiatives facilitating the implementation of a Treat to Target strategy in rheumatological daily practice have also to be considered (level of evidence, international recommendations, importance of the patient's participation, …).

    更新日期:2020-01-09
  • A comprehensive analysis of the clinical characteristics and laboratory features in 179 patients with autoimmune autonomic ganglionopathy
    J. Autoimmun. (IF 7.543) Pub Date : 2020-01-08
    Shunya Nakane; Akihiro Mukaino; Osamu Higuchi; Maeda Yasuhiro; Koutaro Takamatsu; Makoto Yamakawa; Mari Watari; Nozomu Tawara; Kei-ichi Nakahara; Atsushi Kawakami; Hidenori Matsuo; Yukio Ando
    更新日期:2020-01-08
  • Cell-autonomous epithelial activation of AIM2 (absent in melanoma-2) inflammasome by cytoplasmic DNA accumulations in primary Sjögren's syndrome
    J. Autoimmun. (IF 7.543) Pub Date : 2020-01-07
    Aigli G. Vakrakou; Ioanna P. Svolaki; Konstantinos Evangelou; Vassilis G. Gorgoulis; Menelaos N. Manoussakis

    Primary Sjögren's syndrome (SS) is characterized by chronic periductal inflammatory infiltrates in the salivary glands. Several previous studies have indicated that the ductal epithelia of SS patients play a pro-inflammatory role and manifest an intrinsically activated status, as demonstrated in cultured non-neoplastic ductal salivary gland epithelial cell (SGEC) lines. Herein, we investigated the activation of inflammasomes in the salivary epithelia of SS patients and non-SS controls, using salivary biopsy tissues and SGEC lines. The ductal epithelial cells of SS patients were found to display significant activation of the AIM2 (absent in melanoma-2) inflammasome. Such activation occurred in a cell-autonomous manner, as it was illustrated by the constitutively high expression of AIM2 activation-related genes, the presence of cytoplasmic ASC specks and the increased spontaneous IL-1β production observed in patients' SGEC lines. Since AIM2 activation is known to occur in response to cytoplasmic DNA, we further searched for the presence of undegraded extranuclear DNA in the SGEC lines and SG tissues of patients and controls. This investigation revealed marked cytoplasmic accumulations of damaged genomic DNA that co-localized with AIM2 in the specimens of SS patients (but not controls). The SGEC lines and the ductal tissues of SS patients were also found to manifest impaired DNase1 expression and activity, which possibly denotes defective cytoplasmic DNA degradation in patients' cells and AIM2 triggering thereof. In corroboration, DNase1-silencing in normal SGEC was shown to lead to high AIM2-related gene expression and IL-1β production. Our findings indicate that the cell-intrinsic activation status of ductal epithelia in SS patients owes to persistent epithelial AIM2 activation by aberrant cytoplasmic DNA build-up.

    更新日期:2020-01-07
  • An overview of autoantibodies in rheumatoid arthritis
    J. Autoimmun. (IF 7.543) Pub Date : 2020-01-03
    Myrthe A.M. van Delft; Tom W.J. Huizinga

    Rheumatoid arthritis (RA) is a systemic auto-immune disease principally effecting synovial joints. RA is characterized by immune cell infiltration in the joint. The presence of autoantibodies is a hallmark for the disease, among these are rheumatoid factor and antibodies against post-translational modified proteins like citrullination (ACPA) and carbamylation (anti-CarP antibodies). These autoantibodies may form immune complexes in the joint, leading to the attraction of immune cells. Based on the presence of these autoantibodies, RA patients can be subdivided in autoantibody positive and negative disease. Both subsets can be associated with genetic and environmental risk factors for RA, like the human leukocyte antigen (HLA) allele and smoking. Autoantibodies can already be detected years before disease onset in a subgroup of patients and at symptom onset a broad isotype spectrum is observed. This suggests that various events occur prior to the development of RA in which the first autoantibodies develop in predisposed individuals. Therefore, the presence of these autoantibodies can be useful in predicting future RA patients. Research on the characteristics and effector function of these autoantibodies is ongoing and will give more knowledge in the inflammatory responses underlying RA. This will give insight in the pathogenic role of autoantibodies in RA. Recent data are suggestive of a role for mucosal surfaces in the development of auto-immune responses associated with (the development of) RA. In conclusion, investigating the potential pathogenic effector functions of autoantibody isotypes and their molecular- and physicochemical-compositions might improve understanding of the disease origin and its underlying immunological processes. This may lead to the development of new therapeutic targets and strategies.

    更新日期:2020-01-04
  • Prevention and cure: The major unmet needs in the management of rheumatoid arthritis
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-31
    Kulveer Mankia; Andrea Di Matteo; Paul Emery

    The outcome of treatment of patients with rheumatoid arthritis (RA) has qualitatively improved in recent years due to better and earlier treatment approaches, and new drugs. It is now generally accepted that the phenotype of RA is the end-point of a disease continuum. Large retrospective studies have identified anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor in the stored serum of patients, years before the development of clinical RA. Recent data suggest mucosal sites such as the oral mucosa (in particular the periodontium), lung and gut may be the sites where auto-immunity is initiated. The role of bacteria at these sites is reviewed. Much recent work has focussed on the role of high resolution imaging namely ultrasound and magnetic resonance imaging in identifying subclinical inflammation in at-risk individuals with early musculoskeletal symptoms (e.g. arthralgia) but without clinical synovitis. Importantly, the first musculoskeletal site involved is usually not the joint (synovium). Sub-clinical disease predicts the onset of clinical arthritis, and its timing, in symptomatic at-risk individuals. These and other predictive markers will be described. The ability to identify patients at-risk of RA before joint involvement has led to interventions aimed at preventing/delaying disease. Once arthritis occurs, rapid remission is the target of therapy. The percentage of patients with RA achieving clinical remission has improved markedly compared with a few decades ago. The optimum outcome is to induce remission sufficiently profound so that therapy can be stopped, without flare, that is drug-free remission, which is effectively cure. Limitations of the tools used to measure remission, the outcome of tapering therapy, and new approaches to achieve successful drug cessation are described. Overall, this article reviews progress towards meeting the unmet needs of prevention/cure.

    更新日期:2019-12-31
  • Disordered cutaneous microbiota in systemic lupus erythematosus
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-26
    Cancan Huang; Xiaoqing Yi; Hai Long; Guiying Zhang; Haijing Wu; Ming Zhao; Qianjin Lu

    The correlation between systemic lupus erythematosus (SLE) and microbiota colonization has been receiving much attention during recent years. Here, we screened the cutaneous bacterial spectrums of 69 SLE patients, 49 healthy controls and 20 dermatomyositis (DM) patients and identified the specific changes of cutaneous microbial composition and abundance in SLE patients. We observed the decreasing diversity in community richness and evenness and the greater heterogeneity in SLE patients compared to healthy controls, which were also different from the cutaneous microbiome of DM patients. The skin microbial community disorders in SLE patients were correlated with several clinical features such as serum low complement level, gender, renal involvement and myositis. According to the Kruskal-Wallis (KW) test, receiver operating characteristic (ROC) curve and LDA Effect Size (LEfSe) analysis, several bacterial taxa such as Staphylococcus, especially Staphylococcus aureus and Staphylococcus epidermidis, were identified to be potential markers for SLE skin lesions. Furthermore, Picrust analysis showed that Staphylococcus aureus infection pathway was significantly enriched and exhibited a strong correlation with genus Staphylococcus in SLE patients. The changes in the composition and abundance of cutaneous microbiota in SLE patients suggest that the microbial dysbiosis is associated with the pathogenesis of SLE, which may be potentially reliable biomarker or therapeutic target for SLE.

    更新日期:2019-12-27
  • Innate immunity as the trigger of systemic autoimmune diseases
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-26
    Victoria Saferding; Stephan Blüml

    The innate immune system consists of a variety of elements controlling and participating in virtually all aspects of inflammation and immunity. It is crucial for host defense, but on the other hand its improper activation is also thought to be responsible for the generation of autoimmunity and therefore diseases such as autoimmune arthritides like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) or inflammatory bowel disease. The innate immune system stands both at the beginning as well as the end of autoimmunity. On one hand, it regulates the activation of the adaptive immune system and the breach of self-tolerance, as antigen presenting cells (APCs), especially dendritic cells, are essential for the activation of naïve antigen specific T cells, a crucial step in the development of autoimmunity. Various factors controlling the function of dendritic cells have been identified that directly regulate lymphocyte homeostasis and in some instances the generation of organ specific autoimmunity. Moreover, microbial cues have been identified that are prerequisites for the generation of several specific autoimmune diseases. On the other hand, the innate immune system is also responsible for mediating the resulting organ damage underlying the clinical symptoms of a given autoimmune disease via production of proinflammatory cytokines that amplify local inflammation and further activate other immune or parenchymal cells in the vicinity, the generation of matrix degrading and proteolytic enzymes or reactive oxygen species directly causing tissue damage. In the last decades, molecular characterization of cell types and their subsets as well as both positive and negative regulators of immunity has led to the generation of various scenarios of how autoimmunity develops, which eventually might lead to the development of targeted interventions for autoimmune diseases. In this review, we try to summarize the elements that are contributing to the initiation and perpetuation of autoimmune responses.

    更新日期:2019-12-27
  • Histone deacetylase 1 (HDAC1): A key player of T cell-mediated arthritis
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-26
    Lisa Göschl; Teresa Preglej; Nicole Boucheron; Victoria Saferding; Lena Müller; Alexander Platzer; Kiyoshi Hirahara; Han-Yu Shih; Johan Backlund; Patrick Matthias; Birgit Niederreiter; Anastasiya Hladik; Maximilian Kugler; Guido A. Gualdoni; Clemens Scheinecker; Sylvia Knapp; Christian Seiser; Rikard Holmdahl; Michael Bonelli

    Rheumatoid Arthritis (RA) represents a chronic T cell-mediated inflammatory autoimmune disease. Studies have shown that epigenetic mechanisms contribute to the pathogenesis of RA. Histone deacetylases (HDACs) represent one important group of epigenetic regulators. However, the role of individual HDAC members for the pathogenesis of arthritis is still unknown. In this study we demonstrate that mice with a T cell-specific deletion of HDAC1 (HDAC1-cKO) are resistant to the development of Collagen-induced arthritis (CIA), whereas the antibody response to collagen type II was undisturbed, indicating an unaltered T cell-mediated B cell activation. The inflammatory cytokines IL-17 and IL-6 were significantly decreased in sera of HDAC1-cKO mice. IL-6 treated HDAC1-deficient CD4+ T cells showed an impaired upregulation of CCR6. Selective inhibition of class I HDACs with the HDAC inhibitor MS-275 under Th17-skewing conditions inhibited the upregulation of chemokine receptor 6 (CCR6) in mouse and human CD4+ T cells. Accordingly, analysis of human RNA-sequencing (RNA-seq) data and histological analysis of synovial tissue samples from human RA patients revealed the existence of CD4+CCR6+ cells with enhanced HDAC1 expression. Our data indicate a key role for HDAC1 for the pathogenesis of CIA and suggest that HDAC1 and other class I HDACs might be promising targets of selective HDAC inhibitors (HDACi) for the treatment of RA.

    更新日期:2019-12-27
  • Recombinant thrombomodulin ameliorates autoimmune vasculitis via immune response regulation and tissue injury protection
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-26
    Kanako Watanabe-Kusunoki; Daigo Nakazawa; Yoshihiro Kusunoki; Takashi Kudo; Fumihiko Hattanda; Saori Nishio; Sakiko Masuda; Utano Tomaru; Takeshi Kondo; Tatsuya Atsumi; Akihiro Ishizu

    Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by necrotizing vasculitis with the presence of pathogenic ANCA. ANCA can potentially cause neutrophil activation and induce neutrophil extracellular traps (NETs), resulting in endothelial damage as well as activation of autoreactive B cells and alternative complement pathway. Recombinant thrombomodulin (rTM) protects the endothelium from vascular injury during disseminated intravascular coagulation, thus we hypothesized that rTM ameliorates necrotizing vasculitis in AAV. In this study, rTM was administered in an experimental AAV rat model. Treatment of experimental AAV rats with rTM improved pulmonary hemorrhage and glomerulonephritis, with a suppression of ANCA production and NETs formation. In addition, in vitro experiments showed that rTM bound to neutrophils via Mac-1 (macrophage-1 antigen) and inhibited ANCA-induced NETs formation accompanied by a suppression of histone citrullination, leading to a protection of the endothelium from NETs toxicity. Additionally, rTM affected lymphocytes leading to the inhibition of pro-inflammatory cytokine/chemokin in PBMC during the antibody production process, which might indirectly be involved in the reduction of pathogenic ANCA. Our data revealed that the rTM could ameliorate autoimmune vasculitis through a combination of different biological mechanisms.

    更新日期:2019-12-27
  • Treg cells in health and autoimmune diseases: New insights from single cell analysis
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-18
    Clemens Scheinecker; Lisa Göschl; Michael Bonelli

    Autoimmune diseases, such as Systemic Lupus Erythematosus (SLE) or Rheumatoid Arthritis (RA) are characterized by the breakdown of immunological tolerance. Defects of regulatory T cells have been described among the various mechanisms, that are important for the development of autoimmune diseases, due to their critical role as regulators of peripheral immune tolerance and homeostasis. Initially T suppressor cells have been described as one population of peripheral T cells. Based on new technological advances a new understanding of the heterogeneity of different Treg cell populations in the lymphoid and non-lymphoid tissue has evolved over the last years. While initially Foxp3 has been defined as the main master regulator of Treg cells, we have learned that Treg cells from various tissue can be identified by a specific transcriptomic and epigenetic signature. Epigenetic mechanisms allow Treg cell stability, but we have also learned that certain Treg subsets are plastic and can under specific circumstances even enhance autoimmunity and inflammatory processes. Quantitative and functional defects of Treg cells have been observed in a variety of autoimmune diseases. Due to our understanding of the nature of this cell population, Treg cells have been a target of new Treg based therapies, such as low-dose IL-2. In addition, ongoing clinical trials aim to test safety and efficacy of transferred, in vitro expanded Treg cells in patients with autoimmune diseases and transplant patients.

    更新日期:2019-12-18
  • Sjögren's syndrome: Old and new therapeutic targets
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-09
    Clio P. Mavragani, Haralampos M. Moutsopoulos

    Sjögren's syndrome (SS) is a prototype autoimmune disease characterized by oral and ocular mucosal dryness following chronic inflammation of salivary and lachrymal glands, respectively. Profound B cell hyperactivity along with systemic manifestations including fatigue, musculoskeletal complaints, features related to hepatic, pulmonary, renal and nervous system involvement, as well as lymphoma development can be also present. Despite that activation of both innate and adaptive immune pathways has been long well documented in SS pathogenesis, systemic immunosuppression in SS, in contrast to other autoimmune diseases, has been largely inefficacious. Biological agents previously implemented in successful therapeutic outcomes in rheumatoid arthritis (RA), such as anti-TNF agents, anakinra, tocilizumab and rituximab failed to reach primary outcomes in randomized double-blind controlled trials in the context of SS. Abatacept and belimumab, already licensed for the treatment of RA and lupus respectively, as well combination regimens of both rituximab and belimumab hold some promise in alleviation of SS-specific complaints, but data from large controlled trials are awaited. Recent advances in dissecting the molecular pathways underlying SS pathogenesis led to an expanding number of novel biological compounds directed towards type I interferon system, antigen presentation, costimulatory pathways, B and T cell activation, as well as germinal center formation. While targeting of cathepsin-S (Petesicatib), inducible costimulator of T cells ligand (prezalumab), and lymphotoxin beta receptor (baminercept) failed to fulfil the primary outcome measures, preliminary results from two randomized placebo controlled trials on CD40 blockade (Iscalimab) and B-cell activating factor receptor (Ianalumab) inhibition resulted in significant reduction of SS disease activity, with a favorable so far safety profile. Results from administration of other kinase inhibitors, a transmembrane activator and calcium-modulator and cytophilin ligand interactor TACI fusion protein (RC18), as well as low dose recombinant interleukin-2 to expand T-regulatory cells are currently awaited.

    更新日期:2019-12-11
  • The immunobiology of mTOR in autoimmunity
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-09
    Takahito Suto, Thomas Karonitsch

    The mechanistic target of rapamycin (mTOR) is a master regulator of the inflammatory response in immune and non-immune cells. In immune cells mTOR regulates metabolism to fuel cell fate decision, proliferation and effector functions. In non-immune cells, such as fibroblast, it controls inflammation-associated proliferation and migration/invasion, shapes the expression of cytokines and chemokines and promotes extracellular matrix remodeling and fibrosis. Hence, mTOR plays a critical role in chronic inflammation, where a continuous feedback between stromal cells and infiltrating immune cells result in tissue remodeling and organ damage. Activation of mTOR has been implicated in a number of chronic inflammatory diseases, especially rheumatic diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), sjögren syndrome (SS) and seronegative spondyloarthropathy (SpA). Here we review recent advances in our understanding of the mechanism of mTOR activation in inflammation, especially in rheumatic diseases. We further discuss recent findings regarding the beneficial and side effects of mTOR inhibition in rheumatic conditions.

    更新日期:2019-12-11
  • Human herpesvirus-6 is present at higher levels in the pancreatic tissues of donors with type 1 diabetes
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-06
    Somayeh Sabouri, Mehdi A. Benkahla, William B. Kiosses, Teresa Rodriguez-Calvo, Jose Zapardiel-Gonzalo, Ericka Castillo, Matthias G. von Herrath

    Human herpesvirus-6 (HHV-6) is a ubiquitous pathogen associated with nervous and endocrine autoimmune disorders. The aim of this study was to investigate the presence of HHV-6 in pancreatic tissue sections from non-diabetic, auto-antibody positive (AAB+), and donors with type 1 diabetes (T1D) and explore whether there is any association between HHV-6 and MHC class I hyperexpression and CD8 T cell infiltration. HHV-6 DNA was detected by PCR and its protein was examined by indirect immunofluorescence assay followed by imaging using high-resolution confocal microscopy. Viral DNA (U67) was found in most pancreata of non-diabetic (3 out of 4), AAB+ (3 out of 5) and T1D donors (6 out of 7). Interestingly, HHV-6 glycoprotein B (gB) was more expressed in islets and exocrine pancreas of donors with T1D. However, gB expression was not directly associated with other pathologies. Out of 20 islets with high gB expression, only 3 islets (15%) showed MHC class I hyperexpression. Furthermore, no correlation was found between gB expression and CD8 T cell infiltration on a per-islet basis in any of the groups. Our observations indicate that HHV-6 DNA and protein are present in the pancreas of non-diabetic subjects but gB expression is higher in the pancreas of donors with T1D. The possible role of HHV-6 as a contributory factor for T1D should therefore be further investigated.

    更新日期:2019-12-06
  • Inflammatory markers in systemic lupus erythematosus
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-04
    Martin Aringer

    While systemic lupus erythematosus (SLE) is an autoantibody and immune complex disease by nature, most of its organ manifestations are in fact inflammatory. SLE activity scores thus heavily rely on assessing inflammation in the various organs. This focus on clinical items demonstrates that routine laboratory markers of inflammation are still limited in their impact. The erythrocyte sedimentation rate (ESR) is used, but represents a rather crude overall measure. Anemia and diminished serum albumin play a role in estimating inflammatory activity, but both are reflecting more than one mechanism, and the association with inflammation is complex. C-reactive protein (CRP) is a better marker for infections than for SLE activity, where there is only a limited association, and procalcitonin (PCT) is also mainly used for detecting severe bacterial infection. Of the cytokines directly induced by immune complexes, type I interferons, interleukin-18 (IL-18) and tumor necrosis factor (TNF) are correlated with inflammatory disease activity. Still, precise and timely measurement is an issue, which is why they are not currently used for routine purposes. While somewhat more robust in the assays, IL-18 binding protein (IL-18BP) and soluble TNF-receptor 2 (TNF-R2), which are related to the respective cytokines, have not yet made it into clinical routine. The same is true for several chemokines that are increased with activity and relatively easy to measure, but still experimental parameters. In the urine, proteinuria leads and is essential for assessing kidney involvement, but may also result from damage. Similar to the situation in serum and plasma, several cytokines and chemokines perform reasonably well in scientific studies, but are not routine parameters. Cellular elements in the urine are more difficult to assess in the routine laboratory, where sufficient routine is not always available. Therefore, the analysis of urinary T cells may have potential for better monitoring renal inflammation.

    更新日期:2019-12-05
  • Evolving story of autoantibodies in systemic lupus erythematosus
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-04
    David S. Pisetsky

    Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by antinuclear antibody (ANA) production. ANAs bind to DNA, RNA and complexes of proteins and nucleic acids and are important markers for diagnosis and activity. According to current models, ANAs originate from antigen-driven processes; nevertheless, antibody responses to both DNA and RNA binding proteins display features unexpected in terms of current paradigms for antigenicity. These differences may reflect disturbances in both B and T cells critical for autoreactivity. Clinically, ANA testing has new uses for determining classification as well as assessing eligibility for clinical trials. Studies of patients with established disease show frequent seronegativity. In this setting, seronegativity may indicate a stage of disease called post-autoimmunity in which the natural history of disease or effects of immunosuppressive therapies modifies responses. The new uses of ANA testing highlight the importance of understanding autoantigenicity and developing sensitive and informative assays for clinical assessments.

    更新日期:2019-12-04
  • Increased p16INK4a-expressing senescent bile ductular cells are associated with inadequate response to ursodeoxycholic acid in primary biliary cholangitis
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-04
    Motoko Sasaki, Yasunori Sato, Yasuni Nakanuma

    Background & aims Senescent biliary epithelial cells (BECs) may be involved in the pathophysiology of primary biliary cholangitis (PBC) by secreting senescence-associated secretory phenotypes. We examined an association of the extent of cellular senescence in BECs with clinicopathological features including response to ursodeoxycholic acid (UDCA) and a possibility of senolytic therapy in PBC. Methods The expression of senescent markers (p21WAF1/Cip1, p16INK4a) and B-cell lymphoma–extra large (Bcl-xL), a key regulator of senescent cell anti-apoptotic pathway, was immunohistochemically examined in livers from patients with PBC (n = 145) and 103 control livers. Senolytic effect of Bcl-xL inhibitors (A-1331852 and Navitoclax) was examined in senescent murine BECs. Results Senescent BECs were increased in small bile ducts in PBC, compared with control livers (p < 0.01). Senescent BECs were increased in ductular reactions in PBC, stage 3–4, compared with PBC, stage 1–2 and control livers (p < 0.01). The extent of senescent BECs in bile ductules was significantly correlated with stage and hepatitis activity (p < 0.01) and the expression of p16INK4a in bile ductules was significantly correlated to inadequate response to UDCA in PBC (p < 0.01). Double immunofluorescence revealed an increased expression of Bcl-xL in p16INK4a-positive senescent BECs in PBC. Bcl-xL inhibitors selectively induced apoptosis in senescent murine BECs (p < 0.01). Conclusion The extent of senescent BECs in small bile ducts and bile ductules was closely related to stage and activity of PBC and the increased expression of p16 INK4a in bile ductules was correlated with inadequate response to UDCA.

    更新日期:2019-12-04
  • Fine mapping of the MHC region identifies major independent variants associated with Han Chinese primary biliary cholangitis
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-04
    Chan Wang, Xiaodong Zheng, Ruqi Tang, Chongxu Han, Yuzhang Jiang, Jian Wu, Youlin Shao, Yueqiu Gao, Jianjiang Yu, Zhigang Hu, Zhidong Zang, Yi Zhao, Na Dai, Lei Liu, Xudong Wu, Jinshan Nie, Bo Jiang, Maosong Lin, Liangdan Sun

    The genetic association of primary biliary cholangitis with major histocompatibility complex (MHC) has been widely confirmed among different ethnicities. To map specific MHC region variants associated with PBC in a Han Chinese cohort, we imputed HLA antigens and amino acids (AA) in 1126 PBC cases and 1770 healthy control subjects using a Han-MHC reference database. We demonstrate that HLA-DRB1 and/or HLA-DQB1 contributed the strongest signals, and that HLA-DPB1 was a separate independent locus. Regression analyses with classical HLA alleles indicate that HLA-DQB1*03:01 or HLA-DQβ1-Pro55, HLA-DPB1*17:01 or HLA-DPβ1-Asp84 and HLA-DRB1*08:03 could largely explain MHC association with PBC. Forward stepwise regression analyses with HLA amino acid variants localize the major signals to HLA-DRβ1-Ala74, HLA-DQβ1-Pro55 and HLA-DPβ1-Asp84. Electrostatic potential calculations implicated AA variations at HLA-DQβ1 position 55 and HLA-DPβ1 position 84 as critical to peptide binding properties. Furthermore, although several critical Han Chinese AA variants differed from those shown in European populations, the predicted effects on antigen binding are likely to be very similar or identical and underlie the major component of MHC association with PBC.

    更新日期:2019-12-04
  • Ebola virus disease: An emerging and re-emerging viral threat
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-03
    Manuel Rojas, Diana M. Monsalve, Yovana Pacheco, Yeny Acosta-Ampudia, Carolina Ramírez-Santana, Aftab A. Ansari, M. Eric Gershwin, Juan-Manuel Anaya

    The genus Ebolavirus from the family Filoviridae is composed of five species including Sudan ebolavirus, Reston ebolavirus, Bundibugyo ebolavirus, Taï Forest ebolavirus, and Ebola virus (previously known as Zaire ebolavirus). These viruses have a large non-segmented, negative-strand RNA of approximately 19 kb that encodes for glycoproteins (i.e., GP, sGP, ssGP), nucleoproteins, virion proteins (i.e., VP 24, 30,40) and an RNA dependent RNA polymerase. These viruses have become a global health concern because of mortality, their rapid dissemination, new outbreaks in West-Africa, and the emergence of a new condition known as “Post-Ebola virus disease syndrome” that resembles inflammatory and autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus and spondyloarthritis with uveitis. However, there are many gaps in the understanding of the mechanisms that may induce the development of such autoimmune-like syndromes. Some of these mechanisms may include a high formation of neutrophil extracellular traps, an uncontrolled “cytokine storm”, and the possible formation of auto-antibodies. The likely appearance of autoimmune phenomena in Ebola survivors suppose a new challenge in the management and control of this disease and opens a new field of research in a special subgroup of patients. Herein, the molecular biology, pathogenesis, clinical manifestations, and treatment of Ebola virus disease are reviewed and some strategies for control of disease are discussed.

    更新日期:2019-12-03
  • Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-02
    Chen Zhou, Hui Zhao, Xin-yue Xiao, Bei-di Chen, Rui-jin Guo, Qi Wang, Hua Chen, Li-dan Zhao, Chen-chen Zhang, Yu-hao Jiao, Yan-mei Ju, Hua-xia Yang, Yun-yun Fei, Li Wang, Min Shen, Hui Li, Xiao-han Wang, Xin Lu, Xuan Zhang

    Objective Gut dysbiosis has been reported implicated in ankylosing spondylitis (AS), a common chronic inflammatory disease mainly affects sacroiliac joints and spine. Utilizing deep sequencing on the feces of untreated AS patients, our study aimed at providing an in-depth understanding of AS gut microbiota. Methods We analyzed the fecal metagenome of 85 untreated AS patients and 62 healthy controls by metagenomic shotgun sequencing, and 23 post-treatment feces of those AS patients were collected for comparison. Comparative analyses among different cohorts including AS, rheumatoid arthritis and Behcet's disease were performed to uncover some common signatures related to inflammatory arthritis. Molecular mimicry of a microbial peptide was also demonstrated by ELISpot assay. Results We identified AS-enriched species including Bacteroides coprophilus, Parabacteroides distasonis, Eubacterium siraeum, Acidaminococcus fermentans and Prevotella copri. Pathway analysis revealed increased oxidative phosphorylation, lipopolysaccharide biosynthesis and glycosaminoglycan degradation in AS gut microbiota. Microbial signatures of AS gut selected by random forest model showed high distinguishing accuracy. Some common signatures related to autoimmunity, such as Bacteroides fragilis and type III secretion system (T3SS), were also found. Finally, in vitro experiments demonstrated an increased amount of IFN-γ producing cells triggered by a bacterial peptide of AS-enriched species, mimicking type II collagen. Conclusions These findings collectively indicate that gut microbiota was perturbed in untreated AS patients with diagnostic potential, and some AS-enriched species might be triggers of autoimmunity by molecular mimicry. Additionally, different inflammatory arthritis shared some common microbial signatures.

    更新日期:2019-12-03
  • The pathogenesis of systemic lupus erythematosus: Harnessing big data to understand the molecular basis of lupus
    J. Autoimmun. (IF 7.543) Pub Date : 2019-12-02
    Michelle D. Catalina, Katherine A. Owen, Adam C. Labonte, Amrie C. Grammer, Peter E. Lipsky

    Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease that causes damage to multiple organ systems. Despite decades of research and available murine models that capture some aspects of the human disease, new treatments for SLE lag behind other autoimmune diseases such as Rheumatoid Arthritis and Crohn's disease. Big data genomic assays have transformed our understanding of SLE by providing important insights into the molecular heterogeneity of this multigenic disease. Gene wide association studies have demonstrated more than 100 risk loci, supporting a model of multiple genetic hits increasing SLE risk in a non-linear fashion, and providing evidence of ancestral diversity in susceptibility loci. Epigenetic studies to determine the role of methylation, acetylation and non-coding RNAs have provided new understanding of the modulation of gene expression in SLE patients and identified new drug targets and biomarkers for SLE. Gene expression profiling has led to a greater understanding of the role of myeloid cells in the pathogenesis of SLE, confirmed roles for T and B cells in SLE, promoted clinical trials based on the prominent interferon signature found in SLE patients, and identified candidate biomarkers and cellular signatures to further drug development and drug repurposing. Gene expression studies are advancing our understanding of the underlying molecular heterogeneity in SLE and providing hope that patient stratification will expedite new therapies based on personal molecular signatures. Although big data analyses present unique interpretation challenges, both computationally and biologically, advances in machine learning applications may facilitate the ability to predict changes in SLE disease activity and optimize therapeutic strategies.

    更新日期:2019-12-03
  • Dendritic cell upregulation of programmed death ligand-1 via DNA demethylation inhibits experimental autoimmune encephalomyelitis
    J. Autoimmun. (IF 7.543) Pub Date : 2019-11-29
    Chia-Bin Chang, Shiao-Pieng Lee, Wei-Ming Chen, Chuang-Ming Wang, Yu-Chun Song, Michael W-Y Chan, Shu-Fen Wu

    Dendritic cells (DCs) play key roles in regulating T cell proliferation and differentiation, and epigenetic modification involves in this process. In the periphery, programmed death ligand-1 (PD-L1) expressed on antigen-presenting cells interacts with programmed death-1 (PD-1) on T cells to negatively regulate T cell responses. In this study, we investigate whether DNA demethylation in DCs, downmodulates CD4+ T cell activation, to halt progression of experimental autoimmune encephalomyelitis (EAE). These results showed that during the development of bone marrow-derived DCs (BMDCs), DNA hypomethylation by 0.1 μM and 1 μM 5-aza-2′-deoxycytidine (5-aza) upregulated PD-L1, but not CD40, CD80, or CD86, with surprising downregulation of PD-L2. In co-culture, 5-aza-treated BMDCs, as well as CD11c+ cells from 5-aza-treated EAE mice, inhibited EAE CD4+ T cell proliferation and cytokine secretion. Additionally, in vivo 5-aza pretreatment arrested disease progression, inflammatory cell infiltration, and CNS demyelination, in EAE mice. Compared to DCs from vehicle control-treated EAE rodents, DCs from 5-aza-treated EAE mice upregulated PD-L1, in correlation with hypomethylation of the Cd274 promoter. Furthermore, antibody-mediated blockage of PD-L1 rescued EAE progression from 5-aza treatment, in vivo, while also disinhibiting EAE CD4+ T cell proliferation, by 5-aza-treated DCs, in vitro. Consequently, we conclude that PD-L1 is upregulated via DNA hypomethylation in DCs, resulting in downregulation of autoimmune effector T cell functions, thereby halting progression of EAE.

    更新日期:2019-11-29
  • Loss of epigenetic modifications on the inactive X chromosome and sex-biased gene expression profiles in B cells from NZB/W F1 mice with lupus-like disease
    J. Autoimmun. (IF 7.543) Pub Date : 2019-11-25
    Camille M. Syrett, Isabel Sierra, Zachary T. Beethem, Aimee H. Dubin, Montserrat C. Anguera

    The mechanisms underlying the female-bias in autoimmunity are poorly understood. The contribution of genetic and epigenetic factors from the inactive X chromosome (Xi) are beginning to emerge as critical mediators of autoimmunity in females. Here, we ask how epigenetic features of the Xi change during disease development in B cells from the NZB/W F1 spontaneous mouse model of lupus, which is female-biased. We find that Xist RNA becomes increasingly mislocalized from the Xi with disease onset. While NZB/W F1 naïve B cells have H3K27me3 foci on the Xi, which are missing from healthy C57BL/6 and BALB/c mice, these foci are progressively lost in stimulated B cells during disease. Using single-molecule RNA FISH, we show that the X-linked gene Tlr7 is biallelically expressed in ~20% of NZB/W F1 B cells, and that the amount of biallelic expression does not change with disease. We also present sex-specific gene expression profiles for diseased NZB/W F1 B cells, and find female-specific upregulation of 20 genes, including the autoimmunity-related genes Cxcl13, Msr1, Igj, and Prdm1. Together, these studies provide important insight into the loss of epigenetic modifications from the Xi and changes with gene expression in a mouse model of female-biased SLE.

    更新日期:2019-11-26
  • Multidimensional analyses of proinsulin peptide-specific regulatory T cells induced by tolerogenic dendritic cells
    J. Autoimmun. (IF 7.543) Pub Date : 2019-11-24
    Jessica S. Suwandi, Sandra Laban, Kincsὅ Vass, Antoinette Joosten, Vincent van Unen, Boudewijn P.F. Lelieveldt, Thomas Höllt, Jaap Jan Zwaginga, Tatjana Nikolic, Bart O. Roep

    Induction of antigen-specific regulatory T cells (Tregs) in vivo is the holy grail of current immune-regulating therapies in autoimmune diseases, such as type 1 diabetes. Tolerogenic dendritic cells (tolDCs) generated from monocytes by a combined treatment with vitamin D and dexamethasone (marked by CD52hi and CD86lo expression) induce antigen-specific Tregs. We evaluated the phenotypes of these Tregs using high-dimensional mass cytometry to identify a surface-based T cell signature of tolerogenic modulation. Naïve CD4+ T cells were stimulated with tolDCs or mature inflammatory DCs pulsed with proinsulin peptide, after which the suppressive capacity, cytokine production and phenotype of stimulated T cells were analysed. TolDCs induced suppressive T cell lines that were dominated by a naïve phenotype (CD45RA+CCR7+). These naïve T cells, however, did not show suppressive capacity, but were arrested in their naïve status. T cell cultures stimulated by tolDC further contained memory-like (CD45RA-CCR7-) T cells expressing regulatory markers Lag-3, CD161 and ICOS. T cells expressing CD25lo or CD25hi were most prominent and suppressed CD4+ proliferation, while CD25hi Tregs also effectively supressed effector CD8+ T cells. We conclude that tolDCs induce antigen-specific Tregs with various phenotypes. This extends our earlier findings pointing to a functionally diverse pool of antigen-induced and specific Tregs and provides the basis for immune-monitoring in clinical trials with tolDC.

    更新日期:2019-11-26
  • Transethnic associations among immune-mediated diseases and single-nucleotide polymorphisms of the aryl hydrocarbon response gene ARNT and the PTPN22 immune regulatory gene
    J. Autoimmun. (IF 7.543) Pub Date : 2019-11-21
    Shepherd H. Schurman, Terrance P. O'Hanlon, John A. McGrath, Artiom Gruzdev, Arsun Bektas, Hong Xu, Stavros Garantziotis, Darryl C. Zeldin, Frederick W. Miller

    Background Because immune responses are sensitive to environmental changes that drive selection of genetic variants, we hypothesized that polymorphisms of some xenobiotic response and immune response genes may be associated with specific types of immune-mediated diseases (IMD), while others may be associated with IMD as a larger category regardless of specific phenotype or ethnicity. Objective To examine transethnic gene-IMD associations for single nucleotide polymorphism (SNP) frequencies of prototypic xenobiotic response genes—aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), AHR repressor (AHRR) — and a prototypic immune response gene, protein tyrosine phosphatase, non-receptor type 22 (PTPN22), in subjects from the Environmental Polymorphisms Registry (EPR). Methods Subjects (n = 3731) were genotyped for 14 SNPs associated with functional variants of the AHR, ARNT, AHRR, and PTPN22 genes, and their frequencies were compared among African Americans (n = 1562), Caucasians (n = 1838), and Hispanics (n = 331) with previously reported data. Of those genotyped, 2015 EPR subjects completed a Health and Exposure survey. SNPs were assessed via PLINK for associations with IMD, which included those with autoimmune diseases, allergic disorders, asthma, or idiopathic pulmonary fibrosis. Transethnic meta-analyses were performed using METAL and MANTRA approaches. Results ARNT SNP rs11204735 was significantly associated with autoimmune disease by transethnic meta-analyses using METAL (odds ratio, OR [95% confidence interval] = 1.29 [1.08–1.55]) and MANTRA (ORs ranged from 1.29 to 1.30), whereas ARNT SNP rs1889740 showed a significant association with autoimmune disease by METAL (OR = 1.25 [1.06–1.47]). For Caucasian females, PTPN22 SNP rs2476601 was significantly associated with autoimmune disease by allelic association tests (OR = 1.99, [1.30–3.04]). In Caucasians and Caucasian males, PTPN22 SNP rs3811021 was significantly associated with IMD (OR = 1.39 [1.12–1.72] and 1.50 [1.12–2.02], respectively) and allergic disease (OR = 1.39 [1.12–1.71], and 1.62 [1.19–2.20], respectively). In the transethnic meta-analysis, PTPN22 SNP rs3811021 was significantly implicated in IMD by METAL (OR = 1.31 [1.10–1.56]), and both METAL and MANTRA suggested that rs3811021 was associated with IMD and allergic disease in males across all three ethnic groups (IMD METAL OR = 1.50 [1.15–1.95]; IMD MANTRA ORs ranged from 1.47 to 1.50; allergic disease METAL OR = 1.58 [1.20–2.08]; allergic disease MANTRA ORs ranged from 1.55 to 1.59). Conclusions Some xenobiotic and immune response gene polymorphisms were shown here, for the first time, to have associations across a broad spectrum of IMD and ethnicities. Our findings also suggest a role for ARNT in the development of autoimmune diseases, implicating environmental factors metabolized by this pathway in pathogenesis. Further studies are needed to confirm these data, assess the implications of these findings, define gene-environment interactions, and explore the mechanisms leading to these increasingly prevalent disorders.

    更新日期:2019-11-21
  • LncRNA PVT1 links Myc to glycolytic metabolism upon CD4+ T cell activation and Sjögren's syndrome-like autoimmune response
    J. Autoimmun. (IF 7.543) Pub Date : 2019-11-19
    Jiayao Fu, Huan Shi, Baoli Wang, Tianle Zhan, Yanxiong Shao, Lei Ye, Shufeng Wu, Chuangqi Yu, Lingyan Zheng
    更新日期:2019-11-20
  • Immune checkpoint molecules. Possible future therapeutic implications in autoimmune diseases
    J. Autoimmun. (IF 7.543) Pub Date : 2019-09-26
    Chuan Huang, Hao-Xian Zhu, Yuan Yao, Zhen-Hua Bian, Yu-Jian Zheng, Liang Li, Haralampos M. Moutsopoulos, M. Eric Gershwin, Zhe-Xiong Lian

    During host immune response, an initial and sufficient activation is required to avoid infection and cancer, yet an excessive activation bears the risk of autoimmune reactivity and disease development. This fastidious balance of the immune system is regulated by co-stimulatory and co-inhibitory molecules, also known as immune checkpoints. Both excessive co-stimulation and insufficient co-inhibition can induce the activation and proliferation of autoreactive cells that may lead to the development of autoimmune diseases. During the last decade, a growing number of new immune checkpoint receptors and ligands have been discovered, providing an attractive approach to investigate their implication in the pathogenesis of autoimmune diseases and their potential role as targets for effective therapeutic interventions. In this review, we focus on the roles and underlying mechanisms of co-stimulatory and co-inhibitory receptors and other molecules that function as immune checkpoints in autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, Sjögren's syndrome, type I diabetes and inflammatory bowel disease. We also summarize previous and current clinical trials targeting these checkpoint pathways in autoimmune diseases and discuss further therapeutic implications and possible risks and challenges.

    更新日期:2019-11-18
  • Changing epidemiology of immune-mediated inflammatory diseases in immigrants: A systematic review of population-based studies
    J. Autoimmun. (IF 7.543) Pub Date : 2019-07-25
    Manasi Agrawal, Shailja Shah, Anish Patel, Rachel Pinotti, Jean-Frederic Colombel, Johan Burisch

    Background Immune-mediated inflammatory diseases (IMIDs) are systemic diseases of multifactorial etiology that share aberrant immune responses as the common final pathway. With rising globalization, their incidence is increasing in developing countries and among immigrants. Our primary objective was to systematically review the epidemiology of IMIDs in immigrants and conduct a meta-analysis to estimate the risk of IMIDs in immigrant populations according to their origin and destination countries. Methods We systematically searched five biomedical databases and reviewed population-based studies, from inception through August 2018, that reported incidence or prevalence data of inflammatory bowel disease (IBD), multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS) or psoriasis and psoriatic arthritis (PPA) among immigrants and the host population. Results The incidence and prevalence of IMIDs among immigrants differ from host populations, and evolve over subsequent generations. The risk of IBD among immigrants approximates that in hosts, especially among South Asians, with ulcerative colitis incidence changing prior to Crohn’s disease incidence. MS risk is highest in Iranian immigrants, T1D in African immigrants and SLE in African and Iraqi immigrants. Data on other IMIDs are sparse. Significant heterogeneity between the studies precluded meta-analysis. Conclusion Based on our systematic review, the epidemiology of IMIDs among immigrants varies according to native and host countries, immigrant generation, and IMID type. The rapid evolution suggests a role for non-genetic factors and gene-environment interactions. Future studies should focus on these pattern shifts, given implications of rising global burden of IMIDs and immigration.

    更新日期:2019-11-18
  • Autoinflammation: Lessons from the study of familial Mediterranean fever
    J. Autoimmun. (IF 7.543) Pub Date : 2019-07-20
    Panagiotis Skendros, Charalampos Papagoras, Ioannis Mitroulis, Konstantinos Ritis

    Autoinflammatory disorders represent a heterogeneous group of systemic inflammatory diseases caused by genetic or acquired defects in key components of the innate immunity. Familial Mediterranean fever (FMF) is the most common among the other clinical phenotypes of the rare hereditary periodic fevers (HPFs) syndromes. FMF is associated with mutations in the MEFV gene encoding pyrin and is characterized by recurrent, often stress-provoked attacks of fever and serositis, but sometimes also by chronic subclinical inflammation. FMF is prevalent in Greece and other countries of the eastern Mediterranean region. Over the last 17 years, our group has focused on FMF as a model suitable for the research on innate immunity and particularly the role of neutrophils. Therefore, the study of Greek patients with FMF has yielded lessons across several levels: the epidemiology of the disease in Greece, the spectrum of its clinical manifestations and potential overlaps with other idiopathic inflammatory conditions, the demonstration of its rather complex and heterogeneous genetic background and the suggestion of a novel mechanism involved in the crosstalk between environmental stress and inflammation. Mechanistically, during FMF attack, neutrophils release chromatin structures called neutrophil extracellular traps (NETs), which are decorated with bioactive IL-1β. REDD1 (regulated in development and DNA damage responses 1), that encodes a stress-related mTOR repressor, has been found to be the most significantly upregulated gene in neutrophils during disease attacks. Upon adrenergic stress, REDD1-induced autophagy triggers a pyrin-driven IL-1β maturation, and the release of IL-1β-bearing NETs. Consequently, not only the mode of action of IL-1β-targeting therapies is explained, but also new treatment prospects emerge with the evaluation of old or the design of new drugs targeting autophagy-induced NETosis. Information gained from FMF studies may subsequently be applied in more complex but still relevant inflammatory conditions, such as adult-onset Still's disease, gout, ulcerative colitis and Behçet's disease.

    更新日期:2019-11-18
  • A novel spleen-resident immature NK cell subset and its maturation in a T-bet-dependent manner
    J. Autoimmun. (IF 7.543) Pub Date : 2019-07-24
    Baohui Wang, Jing Zhou, Yawen Chen, Haiming Wei, Rui Sun, Zhigang Tian, Hui Peng

    NK cells are thought to develop primarily in the bone marrow during adult life. However, increasing evidence shows that NK cell developmental intermediates can be found in different peripheral tissues with unique characteristics. Here, we identified a unique NK cell subset with the CD49a−CD49b− phenotype in the spleen. These cells displayed an immature phenotype and weak abilities in cytotoxicity and cytokine production. Adoptive transfer experiments revealed that they could develop into mature conventional NK (cNK) cells. Transcriptome analysis further confirmed their immature features. Parabiosis experiments revealed that these cells maintained tissue-resident properties in the spleen. Moreover, T-bet deficiency intrinsically impaired the ability of these cells to develop into mature cNK cells. Thus, our study identified a spleen-resident immature NK cell subset that could undergo extramedullary maturation in a T-bet dependent manner.

    更新日期:2019-11-18
  • Chaperones may cause the focus of diabetes autoimmunity on distinct (pro)insulin peptides
    J. Autoimmun. (IF 7.543) Pub Date : 2019-07-18
    Hubert Kolb, Volker Burkart

    It is still an enigma why T cell autoreactivity in type 1 diabetes targets few beta cell antigens only. Among these, one primary autoantigen is pro(insulin). Autoimmune T cells preferentially recognise three epitopes on the proinsulin molecule, of which the peptide region B:11-23 is the dominant one. Interestingly, the three regions superimpose with binding sites of the chaperone hsp70, the region B:11-23 being the strongest binding one. Absence of an intact core region B:15-17 prevents autoimmune diabetes in NOD as well as binding of hsp70. A role of hsp70 in selecting autoimmune epitopes is supported by the ability of this and other chaperones to deliver bound peptides to MHC class I and II molecules for efficient antigen presentation. Binding of hsp70 to receptors on antigen presenting cells such as TLR4 results in costimulatory signals for T cell activation. Strongest effects are seen for the mixture of hsp70 with the peptide B:11-23. Thus, hsp70 may assist in proinsulin epitope selection and efficient presentation to autoreactive T cells. The concept of chaperone guided immune reactivity may also apply to other autoimmune diseases.

    更新日期:2019-11-18
  • The association of serum interleukin-6 levels with clinical outcomes in antineutrophil cytoplasmic antibody-associated vasculitis
    J. Autoimmun. (IF 7.543) Pub Date : 2019-07-15
    Alvise Berti, Roscoe Warner, Kent Johnson, Divi Cornec, Darrell R. Schroeder, Brian F. Kabat, Carol A. Langford, Cees G.M. Kallenberg, Philip Seo, Robert F. Spiera, E. William St Clair, Fernando C. Fervenza, John H. Stone, Paul A. Monach, Ulrich Specks, Peter A. Merkel
    更新日期:2019-11-18
  • Cellular aging over 13 years associated with incident antinuclear antibody positivity in the Baltimore Longitudinal Study of Aging
    J. Autoimmun. (IF 7.543) Pub Date : 2019-07-11
    Helen C.S. Meier, Christine G. Parks, Hans B. Liu, Dale P. Sandler, Eleanor M. Simonsick, Kevin Deane, Nan-ping Weng

    Age-associated increases in antinuclear antibodies (ANA) in the general population are commonly noted but the mechanisms underlying this observation are unclear. This study aims to evaluate whether shorter peripheral blood mononuclear cell (PBMC) telomere length, a marker of more advanced biological age, is associated with ANA positivity prevalence and incidence in middle and older aged autoimmune disease-free individuals from the Baltimore Longitudinal Study of Aging (BLSA). Telomere length was measured by Southern Blot and categorized into tertiles. ANA was measured in a 1:80 and a 1:160 dilution of sera by immunofluorescence using HEp-2 cells (seropositive = 3 or 4). Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals of ANA positivity comparing the shorter tertiles of telomere length to the longest tertile for two cross-sectional points in time and then longitudinally to assess the association between shorter telomere length and incident ANA positivity. Cross-sectional analyses were adjusted for sex, race and BMI (N = 368 baseline, N = 370 follow-up) and longitudinal analyses were adjusted for sex, race, BMI and time between baseline and follow-up (N = 246). No statistically significant cross-sectional associations were observed at baseline or follow-up. Among those where ANA negative at baseline, individuals with shorter telomeres were more likely to be ANA positive at follow-up, an average 13 years later. Individuals with short telomeres at both time periods were more likely to be ANA positive. Findings suggest that ANA positivity in the general population may be indicative of immune dysfunction resulting from advanced cellular aging processes.

    更新日期:2019-11-18
  • Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity
    J. Autoimmun. (IF 7.543) Pub Date : 2019-07-08
    Ameya S. Gokhale, Arunakumar Gangaplara, Maria Lopez-Occasio, Angela M. Thornton, Ethan M. Shevach

    Eos (lkzf4) is a member of the Ikaros family of transcription factors and is preferentially expressed in T-regulatory (Treg) cells. However, the role of Eos in Treg function is controversial. One study using siRNA knock down of Eos demonstrated that it was critical for Treg suppressor function. In contrast, Treg from mice with a global deficiency of Eos had normal Treg function in vitro and in vivo. To further dissect the function of Eos in Tregs, we generated mice with a conditional knock out of Eos in Treg cells (lkzf4fl/fl X Foxp3YFP−cre, Eos cKO). Deletion of Eos in Treg resulted in activation of CD4+Foxp3- and CD8+ T cells at the age of 3 months, cellular infiltration in non-lymphoid tissues, hyperglobulinemia, and anti-nuclear antibodies. While Tregs from Eos cKO mice displayed normal suppressive function in vitro, Eos cKO mice developed severe Experimental Autoimmune Encephalomyletis (EAE) following immunization with myelin oligodendrocyte glycoprotein (MOG) and Eos cKO Treg were unable to suppress Inflammatory Bowel Disease (IBD). Eos cKO mice had decreased growth of the transplantable murine adenocarcinoma MC38 tumor accompanied by enhanced IFN-γ/TNF-α production by CD8+ T cells in tumor draining lymph nodes. Mice with a global deficiency of Eos or a deficiency of Eos only in T cells developed autoimmunity at a much older age (12 months or 7–8 months, respectively). Taken together, Eos appears to play an essential role in multiple aspects of Treg suppressor function, but also plays an as yet unknown role in the function of CD4+Foxp3- and CD8+ T cells and potentially in non-T cells.

    更新日期:2019-11-18
  • Predicting drug-free remission in rheumatoid arthritis: A prospective interventional cohort study
    J. Autoimmun. (IF 7.543) Pub Date : 2019-07-04
    Kenneth F. Baker, Andrew J. Skelton, Dennis W. Lendrem, Adam Scadeng, Ben Thompson, Arthur G. Pratt, John D. Isaacs

    Background Many patients with rheumatoid arthritis (RA) achieve disease remission with modern treatment strategies. However, having achieved this state, there are no tests that predict when withdrawal of therapy will result in drug-free remission rather than flare. We aimed to identify predictors of drug-free remission in RA. Methods The Biomarkers of Remission in Rheumatoid Arthritis (BioRRA) Study was a unique, prospective, interventional cohort study of complete and abrupt cessation of conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs). Patients with RA of at least 12 months duration and in clinical and ultrasound remission discontinued DMARDs and were monitored for six months. The primary outcome was time-to-flare, defined as disease activity score in 28 joints with C-reactive protein (DAS28-CRP) ≥ 2.4. Baseline clinical and ultrasound measures, circulating inflammatory biomarkers, and peripheral CD4+ T cell gene expression were assessed for their ability to predict time-to-flare and flare/remission status by Cox regression and receiver-operating characteristic (ROC) analysis respectively. Results 23/44 (52%) eligible patients experienced an arthritis flare after a median (IQR) of 48 (31.5–86.5) days following DMARD cessation. A composite score incorporating five baseline variables (three transcripts [FAM102B, ENSG00000228010, ENSG00000227070], one cytokine [interleukin-27], one clinical [Boolean remission]) differentiated future flare from drug-free remission with an area under the ROC curve of 0.96 (95% CI 0.91–1.00), sensitivity 0.91 (0.78–1.00) and specificity 0.95 (0.84–1.00). Conclusion We provide proof-of-concept evidence for predictors of drug-free remission in RA. If validated, these biomarkers could help to personalize immunosuppressant withdrawal: a therapy paradigm shift with ensuing patient and economic benefits.

    更新日期:2019-11-18
  • Extracellular traps and PAD4 released by macrophages induce citrullination and auto-antibody production in autoimmune arthritis
    J. Autoimmun. (IF 7.543) Pub Date : 2019-07-02
    Mohey Eldin M. El Shikh, Riham El Sayed, Alessandra Nerviani, Katriona Goldmann, Christopher Robert John, Rebecca Hands, Liliane Fossati-Jimack, Myles J. Lewis, Costantino Pitzalis

    The mechanisms underlying the transition of rheumatoid arthritis (RA) systemic autoimmunity to the joints remain largely unknown. Here, we demonstrate that macrophages in the secondary lymphoid organs (SLOs) and synovial ectopic lymphoid-like structures (ELSs) express peptidylarginine deiminase 4 (PAD4) in murine collagen induced arthritis (CIA) and synovial biopsies from RA patients. Moreover, peptidyl citrulline colocalized with macrophages in SLOs and ELSs, and depletion of macrophages in CIA decreased lymphoid tissue citrullination and serum anti-citrullinated protein/peptide antibody (ACPA) levels. Furthermore, PAD was released from activated murine and RA synovial tissue and fluid (SF) macrophages which functionally deiminated extracellular proteins/peptides in vitro. Additionally, activated murine and SF macrophages displayed macrophage extracellular trap formation (METosis) and release of intracellular citrullinated histones. Moreover, presentation of citrullinated proteins induced ACPA production in vitro. Thus, lymphoid tissue macrophages contribute to self-antigen citrullination and ACPA production, indicating that their selective targeting would potentially ameliorate citrullination-dependent autoimmune disorders.

    更新日期:2019-11-18
  • PD-1 aborts the activation trajectory of autoreactive CD8+ T cells to prohibit their acquisition of effector functions
    J. Autoimmun. (IF 7.543) Pub Date : 2019-07-02
    Hikari Okamura, Il-mi Okazaki, Kenji Shimizu, Takumi Maruhashi, Daisuke Sugiura, Reina Mizuno, Taku Okazaki

    Anti-PD-1 therapy can induce eradication of tumors and immune-related adverse events (irAEs) in humans and model animals. However, how anti-PD-1 therapy modifies cellular phenotypes of CD8+ T cells to destroy tumors and damage self-tissues remains to be clarified. Here we performed single cell mRNA expression profiling of autoreactive CD8+ T cells under or beyond PD-1 suppression in target tissues and reconstructed their activation trajectory. Autoreactive CD8+ T cells went through four activation phases and PD-1 strongly attenuated the transition from the second- to the third-phase, where effector functions were acquired. Shifts in cluster composition of autoreactive CD8+ T cells markedly reflected the severity of autoimmunity. In addition, genes up-regulated along the activation-trajectory in autoimmunity were highly expressed in responders of melanoma patients in anti-PD-1 therapy, suggesting that tumor-specific T cells need to be activated in a similar trajectory to destroy tumors in human patients upon PD-1 blockade. These findings reveal that PD-1 blockade facilitates the activation trajectory of CD8+ T cells to boost their effector functions. Targeted manipulation of the trajectory could lead to new therapeutic opportunities.

    更新日期:2019-11-18
  • Monocytes contribute to DNA sensing through the TBK1 signaling pathway in type 1 diabetes patients
    J. Autoimmun. (IF 7.543) Pub Date : 2019-06-28
    Irena Zentsova, Zuzana Parackova, Jana Kayserova, Lenka Palova-Jelinkova, Petra Vrabcova, Nikol Volfova, Zdenek Sumnik, Stepanka Pruhova, Lenka Petruzelkova, Anna Sediva

    Background The aberrant recognition of self-nucleic acids by the innate immune system contributes to the pathology of several autoimmune diseases. Although microbial DNA and, in certain instances, self-DNA that is released from damaged cells are primarily recognized by Toll-like receptor 9 (TLR9), recent evidence suggests that other cytosolic sequence-nonspecific DNA sensors contribute to DNA recognition. In this study, we focused on the sensing of microbial and host DNA in type 1 diabetes (T1D) patients. Methods Peripheral blood mononuclear cells (PBMCs) and monocytes from pediatric patients with T1D and from healthy donors were stimulated with microbial DNA (CpG) or with self-DNA (DNA contained within neutrophil extracellular traps, NETs). The production of cytokines was measured by flow cytometry and multiplex bead assays. The internalization of microbial DNA and its colocalization with STING was detected by image cytometry. Furthermore, the involvement of the TBK1 kinase was investigated by detecting its phosphorylation with phospho-flow cytometry or by using a TBK1 inhibition assay. Results We observed a prominent proinflammatory response in T1D PBMCs, especially pDCs and monocytes, to microbial DNA in comparison to that in controls. We further confirmed that monocytes could bind and internalize DNA and respond by releasing proinflammatory cytokines in a more pronounced manner in T1D patients than those in controls. Surprisingly, this cytokine production was not affected by TLR9 blockade, suggesting the involvement of intracellular receptors in DNA recognition. We further identified TBK1 and STING as two crucial molecules in the DNA-sensing pathway that were involved in CpG-DNA sensing by T1D cells. A similar DNA-sensing pathway that was dependent on intracellular DNA sensors and the STING-TBK1 interaction was employed in response to NETs, which were used to model self-DNA. Conclusions Here, we show that there were significant differences in DNA sensing in T1D patients compared to that in controls. We demonstrate that monocytes from T1D patients are able to sense microbial- and self-DNA, leading to proinflammatory cytokine secretion through the adaptor protein STING and the TBK1 kinase.

    更新日期:2019-11-18
  • Myeloid sphingosine-1-phosphate receptor 1 is important for CNS autoimmunity and neuroinflammation
    J. Autoimmun. (IF 7.543) Pub Date : 2019-06-12
    Hsing-Chuan Tsai, Khoa Nguyen, Ezzat Hashemi, Edgar Engleman, Timothy Hla, May H. Han

    The critical role of sphingosine-1-phosphate (S1P) signaling in lymphocyte trafficking is well recognized, however, the contribution of myeloid cell-S1P signaling in neuroimmunity is less well understood. We previously reported that C57BL/6J mice harboring phosphorylation defective S1P receptor 1 (S1P1) (with mutated serines in the carboxyl terminus, leading to impaired receptor internalization) [S1P1(S5A)] developed severe, TH17-dominant experimental autoimmune encephalomyelitis. In this study, we demonstrate that S1P1-mediated TH17 polarization is not an intrinsic T cell effect, but dependent on sustained S1P1 signaling in myeloid cells. First, utilizing the S1P1(S5A) mice in the EAE model, we observed that S1P1 activated and enhanced antigen presentation function in myeloid cells. Second, sequential phosphorylation of STAT3 occurred in dendritic cells, monocytes, and macrophages/microglia during neuroinflammation. Third, we show that pro-inflammatory (CD45hiCD11b+Ly6Chi) monocytes contribute to TH17 differentiation and neuroinflammation by regulating IL-6 expression. Finally, results from experiments utilizing myeloid cell-specific S1P1 overexpression (S1pr1f/stop/f:LysMCre) mice demonstrate that myeloid cell S1P1 directly contributes to severity of neuroinflammation. These findings reveal the critical contribution of myeloid-S1P1 signaling in CNS autoimmunity.

    更新日期:2019-11-18
  • In systemic lupus erythematosus anti-dsDNA antibodies can promote thrombosis through direct platelet activation
    J. Autoimmun. (IF 7.543) Pub Date : 2019-11-12
    Izabella A. Andrianova, Anastasiya A. Ponomareva, Elmira R. Mordakhanova, Giang Le Minh, Amina G. Daminova, Tatiana A. Nevzorova, Lubica Rauova, Rustem I. Litvinov, John W. Weisel

    Systemic lupus erythematosus (SLE) is associated with a high risk of venous and arterial thrombosis, not necessarily associated with prothrombotic antiphospholipid antibodies (Abs). Alternatively, thrombosis may be due to an increased titer of anti-dsDNA Abs that presumably promote thrombosis via direct platelet activation. Here, we investigated effects of purified anti-dsDNA Abs from the blood of SLE patients, alone or in a complex with dsDNA, on isolated normal human platelets. We showed that anti-dsDNA Abs and anti-dsDNA Ab/dsDNA complexes induced strong platelet activation assessed by enhanced P-selectin expression and dramatic morphological and ultrastructural changes. Electron microscopy revealed a significantly higher percentage of platelets that lost their discoid shape, formed multiple filopodia and had a shrunken body when treated with anti-dsDNA Abs or anti-dsDNA Ab/dsDNA complexes compared with control samples. In addition, these platelets activated with anti-dsDNA Ab/dsDNA complexes typically contained a reduced number of secretory α-granules that grouped in the middle and often merged into a solid electron dense area. Many activated platelets released plasma membrane-derived microvesicles and/or fell apart into subcellular cytoplasmic fragments. Confocal microscopy revealed that platelets treated with anti-dsDNA Ab/dsDNA complex had a heterogeneous distribution of septin2 compared with the homogeneous distribution in control platelets. Structural perturbations were concomitant with mitochondrial depolarization and a decreased content of platelet ATP, indicating energetic exhaustion. Most of the biochemical and morphological changes in platelets induced by anti-dsDNA Abs and anti-dsDNA Ab/dsDNA complexes were prevented by pre-treatment with a monoclonal mAb against FcγRIIA. The aggregate of data indicates that anti-dsDNA Abs alone or in a complex with dsDNA strongly affect platelets via the FcγRIIA receptor. The immune activation of platelets with antinuclear Abs may comprise a prothrombotic mechanism underlying a high risk of thrombotic complications in patients with SLE.

    更新日期:2019-11-13
  • Salivary dysbiosis and the clinical spectrum in anti-Ro positive mothers of children with neonatal lupus
    J. Autoimmun. (IF 7.543) Pub Date : 2019-10-31
    R.M. Clancy, M.C. Marion, H.C. Ainsworth, M.J. Blaser, M. Chang, T.D. Howard, P.M. Izmirly, C. Lacher, M. Masson, K. Robins, J.P. Buyon, C.D. Langefeld

    Mothers giving birth to children with manifestations of neonatal lupus (NL) represent a unique population at risk for the development of clinically evident pathologic autoimmunity since many are asymptomatic and only become aware of anti-SSA/Ro positivity (anti-Ro+) based on heart block in their fetus. Accordingly, we hypothesized that the microbiome in saliva is associated with the development of autoreactivity and in some cases the progression in health status from benign to overt clinical disease including Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE). The study comprised a clinical spectrum of anti-Ro+ mothers, all of whom gave birth to a child with NL: 9 were asymptomatic or had an undifferentiated autoimmune disease (Asym/UAS) and 16 fulfilled criteria for SS and/or SLE. Microbial diversity was reduced across all levels from kingdom to species for the anti-Ro+ mothers vs healthy controls; however, there were no significant differences between Asym/UAS and SS/SLE mothers. Relative abundance of Proteobacteria and more specifically class Betaproteobacteria decreased with clinical severity (healthy controls < Asym/UAS < SS/SLE). These ordered differences were maintained through the taxonomic hierarchy to three genera (Lautropia, Comamonas, and Neisseria) and species within these genera (L. mirabilis, N. flavescens and N. oralis). Biometric analysis comparing von Willebrand Factor domains present in human Ro60 with L. mirabilis proteins support the hypothesis of molecular mimicry. These data position the microbiome in the development of anti-Ro reactivity and subsequent clinical spectrum of disease.

    更新日期:2019-11-01
  • Mitochondrial DNA oxidation induces imbalanced activity of NLRP3/NLRP6 inflammasomes by activation of caspase-8 and BRCC36 in dry eye.
    J. Autoimmun. (IF 7.543) Pub Date : 2017-02-28
    Wei Chi,Xia Hua,Xin Chen,Fang Bian,Xiaoyong Yuan,Lili Zhang,Xiaoran Wang,Ding Chen,Ruzhi Deng,Zhijie Li,Yizhi Liu,Cintia S de Paiva,Stephen C Pflugfelder,De-Quan Li

    The concept of innate immunity has been expanded to recognize environmental pathogens other than microbial components. However, whether and how the innate immunity is initiated by epithelium in response to environmental physical challenges such as low humidity and high osmolarity in an autoimmune disease, dry eye, is still largely unknown. Using two experimental dry eye models, primary human corneal epithelial cultures exposed to hyperosmolarity and mouse ocular surface facing desiccating stress, we uncovered novel innate immunity pathway by ocular surface epithelium, where oxidized mitochondrial DNA induces imbalanced activation of NLRP3/NLRP6 inflammasomes via stimulation of caspase-8 and BRCC36 in response to environmental stress. Activated NLRP3 with suppressed NLRP6 stimulates caspase-1 activation that leads to IL-1β and IL-18 maturation and secretion. NLRP3-independent caspase-8 noncanonically activates caspase-1 via reciprocal regulation of NLRP3/NLRP6-mediated inflammasomes. Reactive oxygen species-induced mitochondrial DNA oxidative damage and BRCC36 deubiquitinating activity provide a missing link and mechanism by which innate immunity responds to environmental stress via caspase-8-involved NLRP3/NLRP6 inflammasomes.

    更新日期:2019-11-01
  • B cells contribute to ischemia/reperfusion-mediated tissue injury.
    J. Autoimmun. (IF 7.543) Pub Date : 2009-04-04
    Jie Chen,José C Crispín,Thomas F Tedder,Jurandir Dalle Lucca,George C Tsokos

    Multiple elements are known to participate in ischemia/reperfusion (I/R)-mediated tissue injury. Amongst them, B cells have been shown to contribute by the production of antibodies that bind to ischemic cells and fix complement. It is currently unknown whether B cells participate through antibody-independent mechanisms in the pathogenesis of I/R. In a mesenteric I/R model we found that B cells infiltrate the injured intestine of normal and autoimmune mice 2h after reperfusion is established. B cell depletion protected mice from the development of I/R-mediated intestinal damage. The protection conferred by B cell depletion was significantly greater in MRL/lpr mice. Finally, we show that ischemic tissue expressed the B cell-attractant CXCL13 and infiltrating B cells expressed the corresponding receptor CXCR5. Our data grant B cells an antibody-independent role in the pathogenesis of intestinal I/R and suggest that B cells accumulate in the injured tissue in response to the chemokine CXCL13.

    更新日期:2019-11-01
  • Guillain Barré Syndrome is induced in Non-Obese Diabetic (NOD) mice following Campylobacter jejuni infection and is exacerbated by antibiotics.
    J. Autoimmun. (IF 7.543) Pub Date : 2016-12-13
    J L St Charles,J A Bell,B J Gadsden,A Malik,H Cooke,L K Van de Grift,H Y Kim,E J Smith,L S Mansfield

    Campylobacter jejuni is a leading cause of bacterial gastroenteritis linked to several serious autoimmune sequelae such as the peripheral neuropathies Guillain Barré syndrome (GBS) and Miller Fisher syndrome (MFS). We hypothesized that GBS and MFS can result in NOD wild type (WT) mice or their congenic interleukin (IL)-10 or B7-2 knockouts secondary to C. jejuni infection. Mice were gavaged orally with C. jejuni strains HB93-13 and 260.94 from patients with GBS or CF93-6 from a patient with MFS and assessed for clinical neurological signs and phenotypes, anti-ganglioside antibodies, and cellular infiltrates and lesions in gut and peripheral nerve tissues. Significant increases in autoantibodies against single gangliosides (GM1, GQ1b, GD1a) occurred in infected NOD mice of all genotypes, although the isotypes varied (NOD WT had IgG1, IgG3; NOD B7-2-/- had IgG3; NOD IL-10-/- had IgG1, IgG3, IgG2a). Infected NOD WT and NOD IL-10-/- mice also produced anti-ganglioside antibodies of the IgG1 isotype directed against a mixture of GM1/GQ1b gangliosides. Phenotypic tests showed significant differences between treatment groups of all mouse genotypes. Peripheral nerve lesions with macrophage infiltrates were significantly increased in infected mice of NOD WT and IL-10-/- genotypes compared to sham-inoculated controls, while lesions with T cell infiltrates were significantly increased in infected mice of the NOD B7-2-/- genotype compared to sham-inoculated controls. In both infected and sham inoculated NOD IL-10-/- mice, antibiotic treatment exacerbated neurological signs, lesions and the amount and number of different isotypes of antiganglioside autoantibodies produced. Thus, inducible mouse models of post-C. jejuni GBS are feasible and can be characterized based on evaluation of three factors-onset of GBS clinical signs/phenotypes, anti-ganglioside autoantibodies and nerve lesions. Based on these factors we characterized 1) NOD B-7-/- mice as an acute inflammatory demyelinating polyneuropathy (AIDP)-like model, 2) NOD IL-10-/- mice as an acute motor axonal neuropathy (AMAN)-like model best employed over a limited time frame, and 3) NOD WT mice as an AMAN model with mild clinical signs and lesions. Taken together these data demonstrate that C. jejuni strain genotype, host genotype and antibiotic treatment affect GBS disease outcomes in mice and that many disease phenotypes are possible.

    更新日期:2019-11-01
  • Identification of autoantibody against poly (ADP-ribose) polymerase (PARP) fragment as a serological marker in systemic lupus erythematosus.
    J. Autoimmun. (IF 7.543) Pub Date : 2004-01-08
    Dooil Jeoung,Yoon Lim,Eun Bong Lee,Seongeun Lee,Hae-Yeong Kim,Hansoo Lee,Yeong Wook Song

    OBJECTIVES By utilizing serological analysis of a recombinant cDNA expression library (SEREX), we previously found that autoantibodies to poly (ADP-ribose) polymerase (PARP) are specifically present in the sera of patients with SLE. In this study, recombinant proteins of various domains of PARP were used to determine the PARP domain that is associated with SLE. METHODS We produced four recombinant PARP proteins, which contained various PARP domains, and then carried out enzyme linked immunosorbent assay (ELISA) using these recombinant proteins to identify domains useful for SLE diagnosis. The recombinant proteins used in this analysis were; ADPNF (amino acids 1-234), ET-L2 (amino acids 339-680), ET-L3 (amino acids 681-1014), and ADPCF (amino acids 300-1014). RESULT ELISA with ADPNF or ET-L2 showed low sensitivity in the sera of patients with SLE (14.3% and 17.0% respectively), whereas ELISA with ET-L3 or ADPCF showed high sensitivity in the sera of patients with SLE (34.0% and 49.1%, respectively). Autoantibodies to ADPCF were not found in the sera of patients with rheumatoid arthritis (0/30), systemic sclerosis (0/30) or healthy donors (0/54) and were rarely found in polymyositis/dermatomyositis (1/30) and Sjogren syndrome (1/14). Autoantibodies to ADPCF were closely associated with the presence of an oral ulcer in SLE (P=0.03, by the chi-square test). CONCLUSION The high sensitivity and specificity shown by autoantibodies to ADPCF protein could be used as a valuable serologic maker for the diagnosis of SLE.

    更新日期:2019-11-01
  • Frequency of proteinase 3 (PR3)-specific autoreactive T cells determined by cytokine flow cytometry in Wegener's granulomatosis.
    J. Autoimmun. (IF 7.543) Pub Date : 2004-01-08
    Jolanta Winek,Antje Mueller,Elena Csernok,Wolfgang L Gross,Peter Lamprecht

    OBJECTIVE Previous studies have shown proliferation to Wegener's autoantigen, proteinase 3 (PR3). We tested immunogenicity of PR3-derived peptides and determined frequencies of PR3-specific T cells using cytokine flow cytometry in Wegener's granulomatois (WG). METHODS Peripheral blood T-cell responses were measured after stimulation with previously described PR3-derived peptides. PBMC were stimulated with PR3-derived peptides or control stimuli for up to 10 days. Cells were stained with antibodies against CD4 or CD8, CD69 and intracellular TNF-alpha and analyzed by flow cytometry. PR3-specific T cells were counted as the percentage of CD69(+)TNF-alpha(+)double positive T cells after stimulation. RESULTS Frequencies of PR3-specific peripheral blood T cells after short-term stimulation (

    更新日期:2019-11-01
  • Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type 1 diabetes.
    J. Autoimmun. (IF 7.543) Pub Date : 2004-01-08
    Akane Ide,Eiji Kawasaki,Norio Abiru,Fuyan Sun,Masakazu Kobayashi,Tetsuya Fukushima,Ryoko Takahashi,Hironaga Kuwahara,Atsushi Kita,Katsuya Oshima,Shigeo Uotani,Hironori Yamasaki,Yoshihiko Yamaguchi,Katsumi Eguchi

    Interleukin-18 (IL-18) is a potent proinflammatory cytokine which is strongly associated with the development of diabetes in NOD mice. To test the putative involvement of IL-18 gene polymorphism in predisposition to human type 1 diabetes, the SNPs at position -607 (C/A) and -137 (G/C) in the promoter region of IL-18 gene were analyzed by sequence-specific PCR in 116 patients with type 1 diabetes and 114 normal controls. A linkage disequilibrium found only three of the four possible haplotypes defined by these SNPs. The distribution of the IL-18 gene genotypes at position -607 was significantly different between patients with type 1 diabetes and normal controls (P=0.023). Furthermore, there was a significant increase in haplotype 1 (-607C/-137G) in the patients compared with controls (P=0.006). The association study of the susceptible CTLA-4 genotype (GG at nucleotide position 49 in exon 1) or HLA-DR4-DQB1*0401 and type 1 diabetes showed that the predisposing IL-18 gene haplotype modulates the risk on CTLA-4 GG genotype, but not on HLA-DR4-DQB1*0401 haplotype. Among subjects carrying the CTLA-4 GG genotype, the frequency of IL-18 haplotype 1 in patients with type 1 diabetes was significantly higher than that in controls (91% vs. 71%, P=0.012). However, IL-18 haplotype 1 was not frequent in patients who do not exhibit the CTLA-4 high-risk genotype. These results suggest that the IL-18 gene polymorphism is associated with a type 1 diabetes susceptibility, and there might be a gene-gene interaction between IL-18 gene with susceptible CTLA-4 gene.

    更新日期:2019-11-01
  • One-step cloning of anti tissue transglutaminase scFv from subjects with celiac disease.
    J. Autoimmun. (IF 7.543) Pub Date : 2004-01-08
    Daniele Sblattero,Fiorella Florian,Elisabetta Azzoni,Fabiana Ziberna,Alberto Tommasini,Tarcisio Not,Alessandro Ventura,Andrew Bradbury,Roberto Marzari

    Celiac disease is characterized by intestinal mucosal injury and malabsorption precipitated by dietary exposure to gluten of some cereals with a prominent role being played by gliadins, specific antigenic determinants found in wheat gluten. Patients suffering from celiac disease have serum antibodies recognizing gliadin, as well as the endomysial autoantigen tissue transglutaminase. Phage display antibody libraries have revealed ectopic production of anti-transglutaminase antibodies by intestinal lymphocytes with a biased use of the VH5 antibody gene family. Here we report a study on the pairing of VH and VL families in the antibodies to transglutaminase. Our results led to the construction of small phage display antibody libraries based on the amplification of the two genes in the VH5 family from intestinal lymphocytes. This method can be used for the rapid characterization of the anti-transglutaminase response in a potentially large number of subjects including asymptomatic patients whose serum antibodies may be undetectable.

    更新日期:2019-11-01
  • Epitopes recognised by tissue transglutaminase antibodies in coeliac disease.
    J. Autoimmun. (IF 7.543) Pub Date : 2004-01-08
    Ken Nakachi,Michael Powell,Gillian Swift,Marie-Andrée Amoroso,Rossitza Ananieva-Jordanova,Clare Arnold,Jane Sanders,Jadwiga Furmaniak,Bernard Rees Smith

    The interaction between IgA tissue transglutaminase (tTG) antibodies (Abs) and 35S-labelled tTG produced in a transcription/translation (TnT) system with various amino acid (aa) deletions has been studied. These experiments showed that the tTG N-terminal aa 1-89 were important for tTG Ab binding in all 15 coeliac disease sera studied and the central residues (aa 401-491) were important for binding of tTG Abs in all but one sera. The contribution of C-terminal residues to tTG Ab binding varied in different coeliac sera but overall was less than the contributions of the N terminal and central regions. Mouse monoclonal antibodies (MAbs) to tTG were produced and the tTG aa sequences recognised by the MAbs determined using modified 35S-labelled tTG proteins. Analysis of the inhibiting effects of patient sera tTG Ab on binding of tTG MAbs to tTG confirmed the importance of the N-terminal and central regions of tTG in forming serum tTG Ab binding sites. Recombinant human tTG was expressed in yeast and purified to better than 95% homogeneity using MAb affinity chromatography as a final purification step. This material was highly suitable for use in an ELISA for tTGAb.

    更新日期:2019-11-01
  • Natural anti-FcepsilonRIalpha autoantibodies may interfere with diagnostic tests for autoimmune urticaria.
    J. Autoimmun. (IF 7.543) Pub Date : 2004-01-08
    Jana M Pachlopnik,Michael P Horn,Michaela Fux,Markus Dahinden,Michèle Mandallaz,Dominique Schneeberger,Lucia Baldi,Monique Vogel,Beda M Stadler,Sylvia M Miescher

    IgG autoantibodies against the alpha-chain of the high affinity IgE receptor are claimed to play a pathogenetic role in autoimmune urticaria. The best methods for detection of functional autoantibodies are currently the autologous serum skin test and the basophil histamine release assay. A simplified and feasible screening test would facilitate the diagnosis of autoimmune urticaria. Here we offer an explanation for the difficulties in establishing a screening test for autoantibodies directed against the alpha-chain of the high affinity IgE receptor in autoimmune urticaria. Identical autoantibodies in chronic urticaria patients and healthy donors belonging to the natural autoantibody repertoire were found by sequence analysis of anti-alpha-chain autoantibodies isolated by repertoire cloning from antibody libraries. These natural autoantibodies bound to the receptor and triggered histamine release but only if IgE was previously removed from the receptor. Diagnostic assays used for detection of antibodies directed against the IgE receptor may require signal comparison with and without the artificial removal of IgE, immune complexes, and complement in order to avoid false positive or negative results. After IgE removal diagnostic tests will detect natural autoantibodies against the high affinity IgE receptor regardless of whether they are pathogenic or not.

    更新日期:2019-11-01
  • Inverse correlation between the incidences of autoimmune disease and infection predicted by a model of T cell mediated tolerance.
    J. Autoimmun. (IF 7.543) Pub Date : 2004-01-08
    Kalet León,Jose Faro,Agustin Lage,Jorge Carneiro

    The contribution of pathogenic infections to the etiology of autoimmune diseases remains one of the outstanding problems in immunology. According to the classical concept of antigen mimicry, a direct correlation between the incidence of autoimmunity and infections would be expected. This view is supported by a few examples of autoimmune disorders, which are documented as being caused by infection with particular pathogens. In contrast, there are several experimental animal models where infection appears to prevent the onset of autoimmunity. Moreover, some epidemiological studies suggest an inverse correlation between the incidence of autoimmunity and infections in human populations. Here we propose a solution to this puzzle based on a theoretical model of tolerance driven by regulatory T cells. The concepts here developed delineate the conditions predicting an inverse correlation between the incidence of autoimmunity and exposition to common infections, and those in which antigen mimicry and inflammation of target organs have a role in the etiology of specific autoimmune disorders.

    更新日期:2019-11-01
  • Apoptosis in feathers of Smyth line chickens with autoimmune vitiligo.
    J. Autoimmun. (IF 7.543) Pub Date : 2004-01-08
    X Wang,G F Erf

    Vitiligo is an acquired dermatological disorder characterized by a loss of epidermal melanocytes resulting in depigmentation of the skin. Mechanisms underlying the destruction of melanocytes in vitiligo remain unclear. An animal model to study spontaneously occurring autoimmune vitiligo is the mutant Smyth line (SL) of chickens. This investigation was designed to determine whether the pathogenesis of depigmentation in Smyth line chicken vitiligo (SLV) involves an apoptotic mechanism. Terminal deoxynucleotide transferase-mediated fluorescein-dUTP nick end labeling (TUNEL) was used to detect in situ cell apoptosis in cryostat sections of 2-week-old regenerating feathers. Two-week-old regenerating feathers were obtained from SL chickens and their normally pigmented controls including the parental Brown line (BL) and Light Brown Leghorn (LBL) chickens at 6, 8, 10 and 12 weeks of age. In feathers from vitiliginous SL chickens, the number of TUNEL+ cells was significantly (P

    更新日期:2019-11-01
  • Nasal instillation of gpMBP can exacerbate murine EAE: effect of mucosal priming is an age-dependent phenomenon.
    J. Autoimmun. (IF 7.543) Pub Date : 2004-01-08
    Marco E F Melo,David B Stevens,Eli E Sercarz,Claudia Raja Gabaglia

    Nasal installation or oral feeding of antigens can alter the subsequent immune response in animals and humans. Most mucosal treatments with antigens tend to down-regulate disease, inducing full tolerance or immune deviation; however, priming has also been reported. We evaluated the course of experimental autoimmune encephalomyelitis (EAE) in (SJL x B10.PL)F1 mice after nasal instillation of myelin basic protein. There was a tendency towards exacerbation of subsequent disease in animals if they were nasally exposed to gpMBP during the neonatal period (first week of life), compared to exposure during adulthood. Later, at 11 months of age, this tendency to exacerbate disappeared. Our results suggest that mucosal exposure during early life may regularly modulate the anti-self immune response upwards in individuals genetically predisposed to autoimmune diseases.

    更新日期:2019-11-01
  • Tumor necrosis factor alpha is not implicated in the genesis of experimental autoimmune gastritis.
    J. Autoimmun. (IF 7.543) Pub Date : 2004-01-08
    Aiden C J Marshall,Ban-Hock Toh,Frank Alderuccio

    Experimental autoimmune gastritis (EAG) characterised by mononuclear cell infiltrate, parietal and zymogenic cell destruction and circulating autoantibodies to gastric H(+)/K(+)ATPase is an animal model for human autoimmune gastritis, that leads to pernicious anaemia. We have previously shown that Fas has a role in initiating damage to target cells in EAG. Here we used three strategies to examine the role of TNFalpha in this disease. We administered neutralising anti-TNFalpha antibody either as a single injection or as twice weekly injections for 8 weeks to mice subjected to neonatal thymectomy-induced EAG. To address the role of apoptotic signals through TNFR1, TNFR1 deficient mice were either neonatally thymectomised or crossed to PC-GMCSF transgenic mice that spontaneously develop EAG. Neonatally thymectomised mice treated with anti-TNFalpha antibody developed destructive gastritis and autoantibodies to gastric H(+)/K(+)ATPase similar to control mice. Following either neonatal thymectomy or crossing to PC-GMCSF transgenic mice, TNFR1 deficient mice developed autoantibody-positive destructive gastritis at similar frequency compared with wild type and heterozygous littermates. Our observations that neutralisation of TNFalpha and absence of TNFR1 has no discernible effect on development of EAG suggest that TNFalpha is not required for mucosal cell damage or development of autoimmune gastritis. While blocking TNFalpha activity has therapeutic benefit in certain autoimmune diseases, this is not the case for EAG.

    更新日期:2019-11-01
  • Epitopes of calreticulin recognised by IgA autoantibodies from patients with hepatic and coeliac disease.
    J. Autoimmun. (IF 7.543) Pub Date : 2003-11-20
    Daniel Sánchez,Ludmila Tucková,Thomas Mothes,Wolfgang Kreisel,Zdenek Benes,Helena Tlaskalová-Hogenová

    Calreticulin (CRT) was identified as a frequent target of serum autoantibodies (Ab) in various diseases, but anti-CRT Ab of IgA isotype were described only in coeliac (CLD) and some hepatic diseases. Employing ELISA with recombinant CRT we found significantly higher (P<0.001) levels of IgA anti-CRT Ab in sera of patients with primary biliary cirrhosis (PBC) (77.6+/-8.9 AU/mean+/-SE), autoimmune hepatitis (AIH) (105.1+/-9.2 AU) and alcoholic liver cirrhosis (ALC) (193.5+/-21.0 AU) relative to healthy controls (38.6+/-2.0 AU). The levels of IgG anti-CRT Ab in sera of patients with PBC (59.5+/-3.4 AU), AIH (89.7+/-7.9 AU) and ALC (86.4+/-6.2 AU) were also significantly increased (P<0.001) when compared with controls (38.5+/-2.1 AU). Pepscan technique with decapeptides of CRT (each overlapping by eight amino acids) revealed antigenic epitopes of this molecule recognised by IgA Ab of almost all tested patients-KGKNVLINKD and QVKSGTIFDNFL. We also identified disease specific antigenic epitopes on CRT molecule, predominantly recognised by IgA Ab of patients suffering from a particular disease: GGYVKLFPNS and YVKLFPNSLD in AIH (83%, 92% of patients), GLQTSQDARF and EQRLKEEEED in CLD (both 75%) and ASKPEDWDER in ALC (67%). Identification of disease specific CRT epitopes contributes to clarification of autoreactivity against this molecule.

    更新日期:2019-11-01
  • Fine mapping of diabetes-associated IA-2 specific autoantibodies.
    J. Autoimmun. (IF 7.543) Pub Date : 2003-11-20
    Massimo Bearzatto,Vito Lampasona,Cristina Belloni,Ezio Bonifacio

    The related tyrosine phosphatase-like proteins (PTP) IA-2 and IA-2beta are autoantigens of type 1 diabetes. Autoantibodies are predominantly against IA-2. We utilized the close homology between IA-2 and IA-2beta PTP domains to design chimeras and mutants in order to identify humoral IA-2-specific epitopes. Fifteen sera with antibodies to IA-2 specific PTP domain epitopes were tested against IA-2beta(741-848)/IA-2(795-889)/IA-2beta(943-1033), IA-2beta(741-848)/IA-2(795-845)/IA-2beta(900-1033), and IA-2beta(741-898)/IA-2(845-875)/IA-2beta(930-1033)chimeras. Two sera bound IA-2beta(741-848)/IA-2(795-889)/IA-2beta(943-1033)and IA-2beta(741-848)/IA-2(795-845)/IA-2beta(900-1033)only indicating that the IA-2 specific residues 859, 862, and/or 867 were critical for antibody binding. Mutation of glutamine 862 abolished binding in one of these sera. Seven sera bound only the IA-2beta(741-848)/IA-2(795-889)/IA-2beta(943-1033)chimera, indicating that binding required IA-2 specific amino acids within both 795-845 and 846-875, or that IA-2 residues 876-888 were important for binding. Mutation of glutamine 862 abolished binding in two of these sera, and mutation of residues 876, 877, 878, and 880 markedly reduced binding in two others. Six sera bound all three chimeras indicating that they contained multiple IA-2 specific PTP domain antibodies. In three of these sera, mutation of residues at positions 876, 877, 878, 880, and/or residues 862 and 822 reduced antibody binding by more than 50%. These findings indicate that glutamine at position 862, and residues 876-880 of the WPD loop of IA-2 are important for several of the IA-2 specific PTP domain epitopes.

    更新日期:2019-11-01
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