Autoimmunity

Adipocytes orchestrate the formation of tertiary lymphoid organs in the creeping fat of Crohn's disease affected mesentery Publication date: Available online 4 June 2019 Source: Journal of Autoimmunity Author(s): Kevin Guedj, Yaël Abitbol, Dominique Cazals-Hatem, Marion Morvan, Léon Maggiori, Yves Panis, Yoram Bouhnik, Giuseppina Caligiuri, Olivier Corcos, Antonino Nicoletti Abstract The formation of tertiary lymphoid organs (TLOs) is orchestrated by the stromal cells of tissues chronically submitted to inflammatory stimuli, in order to uphold specific adaptive immune responses. We have recently shown that the smooth muscle cells of the arterial wall orchestrate the formation of the TLOs associated with atherosclerosis in response to the local release of TNF-α. Observational studies have recently documented the presence of structures resembling TLOs the creeping fat that develops in the mesentery of patients with Crohn's disease (CD), an inflammatory condition combining a complex and as yet not elucidated infectious and autoimmune responses. We have performed a comprehensive analysis of the TLO structures in order to decipher the mechanism leading to their formation in the mesentery of CD patients, and assessed the effect of infectious and/or inflammatory inducers on the potential TLO-organizer functions of adipocytes. Quantitative analysis showed that both T and B memory cells, as well as plasma cells, are enriched in the CD-affected mesentery, as compared with tissue from control subjects. Immunohistochemistry revealed that these cells are concentrated within the creeping fat of CD patients, in the vicinity of transmural lesions; that T and B cells are compartmentalized in clearly distinct areas; that they are supplied by post-capillary high endothelial venules and drained by lymphatic vessels indicating that these nodules are fully mature TLOs. Organ culture showed that mesenteric tissue samples from CD patients contained greater amounts of adipocyte-derived chemokines and the use of the conditioned medium from these cultures in functional assays was able to actively recruit T and B lymphocytes. Finally, the production of chemokines involved in TLO formation by 3T3-L1 adipocytes was directly elicited by a combination of TNF-α and LPS in vitro. We therefore propose a mechanism in which mesenteric adipocyte, through their production of key chemokines in response to inflammatory/bacterial stimuli, may orchestrate the formation of functional TLOs developing in CD-affected mesentery. Graphical abstract

The proteasome activator REGγ counteracts immunoproteasome expression and autoimmunity Publication date: Available online 4 June 2019 Source: Journal of Autoimmunity Author(s): Liangfang Yao, Lei Zhou, Yang Xuan, Pei Zhang, Xiaoshuang Wang, Tianzhen Wang, Tianyuan Meng, Yanyan Xue, Xueqing Ma, Abdus Saboor Shah, Shiwang Shang, Xinglong Ma, Wei Xie, Hao Wang, Qing Fu, Yanyang Xia, Robb E. Moses, Hongyan Wang, Lei Li, Jianru Xiao Abstract For quite a long time, the 11S proteasome activator REGɑ and REGβ, but not REGγ, are known to control immunoproteasome and promote antigen processing. Here, we demonstrate that REGγ functions as an inhibitor for immunoproteasome and autoimmune disease. Depletion of REGγ promotes MHC class I-restricted presentation to prime CD8+ T cells in vitro and in vivo. Mice deficient for REGγ have elevation of CD8+ T cells and DCs, and develop age-related spontaneous autoimmune symptoms. Mechanistically, REGγ specifically interacts with phosphorylated STAT3 and promotes its degradation in vitro and in cells. Inhibition of STAT3 dramatically attenuates levels of LMP2/LMP7 and antigen presentation in cells lacking REGγ. Importantly, treatment with STAT3 or LMP2/7 inhibitor prevented accumulation of immune complex in REGγ−/− kidney. Moreover, REGγ−/−mice also expedites Pristane-induced lupus. Bioinformatics and immunohistological analyses of clinical samples have correlated lower expression of REGγ with enhanced expression of phosphorylated STAT3, LMP2 and LMP7 in human Lupus Nephritis. Collectively, our results support the concept that REGγ is a new regulator of immunoproteasome to balance autoimmunity.

Inflammatory myopathy associated with PD-1 inhibitors Publication date: June 2019 Source: Journal of Autoimmunity, Volume 100 Author(s): Morinobu Seki, Akinori Uruha, Yuko Ohnuki, Sachiko Kamada, Tomoko Noda, Asako Onda, Masayuki Ohira, Aiko Isami, Sumie Hiramatsu, Makoto Hibino, Shunya Nakane, Seiya Noda, Sachiko Yutani, Akira Hanazono, Hiroshi Yaguchi, Masaki Takao, Takashi Shiina, Masahisa Katsuno, Jin Nakahara, Shiro Matsubara Abstract Objective To characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). Methods We studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. Results In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%) patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. Conclusions Based on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.

Expansion of circulating extrafollicular helper T-like cells in patients with chronic graft-versus-host disease Publication date: June 2019 Source: Journal of Autoimmunity, Volume 100 Author(s): Hua Jin, Kaibo Yang, Haiyan Zhang, Yanqiu Chen, Hanzhou Qi, Zhiping Fan, Fen Huang, Li Xuan, Ren Lin, Ke Zhao, Qifa Liu Abstract Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have shown that T follicular helper cells (Tfh) contribute to immune pathology in cGVHD, but the function of extrafollicular helper T cells during cGVHD pathogenesis remains largely unknown. In the current study, we identified circulating extrafollicular helper T-like cells (CD44hiCD62LloPSGL-1loCD4+, c-extrafollicular Th-like) in human peripheral blood. We performed phenotypic and functional analyses of c-extrafollicular Th-like cells from 80 patients after allo-HSCT to explore the role of these cells in the development of human cGVHD. Patients with active cGVHD had significantly higher frequencies and counts of c-extrafollicular Th-like cells than those of patients without cGVHD. The expansion of c-extrafollicular Th-like cells was more significant in patients with moderate/severe cGVHD than that of patients with mild cGVHD. C-extrafollicular Th-like cells from patients with active cGVHD exhibited increased functional abilities to induce plasmablast differentiation and IgG1 secretion compared to those of patients without cGVHD. Moreover, c-extrafollicular Th-like cell levels were highly correlated with the generation of autoreactive B cells, plasmablasts and IgG1 antibodies. Our studies provide new insights into human cGVHD pathogenesis and identify c-extrafollicular Th-like cells as a key element in the development of human cGVHD.

cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model Publication date: June 2019 Source: Journal of Autoimmunity, Volume 100 Author(s): Nanyang Xiao, Jingjing Wei, Shan Xu, Hekang Du, Miaohui Huang, Sitong Zhang, Weiwei Ye, Lijun Sun, Qi Chen Abstract TREX1 encodes a major cellular DNA exonuclease. Mutations of this gene in human cause cellular accumulation of DNA that triggers autoimmune diseases including Aicardi–Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE). We created a lupus mouse model by engineering a D18 N mutation in the Trex1 gene which inactivates the enzyme and has been found in human patients with lupus-like disorders. The Trex1D18N/D18N mice exhibited systemic inflammation that consistently recapitulates many characteristics of human AGS and SLE. Importantly, ablation of cGas gene in the Trex1D18N/D18N mice rescued the lethality and all detectable pathological phenotypes, including multi-organ inflammation, interferon stimulated gene induction, autoantibody production and aberrant T-cell activation. These results indicate that cGAS is a key mediator in the autoimmune disease associated with defective TREX1 function, providing additional insights into disease pathogenesis and guidance to the development of therapeutics for human systemic autoimmune disorders.

Transcriptomic and proteomic analysis of iris tissue and aqueous humor in juvenile idiopathic arthritis-associated uveitis Publication date: June 2019 Source: Journal of Autoimmunity, Volume 100 Author(s): Lena Wildschütz, Doreen Ackermann, Anika Witten, Maren Kasper, Martin Busch, Shirin Glander, Harutyun Melkonyan, Karoline Walscheid, Christoph Tappeiner, Solon Thanos, Andrei Barysenka, Jörg Koch, Carsten Heinz, Björn Laffer, Dirk Bauer, Monika Stoll, Simone König, Arnd Heiligenhaus Abstract Gene and protein expression profiles of iris biopsies, aqueous humor (AqH), and sera in patients with juvenile idiopathic arthritis-associated uveitis (JIAU) in comparison to control patients with primary open-angle glaucoma (POAG) and HLA-B27-positive acute anterior uveitis (AAU) were investigated. Via RNA Sequencing (RNA-Seq) and mass spectrometry-based protein expression analyses 136 genes and 56 proteins could be identified as being significantly differentially expressed (DE) between the JIAU and POAG group. Gene expression of different immunoglobulin (Ig) components as well as of the B cell-associated factors ID3, ID1, and EBF1 was significantly upregulated in the JIAU group as compared to POAG patients. qRT-PCR analysis showed a significantly higher gene expression of the B cell-related genes CD19, CD20, CD27, CD138, and MZB1 in the JIAU group. At the protein level, a significantly higher expression of Ig components in JIAU than in POAG was confirmed. The B cell-associated protein MZB1 showed a higher expression in JIAU patients than in POAG which was confirmed by western blot analysis. Using bead-based immunoassay analysis we were able to detect a significantly higher concentration of the B cell-activating and survival factors BAFF, APRIL, and IL-6 in the AqH of JIAU and AAU patients than in POAG patients. The intraocularly upregulated B cell-specific genes and proteins in iris tissue suggest that B cells participate in the immunopathology of JIAU. The intracameral environment in JIAU may facilitate local effector and survival functions of B cells, leading to disease course typical for anterior uveitis.

Plcγ2/Tmem178 dependent pathway in myeloid cells modulates the pathogenesis of cytokine storm syndrome Publication date: June 2019 Source: Journal of Autoimmunity, Volume 100 Author(s): Sahil Mahajan, Corinne E. Decker, Zhengfeng Yang, Deborah Veis, Elizabeth D. Mellins, Roberta Faccio Abstract Cytokine storm syndrome (CSS) is a life-threatening condition characterized by excessive activation of T cells and uncontrolled inflammation, mostly described in patients with familial hemophagocytic lymphohistiocytosis and certain systemic auto-inflammatory diseases, such as systemic juvenile idiopathic arthritis (sJIA). Defects in T cell cytotoxicity as a mechanism for uncontrolled inflammation following viral infections fail to represent the whole spectrum of CSS. Evidence implicates dysregulated innate immune responses, especially activation of monocytes and macrophages, in patients with CSS. However, the direct contribution of monocytes/macrophages to CSS development and the signaling pathways involved in their activation have not been formally investigated. We find that depletion of monocytes/macrophages during early stages of CSS development, by clodronate-liposomes or neutralizing anti-CSF1 antibody, reduces mortality and inflammatory cytokine levels in two CSS mouse models, one dependent on T cells and the second induced by repeated TLR9 stimulation. We further demonstrate that activation of Plcγ2 in myeloid cells controls CSS development by driving macrophage pro-inflammatory responses. Intriguingly, the Plcγ2 downstream effector Tmem178, a negative modulator of calcium levels, acts in a negative feedback loop to restrain inflammatory cytokine production. Genetic deletion of Tmem178 leads to pro-inflammatory macrophage polarization in vitro and more severe CSS in vivo. Importantly, Tmem178 levels are reduced in macrophages from mice with CSS and after exposure to plasma from sJIA patients with active disease. Our data identify a novel Plcγ2/Tmem178 axis as a modulator of inflammatory cytokine production by monocytes/macrophages. We also find that loss of Tmem178 accentuates the pro-inflammatory responses in CSS.

AS101 ameliorates experimental autoimmune uveitis by regulating Th1 and Th17 responses and inducing Treg cells Publication date: June 2019 Source: Journal of Autoimmunity, Volume 100 Author(s): So Jin Bing, Itay Shemesh, Wai Po Chong, Reiko Horai, Yingyos Jittayasothorn, Phyllis B. Silver, Benjamin Sredni, Rachel R. Caspi Abstract AS101 is an organotellurium compound with multifaceted immunoregulatory properties that is remarkable for its lack of toxicity. We tested the therapeutic effect of AS101 in experimental autoimmune uveitis (EAU), a model for human autoimmune uveitis. Unexpectedly, treatment with AS101 elicited Treg generation in vivo in otherwise unmanipulated mice. Mice immunized for EAU with the retinal antigen IRBP and treated with AS101 developed attenuated disease, as did AS101-treated recipients of retina-specific T cells activated in vitro. In both settings, eye-infiltrating effector T cells were decreased, whereas regulatory T (Treg) cells in the spleen were increased. Mechanistic studies in vitro revealed that AS101 restricted polarization of retina-specific T cells towards Th1 or Th17 lineage by repressing activation of their respective lineage-specific transcription factors and downstream signals. Retina-specific T cells polarized in vitro towards Th1 or Th17 in the presence of AS101 had impaired ability to induce EAU in naïve recipients. Finally, AS101 promoted differentiation of retina-specific T cells to Tregs in vitro independently of TGF-β. We conclude that AS101 modulates autoimmune T cells by inhibiting acquisition and expression of effector function and by promoting Treg generation, and suggest that AS101 could be useful as a therapeutic approach for autoimmune uveitis.

Endogenous double-stranded Alu RNA elements stimulate IFN-responses in relapsing remitting multiple sclerosis Publication date: June 2019 Source: Journal of Autoimmunity, Volume 100 Author(s): Maxwell J. Heinrich, Caroline A. Purcell, Andrea J. Pruijssers, Yang Zhao, Charles F. Spurlock, Subramaniam Sriram, Kristen M. Ogden, Terence S. Dermody, Matthew B. Scholz, Philip S. Crooke, John Karijolich, Thomas M. Aune Abstract Various sensors that detect double-stranded RNA, presumably of viral origin, exist in eukaryotic cells and induce IFN-responses. Ongoing IFN-responses have also been documented in a variety of human autoimmune diseases including relapsing-remitting multiple sclerosis (RRMS) but their origins remain obscure. We find increased IFN-responses in leukocytes in relapsing-remitting multiple sclerosis at distinct stages of disease. Moreover, endogenous RNAs isolated from blood cells of these same patients recapitulate this IFN-response if transfected into naïve cells. These endogenous RNAs are double-stranded RNAs, contain Alu and Line elements and are transcribed from leukocyte transcriptional enhancers. Thus, transcribed endogenous retrotransposon elements can co-opt pattern recognition sensors to induce IFN-responses in RRMS.

Soluble siglec-5 is a novel salivary biomarker for primary Sjogren's syndrome Publication date: June 2019 Source: Journal of Autoimmunity, Volume 100 Author(s): Jennifer Lee, Jaeseon Lee, SeungYe Baek, Jung Hee Koh, Ji-Won Kim, Sang-Yeon Kim, So-Hyang Chung, Sun Shim Choi, Mi-La Cho, Seung-Ki Kwok, Ji Hyeon Ju, Sung-Hwan Park Abstract Despite advances in the understanding of the pathogenesis, disease-specific biomarkers have not been included in the classification criteria for Primary Sjogren's syndrome (pSS). Based on a microarray of peripheral blood mononuclear cells (PBMCs) from patients with primary Sjogren's syndrome (pSS), we aimed to investigate whether soluble sialic acid-binding immunoglobulin-like lectin (siglec)-5 in saliva might be a biomarker for pSS. The concentration of siglec-5 in saliva and sera was determined by ELISA. Clinical parameters related with pSS were obtained from pSS registry and correlation with salivary siglec-5 level was evaluated. Receiver operating curve (ROC) analysis was performed to determine cut off value. A separate validation cohort consisted of subjects with suspicious pSS was evaluated to determine the performance. The level of salivary siglec-5 was significantly higher in pSS patients (n = 170) compared with HCs (n = 25), non SS sicca patients (n = 78) or patients with systemic lupus erythematosus (SLE) (n = 43) (1346.8 [202.8–4280.0] pg/mL, 6.08 [0–134.0] pg/mL, 195 [0–947.5] pg/mL, and 0 [0–238.7] pg/mL, median [interquartile range], P < 0.001). Salivary siglec-5 level negatively correlated with salivary flow rate (spearman's rho: −0.420, P < 0.001), and positively correlated with ocular surface score (rho: 0.331, P < 0.001) and serum immunoglobulin G level (rho = 0.202, P = 0.008). In ROC analysis, area under the curve was 0.774[0.724–0.826]. With a cut off value of 400 pg/mL, sensitivity and specificity was 0.69 and 0.70 respectively. In validation cohort (45 pSS patients and 45 non SS sicca patients), sensitivity and specificity of siglec-5 was 64.4% and 77.8%, respectively. In conclusion, the level of soluble siglec-5 is significantly higher in the saliva from pSS patients, which reflects the severity of hyposalivation and ocular surface damage. This novel salivary biomarker may provide benefits for pSS diagnosis.

Alexandros Sfakianakis
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6948891480

alsfakia@gmail.com