Journal of autoimmunity最新文献

{"title":"Lupus-prone NZM2328 mice exhibit enhanced UV-induced myeloid cell recruitment and activation in a type I interferon dependent manner","authors":"Mitra P. Maz ,&nbsp;Alayka L. Reddy ,&nbsp;Celine C. Berthier ,&nbsp;Lam C. Tsoi ,&nbsp;Deborah J. Colesa ,&nbsp;Sonya J. Wolf ,&nbsp;Hong Shi ,&nbsp;Shannon N. Loftus ,&nbsp;Rezvan Moallemian ,&nbsp;Rachael Bogle ,&nbsp;Matthias Kretzler ,&nbsp;Chaim O. Jacob ,&nbsp;Johann E. Gudjonsson ,&nbsp;J. Michelle Kahlenberg","doi":"10.1016/j.jaut.2024.103296","DOIUrl":"10.1016/j.jaut.2024.103296","url":null,"abstract":"<div><p>Though the exact causes of systemic lupus erythematosus (SLE) remain unknown, exposure to ultraviolet (UV) light is one of the few well-known triggers of cutaneous inflammation in SLE. However, the precise cell types which contribute to the early cutaneous inflammatory response in lupus, and the ways that UV dosing and interferons modulate these findings, have not been thoroughly dissected. Here, we explore these questions using the NZM2328 spontaneous murine model of lupus. In addition, we use iNZM mice, which share the NZM2328 background but harbor a whole-body knockout of the type I interferon (IFN) receptor, and wild-type BALB/c mice. 10-13-week-old female mice of each strain were treated with acute (300 mJ/cm² x1), chronic (100 mJ/cm² daily x5 days), or no UVB, and skin was harvested and processed for bulk RNA sequencing and flow cytometry. We identify that inflammatory pathways and gene signatures related to myeloid cells – namely neutrophils and monocyte-derived dendritic cells – are a shared feature of the acute and chronic UVB response in NZM skin greater than iNZM and wild-type skin. We also verify recruitment and activation of these cells by flow cytometry in both acutely and chronically irradiated NZM and WT mice and demonstrate that these processes are dependent on type I IFN signaling. Taken together, these data indicate a skewed IFN-driven inflammatory response to both acute and chronic UVB exposure in lupus-prone skin dominated by myeloid cells, suggesting both the importance of type I IFNs and myeloid cells as therapeutic targets for photosensitive patients and highlighting the risks of even moderate UV exposure in this patient population.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103296"},"PeriodicalIF":7.9,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amelioration of immunoglobulin A vasculitis by suppression of the pathological expansion of T follicular helper 17 cells","authors":"Qinglian Jiang ,&nbsp;Xuyang Chi ,&nbsp;Tong Wei ,&nbsp;Shingo Nakayamada ,&nbsp;Yu Shan ,&nbsp;Yini Sun ,&nbsp;Xing Zhao ,&nbsp;Jieqing Zhou ,&nbsp;Yan Fan ,&nbsp;Jia Gu ,&nbsp;Hong Jiang ,&nbsp;Xiaoxue Ma","doi":"10.1016/j.jaut.2024.103304","DOIUrl":"10.1016/j.jaut.2024.103304","url":null,"abstract":"<div><p>The main pathogenic features of immunoglobulin A vasculitis (IgAV) are overactive B cells and elevated production of IgA, which requires help from T follicular helper 17 (Tfh17) cells. To evaluate the pathological role of Tfh17 cells in IgAV, we investigated the mechanism responsible for Tfh17 differentiation and explored how to ameliorate IgAV by modulating Tfh17 generation.</p><p>Peripheral blood mononuclear cells from IgAV patients were analyzed by flow cytometry. In vitro culture was performed to assess the modulation of cytokine-induced phenotypes. IgAV rats were used to explore the therapeutic effects of IL-6 blockade and the regulatory functions of IL-6 in Tfh17 cells. Serum cytokine and IgA levels were measured by ELISA while histopathological changes were evaluated by H&amp;E,PAS or immunofluorescence staining.</p><p>Frequency of CD4⁺CXCR5⁺CCR6⁺ Tfh17 cells were increased in IgAV patients and associated with disease severity. There was also a significant infiltration of Tfh17 cells in the kidney of human IgAV nephritis patients. IL-6 promoted the dendritic cell production of TGF-β and Tfh17 differentiation. In IgAV rats, the in vivo blockade of IL-6 signaling inhibited Tfh17 differentiation, resulting in reduction of the germinal center and IgA production. Suppression of Tfh17 cells using IL-6 blockade greatly ameliorated clinical symptoms such as hemorrhagic rash and bloody stool and decreased IgA deposition and mesangial proliferation in the kidney in IgAV rats.</p><p>Our findings suggest that suppression of Tfh17 differentiation can alleviate IgA-mediated vasculitis and may permit the development of tailored medicines for treating IgAV.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103304"},"PeriodicalIF":7.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142130002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety of biologic immunosuppressants in pregnant women with immune-mediated inflammatory diseases.","authors":"Martínez-Sánchez N, J Álvarez-Troncoso, Á Robles-Marhuenda, M De la Calle Fernández-Miranda, M L Muner Hernando, J L Bartha","doi":"10.1016/j.jaut.2024.103301","DOIUrl":"10.1016/j.jaut.2024.103301","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Immune-mediated inflammatory diseases (IMIDs) typically affect women of childbearing age. One of the challenges in treating these women during pregnancy is to manage the disease while minimizing or avoiding the use of disease-modifying antirheumatic drugs (DMARDs) that may increase the risk to the mother or fetus. Biologic therapy has transformed the management of these patients. This study aimed to evaluate the maternal-fetal safety and perinatal outcomes in pregnant women with IMID exposed to biologic DMARDs either preconceptionally or during pregnancy and compare them with women using conventional DMARDs and a group of healthy pregnant women.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We conducted a retrospective study with prospective follow-up of pregnant women with IMID at a single center. We analyzed baseline maternal demographic characteristics, diseases, DMARDs, and maternal-fetal outcomes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A cohort of 244 pregnancies was studied. One hundred twenty-eight patients met classificatory criteria for rheumatic and musculoskeletal diseases (RMD) or inflammatory bowel disease (IBD), and 116 pregnancies of healthy women were evaluated from the same study period. One hundred and one pregnancies in IMID patients (89.84 %) occurred under immunosuppressive treatment, 78.91 % of IMID pregnancies were under cDMARD (33.59 % exclusive cDMARD), 56.25 % under bDMARD, and 27.34 % under oral glucocorticoids. Anti-TNF was the most frequent (88.88 %) bDMARD and was used in 50.78 % of the IMIDs. There was at least one flare in 37.10 % of the IMID pregnancies, and 9.38 % experienced more than one. Among flares, 43.48 % happened in the first trimester, 34.78 % in the second trimester, and 19.57 % in the third. Flares were more frequent in the RMD patients compared with IBD (p = 0.041; OR 2.15, 95%CI: 1.03-4.52). Flare was associated with discontinuation of bDMARD before the eighth week of gestation (p = 0.016), but especially in the second (p = 0.042) and third trimester (p = 0.012). Maternal infections were an infrequent complication overall (7.66 %), although more frequent in patients with IMIDs (p = 0.004) but were not associated with cDMARD or bDMARD. IMID patients needed assisted reproductive techniques (ART) more often (p = 0.001, OR 2.83, 95%CI: 1.02-7.90). More cesarean sections were performed in gestations under treatment with bDMARD (p = 0.020) and especially in those under treatment with anti-TNF. Aneuploidies calculation risk and fetal malformations were not correlated with DMARDs (cDMARDs, bDMARDs, or its combination) nor with any of the DMARDs individually preconcepcionally or during gestation. Small for gestational age (SGA) newborns were higher in patients with IMIDs however, it was not associated with DMARD use.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;In general, patients with IMIDs who require treatment with bDMARDs have a more severe or refractory disease prior to gestation. In our cohort, we fou","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"103301"},"PeriodicalIF":7.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High throughput screening identifies repurposable drugs for modulation of innate and acquired immune responses","authors":"Saeedeh Ghorbanalipoor ,&nbsp;Kazuko Matsumoto ,&nbsp;Natalie Gross ,&nbsp;Linda Heimberg ,&nbsp;Malin Krause ,&nbsp;Wendelien Veldkamp ,&nbsp;Moritz Magens ,&nbsp;Johannes Zanken ,&nbsp;Kerstin J. Neuschutz ,&nbsp;David A. De Luca ,&nbsp;Khalaf Kridin ,&nbsp;Gestur Vidarsson ,&nbsp;Lenche Chakievska ,&nbsp;Remco Visser ,&nbsp;Sven Kunzel ,&nbsp;Andreas Recke ,&nbsp;Yask Gupta ,&nbsp;Katharina Boch ,&nbsp;Artem Vorobyev ,&nbsp;Kathrin Kalies ,&nbsp;Ralf J. Ludwig","doi":"10.1016/j.jaut.2024.103302","DOIUrl":"10.1016/j.jaut.2024.103302","url":null,"abstract":"<div><p>A balanced immune system is essential to maintain adequate host defense and effective self-tolerance. While an immune system that fails to generate appropriate response will permit infections to develop, uncontrolled activation may lead to autoinflammatory or autoimmune diseases. To identify drug candidates capable of modulating immune cell functions, we screened 1200 small molecules from the Prestwick Chemical Library for their property to inhibit innate or adaptive immune responses. Our studies focused specifically on drug interactions with T cells, B cells, and polymorphonuclear leukocytes (PMNs). Candidate drugs that were validated <em>in vitro</em> were examined in preclinical models to determine their immunomodulatory impact in chronic inflammatory diseases, here investigated in chronic inflammatory skin diseases. Using this approach, we identified several candidate drugs that were highly effective in preclinical models of chronic inflammatory disease. For example, we found that administration of pyrvinium pamoate, an FDA-approved over-the-counter anthelmintic drug, suppressed B cell activation <em>in vitro</em> and halted the progression of B cell-dependent experimental pemphigoid by reducing numbers of autoantigen-specific B cell responses. In addition, in studies performed in gene-deleted mouse strains provided additional insight into the mechanisms underlying these effects, for example, the receptor-dependent actions of tamoxifen that inhibit immune-complex-mediated activation of PMNs. Collectively, our methods and findings provide a vast resource that can be used to identify drugs that may be repurposed and used to promote or inhibit cellular immune responses.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103302"},"PeriodicalIF":7.9,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0896841124001367/pdfft?md5=6df75e17d608bfa2255c8ac64d58e9a8&pid=1-s2.0-S0896841124001367-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142006973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Telitacicept: A novel horizon in targeting autoimmunity and rheumatic diseases","authors":"Liuting Zeng ,&nbsp;Kailin Yang ,&nbsp;Yang Wu ,&nbsp;Ganpeng Yu ,&nbsp;Yexing Yan ,&nbsp;Moujia Hao ,&nbsp;Tian Song ,&nbsp;Yuwei Li ,&nbsp;Junpeng Chen ,&nbsp;Lingyun Sun","doi":"10.1016/j.jaut.2024.103291","DOIUrl":"10.1016/j.jaut.2024.103291","url":null,"abstract":"<div><p>BLyS and APRIL have the capability to bind to B cells within the body, allowing these cells to evade elimination when they should naturally be removed. While BLyS primarily plays a role in B cell development and maturation, APRIL is linked to B cell activation and the secretion of antibodies. Thus, in theory, inhibiting BLyS or APRIL could diminish the population of aberrant B cells that contribute to SLE and reduce disease activity in patients. Telitacicept functions by binding to and neutralizing the activities of both BLyS and APRIL, thus hindering the maturation and survival of plasma cells and fully developed B cells. The design of telitacicept is distinctive; it is not a monoclonal antibody but a TACI-Fc fusion protein generated through recombinant DNA technology. This fusion involves merging gene segments of the TACI protein, which can target BLyS/APRIL simultaneously, with the Fc gene segment of the human IgG protein. The TACI-Fc fusion protein exhibits the combined characteristics of both proteins. Currently utilized for autoimmune disease treatment, telitacicept is undergoing clinical investigations globally to assess its efficacy in managing various autoimmune conditions. This review consolidates information on the mechanistic actions, dosing regimens, pharmacokinetics, efficacy, and safety profile of telitacicept—a dual-targeted biological agent. It integrates findings from prior experiments and pharmacokinetic analyses in the treatment of RA and SLE, striving to offer a comprehensive overview of telitacicept's research advancements.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103291"},"PeriodicalIF":7.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141985310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WTAP promotes the progression of ulcerative colitis by silencing the expression of CES2 through m6A modification","authors":"Xiaoran Xie ,&nbsp;Sha Cheng ,&nbsp;Xiong Chen ,&nbsp;Xia Wang","doi":"10.1016/j.jaut.2024.103295","DOIUrl":"10.1016/j.jaut.2024.103295","url":null,"abstract":"<div><h3>Objective</h3><p>This study will explore the function of WTAP, the critical segment of m⁶A methyltransferase complex, in UC and its regulation on immune response.</p></div><div><h3>Methods</h3><p>The expression levels of key proteins were detected in colon tissues which were derived from UC patients and mice. Macrophage polarization and CD4⁺ T cell infiltration were detected by flow cytometry and IF staining. ELISA assay was utilized to analyze the level of the inflammatory cytokines. m⁶A-RIP-PCR, actinomycin D test, and RIP assays were utilized to detect the m⁶A level, stability, and bound proteins of CES2 mRNA. A dual luciferase reporter assay was conducted to confirm the transcriptional interactions between genes. A co-culture system of intestinal epithelium-like organs was constructed to detect the primary mouse intestinal epithelial cells (PMIEC) differentiation. The interaction between proteins was detected via Co-IP assay.</p></div><div><h3>Results</h3><p>The expression of WTAP and CES2 in UC tissues was increased and decreased, respectively. Knockdown of WTAP inhibited the progression of UC in mice by inhibiting M1 macrophage polarization and CD4⁺ T cell infiltration. WTAP combined YTHDF2 to promote the m⁶A modification of CES2 mRNA and inhibited its expression. CES2 co-expressed with EPHX2 and overexpression of CES2 promoted the differentiation of PMIEC. The inhibitory effect of WTAP knockdown on the progress of UC was partially abrogated by CES2 knockdown.</p></div><div><h3>Conclusion</h3><p>WTAP/YTHDF2 silences CES2 by promoting its m⁶A modification and then promotes the progression of UC. WTAP could be a promoting therapy target of UC.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103295"},"PeriodicalIF":7.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141978305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antigen-specific T cells and autoimmunity","authors":"Manuel Rojas ,&nbsp;Yeny Acosta-Ampudia ,&nbsp;Luke S. Heuer ,&nbsp;Weici Zang ,&nbsp;Diana M Monsalve ,&nbsp;Carolina Ramírez-Santana ,&nbsp;Juan-Manuel Anaya ,&nbsp;William M Ridgway ,&nbsp;Aftab A Ansari ,&nbsp;M. Eric Gershwin","doi":"10.1016/j.jaut.2024.103303","DOIUrl":"10.1016/j.jaut.2024.103303","url":null,"abstract":"<div><p>Autoimmune diseases (ADs) showcase the intricate balance between the immune system's protective functions and its potential for self-inflicted damage. These disorders arise from the immune system's erroneous targeting of the body's tissues, resulting in damage and disease. The ability of T cells to distinguish between self and non-self-antigens is pivotal to averting autoimmune reactions. Perturbations in this process contribute to AD development. Autoreactive T cells that elude thymic elimination are activated by mimics of self-antigens or are erroneously activated by self-antigens can trigger autoimmune responses. Various mechanisms, including molecular mimicry and bystander activation, contribute to AD initiation, with specific triggers and processes varying across the different ADs. In addition, the formation of neo-epitopes could also be implicated in the emergence of autoreactivity. The specificity of T cell responses centers on the antigen recognition sequences expressed by T cell receptors (TCRs), which recognize peptide fragments displayed by major histocompatibility complex (MHC) molecules. The assortment of TCR gene combinations yields a diverse array of T cell populations, each with distinct affinities for self and non-self antigens. However, new evidence challenges the traditional notion that clonal expansion solely steers the selection of higher-affinity T cells. Lower-affinity T cells also play a substantial role, prompting the “two-hit” hypothesis. High-affinity T cells incite initial responses, while their lower-affinity counterparts perpetuate autoimmunity. Precision treatments that target antigen-specific T cells hold promise for avoiding widespread immunosuppression. Nevertheless, detection of such antigen-specific T cells remains a challenge, and multiple technologies have been developed with different sensitivities while still harboring several drawbacks. In addition, elements such as human leukocyte antigen (HLA) haplotypes and validation through animal models are pivotal for advancing these strategies. In brief, this review delves into the intricate mechanisms contributing to ADs, accentuating the pivotal role(s) of antigen-specific T cells in steering immune responses and disease progression, as well as the novel strategies for the identification of antigen-specific cells and their possible future use in humans. Grasping the mechanisms behind ADs paves the way for targeted therapeutic interventions, potentially enhancing treatment choices while minimizing the risk of systemic immunosuppression.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103303"},"PeriodicalIF":7.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141978306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory disease status and response to TNF blockade are associated with mechanisms of endotoxin tolerance","authors":"Felix IL. Clanchy ,&nbsp;Federica Borghese ,&nbsp;Jonas Bystrom ,&nbsp;Attila Balog ,&nbsp;Henry Penn ,&nbsp;Dobrina N. Hull ,&nbsp;Rizgar A. Mageed ,&nbsp;Peter C. Taylor ,&nbsp;Richard O. Williams","doi":"10.1016/j.jaut.2024.103300","DOIUrl":"10.1016/j.jaut.2024.103300","url":null,"abstract":"<div><p>The mechanisms of endotoxin tolerance (ET), which down-regulate inflammation, are well described in response to exogenous toll-like receptor ligands, but few studies have focused on ET-associated mechanisms in inflammatory disease. As blocking TNF can attenuate the development of ET, the effect of anti-TNF on the expression of key ET-associated molecules in inflammatory auto-immune disease was measured; changes in inflammatory gene expression were confirmed using an ET bioassay. The expression of immunomodulatory molecules was measured in a murine model of arthritis treated with anti-TNF and the expression of ET-associated molecules was measured in whole blood in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients, before and after therapy. The expression of ET-associated genes was also measured in RA patient monocytes before and after therapy, in anti-TNF responders and non-responders. <em>Tnfaip3</em>, <em>Ptpn6</em> and <em>Irak3</em> were differentially expressed in affected paws, spleens, lymph nodes and circulating leucocytes in experimental murine arthritis treated with anti-TNF. Prior to therapy, the expression of <em>TNFAIP3</em>, <em>INPP5D</em>, <em>PTPN6, CD38</em> and <em>SIGIRR</em> in whole blood differed between human healthy controls and RA or AS patients. In blood monocytes from RA patients, the expression of <em>TNFAIP3</em> was significantly reduced by anti-TNF therapy in non-responders. Prior to therapy, anti-TNF non-responders had higher expression of <em>TNFAIP3</em> and <em>SLPI</em>, compared to responders. Although the expression of <em>TNFAIP3</em> was significantly higher in RA non-responders prior to treatment, the post-treatment reduction to a level similar to responders did not coincide with a clinical response to therapy.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103300"},"PeriodicalIF":7.9,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0896841124001343/pdfft?md5=25d05f69750e974a5293366990c00329&pid=1-s2.0-S0896841124001343-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic analyses of lung tissues reveal key genes associated with progression of systemic sclerosis-interstitial lung disease (SSc-ILD)","authors":"Yehya Al-Adwi ,&nbsp;Johanna Westra ,&nbsp;Harry van Goor ,&nbsp;Leon C. van Kempen ,&nbsp;Mohammed Osman ,&nbsp;C. Tji Gan ,&nbsp;Wim Timens ,&nbsp;Douwe J. Mulder","doi":"10.1016/j.jaut.2024.103297","DOIUrl":"10.1016/j.jaut.2024.103297","url":null,"abstract":"<div><h3>Objective</h3><p>Systemic sclerosis-interstitial lung disease (SSc-ILD) is the leading cause of death in SSc, affecting around 50 % of the patients. Lung tissue of patients with early-stage SSc-ILD is characterized by a predominant inflammatory response with inconspicuous fibrosis, which may progress to honeycombing fibrosis. Hence, a better understanding of the molecular mechanisms underpinning SSc-ILD pathogenesis is needed to improve treatment options and progression prediction. This transcriptomic study aims to reveal the differential gene expression between control (ctrl) lung tissue and inflammatory, prefibrotic and fibrotic lung tissue to capture progression of early to late phase SSc-ILD.</p></div><div><h3>Methods</h3><p>Twelve explanted lungs from patients with SSc-ILD were used to analyze gene expression from formalin-fixed paraffin-embedded lung tissues with varying stages of ILD (n = 18) and control lung tissue (n = 6). The SSc-ILD tissues were stratified into three ROIs: inflammatory, prefibrotic, and fibrotic using histological assessments to define a longitudinal simulation of early to late phases of SSc-ILD. The nanoString (nS) nCounter Human Fibrosis Panel was used to profile the transcriptome in the regions of interest. Validation of potential targetswas performed with immunohistochemistry in the same tissues that were used for transcriptome analysis.</p></div><div><h3>Results</h3><p>To validate our simulation model, we performed subgroup analysis that showed an incremental increase in pathway scores related to the severity of fibrosis. Ctrl vs SSc-ILD comparison demonstrated 24 differentially expressed genes, two of which had the most pronounced p-values. Cyclin-dependent kinase inhibitor (<em>cdkn2c</em>) was overexpressed (<em>P</em> = 0.00052) in SSc-ILD compared to ctrl, while expression of Pellino E3 ubiquitin-protein ligase 1 (<em>peli1</em>) showed lower expression (<em>P</em> = 0.0012). Additionally, in all four groups, <em>cdkn2c</em> and <em>peli1</em> gene expression showed an incremental increase and decrease, respectively. Immunohistochemistry of <em>cdkn2c</em> showed consistent results with the nS analysis.</p></div><div><h3>Conclusion</h3><p>More <em>cdkn2c</em> and less <em>peli1</em> expression were associated with more advanced stages of SSc-ILD on histologic assessment. We report the potential of the cell cycle inhibitor and senescence marker, <em>cdkn2c</em> (p18) to be associated with fibrosis progression.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103297"},"PeriodicalIF":7.9,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0896841124001318/pdfft?md5=aa713571c16709788cf60e7237102da2&pid=1-s2.0-S0896841124001318-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Earlier vs. later time period of COVID-19 infection and emergent autoimmune signs, symptoms, and serologies","authors":"Emily G. Oakes ,&nbsp;Eilish Dillon ,&nbsp;Katherine A. Buhler ,&nbsp;Hongshu Guan ,&nbsp;Misti Paudel ,&nbsp;Kathryne Marks ,&nbsp;Ifeoluwakiisi Adejoorin ,&nbsp;Jeong Yee ,&nbsp;Jack Ellrodt ,&nbsp;Sara Tedeschi ,&nbsp;Jeffrey Sparks ,&nbsp;Siobhan M. Case ,&nbsp;Tiffany Hsu ,&nbsp;Daniel H. Solomon ,&nbsp;A. Helena Jonsson ,&nbsp;Roberta Vezza Alexander ,&nbsp;Deepak A. Rao ,&nbsp;May Y. Choi ,&nbsp;Karen H. Costenbader","doi":"10.1016/j.jaut.2024.103299","DOIUrl":"10.1016/j.jaut.2024.103299","url":null,"abstract":"<div><h3>Objective</h3><p>Autoantibodies and autoimmune diseases after SARS-CoV-2 infection are widely reported. Given evolving variants, milder infections, and increasing population vaccination, we hypothesized that SARS-CoV-2 infection earlier in the pandemic would be associated with more autoimmune connective tissue disease (CTD) symptoms and immunologic abnormalities.</p></div><div><h3>Methods</h3><p>Patients ≥18 years old with COVID-19 3/1/2020-8/15/2022 completed the CTD Screening Questionnaire and were tested for 27 autoimmune serologies, SARS-CoV-2 serologies, cell-bound complement activation products (CB-CAPs), and T and B lymphocyte immunophenotypes by flow cytometry. We assessed relationships between symptoms, serologies, and immunophenotypes in earlier (3/1/2020-1/31/2021) vs. later (2/1/2021-8/15/2022) periods, with different predominating SARS-CoV-2 viruses.</p></div><div><h3>Results</h3><p>57 subjects had earlier and 23 had later pandemic COVID-19. 35 % of earlier vs. 17 % of later pandemic patients had CTD symptoms (p 0.18). More patients were antinuclear antibody (ANA) positive (44 % vs. 13 %, p 0.01) and had lupus anticoagulant (11 % vs. 4 %, p 0.67). After adjustment for age, race, and sex, earlier (vs. later) COVID-19 was associated with increased ANA positivity (OR 4.60, 95%CI 1.17, 18.15). No subjects had positive CB-CAPs. T and B cell immunophenotypes and SARS-CoV-2 serologies did not differ by group. In heatmap analyses, higher autoantibody variety was seen among those with infection in the early pandemic.</p></div><div><h3>Conclusion</h3><p>In this sample, having COVID-19 infection in the earlier (pre-2/1/2021) vs. later pandemic was associated with more CTD symptoms, ANA positivity, and autoantibody reactivities. Earlier SARS-CoV-2 variants circulating in a less vaccinated population with less natural immunity may have been more immunogenic.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"148 ","pages":"Article 103299"},"PeriodicalIF":7.9,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141881937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}