Journal of autoimmunity最新文献

{"title":"Reconstituted CD74+ NK cells trigger chronic graft versus host disease after allogeneic bone marrow transplantation","authors":"Yingchao Dou ,&nbsp;Zhigang Nian ,&nbsp;Dongyao Wang ,&nbsp;Guangyu Sun ,&nbsp;Li Zhou ,&nbsp;Ziming Hu ,&nbsp;Jieqi Ke ,&nbsp;Xiaoyu Zhu ,&nbsp;Rui Sun ,&nbsp;Zhigang Tian ,&nbsp;Binqing Fu ,&nbsp;Yonggang Zhou ,&nbsp;Haiming Wei","doi":"10.1016/j.jaut.2024.103274","DOIUrl":"10.1016/j.jaut.2024.103274","url":null,"abstract":"<div><p>Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients with pulmonary cGVHD in particular have a very poor prognosis. NK cells are the first reconstituted lymphocyte subset after allo-HSCT; however, the impact of reconstituted NK cells on cGVHD is unclear. Here, we found allogeneic recipients showed obvious pulmonary cGVHD. Surprisingly, deletion of reconstituted NK cells resulted in maximal relief of pulmonary cGVHD. Mechanistically, reconstituted NK cells with donor profiles modulated the pulmonary inflammatory microenvironment to trigger cGVHD. Reconstituted NK cells secreted IFN-γ and TNF-α to induce CXCL10 production by epithelial cells, which recruited macrophages and CD4⁺ T cells to the lungs. Then macrophages and CD4⁺ T cells were activated by the inflammatory microenvironment, thereby mediating lung injury. Through assessment of differences in cellular energy, we found that CD74⁺ NK cells with high mitochondrial potential and pro-inflammatory activity triggered pulmonary cGVHD. Furthermore, targeted elimination of CD74⁺ NK cells using the anti-CD74 antibody significantly alleviated pulmonary cGVHD but preserved the CD74⁻ NK cells to exert graft-versus-leukemia (GVL) effects. Data from human samples corroborated our findings in mouse models. Collectively, our results reveal that reconstituted CD74⁺ NK cells trigger pulmonary cGVHD and suggest that administration of CD74 antibody was a potential therapeutic for patients with cGVHD.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"147 ","pages":"Article 103274"},"PeriodicalIF":7.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0896841124001082/pdfft?md5=2e392b4331bc2156fe4a990a2503a2b4&pid=1-s2.0-S0896841124001082-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468273","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":"Inflammation dynamically regulates steroid hormone metabolism and action within macrophages in rheumatoid arthritis","authors":"C.S Martin ,&nbsp;A. Crastin ,&nbsp;M.S. Sagmeister ,&nbsp;M.S. Kalirai ,&nbsp;J.D. Turner ,&nbsp;L. MacDonald ,&nbsp;M. Kurowska-Stolarska ,&nbsp;D. Scheel-Toellner ,&nbsp;A.E. Taylor ,&nbsp;L.C. Gilligan ,&nbsp;K. Storbeck ,&nbsp;M. Price ,&nbsp;C.M. Gorvin ,&nbsp;Filer A ,&nbsp;R. Mahida ,&nbsp;A.R. Clark ,&nbsp;S.W. Jones ,&nbsp;K. Raza ,&nbsp;M. Hewison ,&nbsp;R.S. Hardy","doi":"10.1016/j.jaut.2024.103263","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103263","url":null,"abstract":"<div><h3>Rationale</h3><p>In inflammatory diseases such as rheumatoid arthritis (RA), steroid metabolism is a central component mediating the actions of immuno-modulatory glucocorticoids and sex steroids. However, the regulation and function of cellular steroid metabolism within key leukocyte populations such as macrophages remain poorly defined. In this study, the inflammatory regulation of global steroid metabolism was assessed in RA macrophages.</p></div><div><h3>Methods</h3><p>Bulk RNA-seq data from RA synovial macrophages was used to assess transcripts encoding key enzymes in steroid metabolism and signalling. Changes in metabolism were assessed in synovial fluids, correlated to measures of disease activity and functionally validated in primary macrophage cultures.</p></div><div><h3>Results</h3><p>RNA-seq revealed a unique pattern of differentially expressed genes, including changes in genes encoding the enzymes 11β-HSD1, SRD5A1, AKR1C2 and AKR1C3. These correlated with disease activity, favouring increased glucocorticoid and androgen levels. Synovial fluid 11β-HSD1 activity correlated with local inflammatory mediators (TNFα, IL-6, IL-17), whilst 11β-HSD1, SRD5A1 and AKR1C3 activity correlated with systemic measures of disease and patient pain (ESR, DAS28 ESR, global disease activity). Changes in enzyme activity were evident in inflammatory activated macrophages <em>in vitro</em> and revealed a novel androgen activating role for 11β-HSD1. Together, increased glucocorticoids and androgens were able to suppress inflammation in macrophages and fibroblast-like-synoviocytes.</p></div><div><h3>Conclusions</h3><p>This study underscores the significant increase in androgen and glucocorticoid activation within inflammatory polarized macrophages of the synovium, contributing to local suppression of inflammation. The diminished profile of inactive steroid precursors in postmenopausal women may contribute to disturbances in this process, leading to increased disease incidence and severity.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"147 ","pages":"Article 103263"},"PeriodicalIF":12.8,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0896841124000970/pdfft?md5=fbf43a91254aa6b252f689124460d92d&pid=1-s2.0-S0896841124000970-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141292204","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":"Regulatory T cells effectively downregulate the autoimmune anti-MPO response and ameliorate anti-MPO induced glomerulonephritis in mice","authors":"Peiqi Hu ,&nbsp;Hong Xiao ,&nbsp;Sandra Elmore ,&nbsp;Christian Agosto-Burgos ,&nbsp;Yichun Hu ,&nbsp;Susan L. Hogan ,&nbsp;Dominic J. Ciavatta ,&nbsp;Ronald J. Falk ,&nbsp;J. Charles Jennette ,&nbsp;Meghan E. Free","doi":"10.1016/j.jaut.2024.103266","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103266","url":null,"abstract":"<div><p>Regulation of autoreactive cells is key for both prevention and amelioration of autoimmune disease. A better understanding of the key cell population(s) responsible for downregulation of autoreactive cells would provide necessary foundational insight for cellular-based therapies in autoimmune disease. Utilizing a mouse model of anti-myeloperoxidase (MPO) glomerulonephritis, we sought to understand which immune cells contribute to downregulation of the anti-MPO autoimmune response. MPO−/− mice were immunized with whole MPO to induce an anti-MPO response. Anti-MPO splenocytes were then transferred into recipient mice (Rag2−/− mice or WT mice). Anti-MPO titers were followed over time. After anti-MPO splenocyte transfer, WT mice are able to downregulate the anti-MPO response while anti-MPO titers persist in Rag2−/− recipients. Reconstitution with WT splenocytes into Rag2−/− recipients prior to anti-MPO splenocyte transfer enabled mice to downregulate the anti-MPO immune response. Therefore, wildtype splenocytes contain a cellular population that is capable of downregulating the autoimmune response. Through splenocyte transfer, antibody depletion experiments, and purified cell population transfers, we confirmed that the regulatory T cell (Treg) population is responsible for the downregulation of the anti-MPO autoimmune response. Further investigation revealed that functional Tregs from WT mice are capable of downregulating anti-MPO antibody production and ameliorate anti-MPO induced glomerulonephritis. These data underscore the importance of functional Tregs for control of autoimmune responses and prevention of end-organ damage due to autoimmunity.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"147 ","pages":"Article 103266"},"PeriodicalIF":12.8,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0896841124001008/pdfft?md5=6ac2e44873cca339cd969e68c0a0d9ee&pid=1-s2.0-S0896841124001008-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141292203","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":"Prevalence and clinical profiles of primary sclerosing cholangitis in China: Data from electronic medical records and systematic literature retrieval","authors":"Xiaoqian Xu ,&nbsp;Tongtong Meng ,&nbsp;Lichen Shi ,&nbsp;Weijia Duan ,&nbsp;Junqi Niu ,&nbsp;Huiguo Ding ,&nbsp;Wen Xie ,&nbsp;Lu Zhou ,&nbsp;Bangmao Wang ,&nbsp;Jie Li ,&nbsp;Lingyi Zhang ,&nbsp;Yu Wang ,&nbsp;Xiaojuan Ou ,&nbsp;Xinyan Zhao ,&nbsp;Hong You ,&nbsp;Jidong Jia ,&nbsp;Yuanyuan Kong","doi":"10.1016/j.jaut.2024.103264","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103264","url":null,"abstract":"<div><h3>Background &amp; aims</h3><p>Epidemiology of primary sclerosing cholangitis (PSC) is lacking in China. We aimed to estimate the period prevalence and depict the clinical features of PSC in China.</p></div><div><h3>Methods</h3><p>We identified and included PSC cases between 2000 and 2023 from two sources: electronic medical records (EMR) and systematical literature retrieval (SLR). The period prevalence of PSC was estimated by the multiplier method. Rate ratios (RRs) for PSC prevalence in relation to macroeconomic indicators were calculated by the negative binomial regression model.</p></div><div><h3>Results</h3><p>A total of 1358 PSC cases were retrieved from 299 hospitals (162 from EMR and 1196 from SLR). Males accounted for 55.7 % of the PSC cases and 25.7 % had concomitant inflammatory bowel disease (IBD). The estimated period prevalence of PSC from 2000 to 2023 was 2.36 (95 % CI: 1.82, 3.34) per 100,000. Males had a numerically higher PSC prevalence than females (2.56, 95 % CI: 1.97, 3.63 vs. 2.14, 95 % CI: 1.65, 3.04 per 100,000). The highest prevalence of PSC was in East China at 4.87 (95 % CI: 3.44, 7.18) per 100,000, followed by North China at 2.94 (95 % CI: 2.33, 3.74) per 100,000, and the lowest in South China at 0.92 (95 % CI: 0.66, 1.30) per 100,000. Regional per capita GDP (RR 1.65, 95 % CI: 1.03, 2.65) and healthcare expenditure (RR 1.94, 95 % CI: 1.13, 3.38) were identified to be associated with PSC prevalence.</p></div><div><h3>Conclusion</h3><p>Our study showed the estimated PSC prevalence varied within China, but was generally lower than that in Western countries.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"147 ","pages":"Article 103264"},"PeriodicalIF":12.8,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141249669","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":"The HyperPed-COVID international registry: Impact of age of onset, disease presentation and geographical distribution on the final outcome of MIS-C","authors":"Roberta Caorsi ,&nbsp;Alessandro Consolaro ,&nbsp;Camilla Speziani ,&nbsp;Betul Sozeri ,&nbsp;Kadir Ulu ,&nbsp;Enrique Faugier-Fuentes ,&nbsp;Hector Menchaca-Aguayo ,&nbsp;Seza Ozen ,&nbsp;Seher Sener ,&nbsp;Shahana Akhter Rahman ,&nbsp;Mohammad Imnul Islam ,&nbsp;Filomeen Haerynck ,&nbsp;Gabriele Simonini ,&nbsp;Mariel Viviana Mastri ,&nbsp;Tadej Avcin ,&nbsp;Saša Sršen ,&nbsp;Taciana de Albuquerque Pedrosa Fernandes ,&nbsp;Valda Stanevicha ,&nbsp;Jelena Vojinovic ,&nbsp;Ali Sobh ,&nbsp;Svitlana Samsonenko","doi":"10.1016/j.jaut.2024.103265","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103265","url":null,"abstract":"<div><h3>Objectives</h3><p>The aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome.</p></div><div><h3>Study design</h3><p>Multicenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected. Five age groups (&lt;1, 1–4, 5–11, 12–16, &gt;16 years) and four geographic macro-areas, Western Europe, Central-Eastern Europe, Latin America, Asian-African resource-limited countries (LRC), were identified.</p></div><div><h3>Results</h3><p>Time to referral was significantly higher in LRC. Intensive anti-inflammatory treatment, including biologics, respiratory support and mechanic ventilation were more frequently used in older children and in European countries. The mortality rate was higher in very young children (&lt;1 year), in older patients (&gt;16 years of age) and in LRC. Multivariate analysis identified the residence in LRC, presence of severe cardiac involvement, renal hypertension, lymphopenia and non-use of heparin prophylaxis, as the factors most strongly associated with unfavorable outcomes.</p></div><div><h3>Conclusions</h3><p>The stratification of patients by age and geographic macro-area provided insights into the clinical presentation, treatment and outcome of MIS-C. The mortality and sequelae rates exhibited a correlation with the age and geographical areas. Patients admitted and treated in LRC displayed more severe outcomes, possibly due to delays in hospital admission and limited access to biologic drugs and to intensive care facilities.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"147 ","pages":"Article 103265"},"PeriodicalIF":12.8,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141242866","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":"Pin1 maintains the effector program of pathogenic Th17 cells in autoimmune neuroinflammation","authors":"Guangyue Fan ,&nbsp;Guangliang Li ,&nbsp;Long Li ,&nbsp;Yurong Da","doi":"10.1016/j.jaut.2024.103262","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103262","url":null,"abstract":"<div><p>Th17 cells mediated immune response is the basis of a variety of autoimmune diseases, including multiple sclerosis and its mouse model of immune aspects, experimental autoimmune encephalomyelitis (EAE). The gene network that drives both the development of Th17 and the expression of its effector program is dependent on the transcription factor RORγt. In this report, we showed that Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (Pin1) formed a complex with RORγt, and enhanced its transactivation activity, thus sustained the expression of the effector genes as well as RORγt in the EAE-pathogenic Th17 cells. We first found out that <em>PIN1</em> was highly expressed in the samples from patients of multiple sclerosis, and the expression of Pin1 by the infiltrating lymphocytes in the central nerve system of EAE mice was elevated as well. An array of experiments with transgenic mouse models, cellular and molecular assays was included in the study to elucidate the role of Pin1 in the pathology of EAE. It turned out that Pin1 promoted the activation and maintained the effector program of EAE-pathogenic Th17 cells in the inflammation foci, but had little effect on the priming of Th17 cells in the draining lymph nodes. Mechanistically, Pin1 stabilized the phosphorylation of STAT3 induced by proinflammatory stimuli, and interacted with STAT3 in the nucleus of Th17 cells, which resulted in the increased expression of <em>Rorc</em>. Moreover, Pin1 formed a complex with RORγt, and enhanced the transactivation of RORγt to the +11 kb enhancer of <em>Rorc</em>, which enforced and maintained the expression of both <em>Rorc</em> and the effector program of pathogenic Th17 cells in EAE. Finally, the inhibition of Pin1, by genetic knockdown or by small molecule inhibitor, deceased the population of Th17 cells and the neuroinflammation, and alleviated the symptoms of EAE. These findings suggest that Pin1 is a potential therapeutic target for MS and other autoimmune inflammatory diseases.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"147 ","pages":"Article 103262"},"PeriodicalIF":12.8,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141243015","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":"Adding salt to foods and risk of psoriasis: A prospective cohort study","authors":"Guowei Zhou ,&nbsp;Lu Gan ,&nbsp;Bin Zhao ,&nbsp;Fang Fang ,&nbsp;Hong Liu ,&nbsp;Xiang Chen ,&nbsp;Jiaqi Huang","doi":"10.1016/j.jaut.2024.103259","DOIUrl":"10.1016/j.jaut.2024.103259","url":null,"abstract":"<div><h3>Background</h3><p>High salt intake may play a critical role in the etiology of psoriasis. Yet, evidence on the association of high salt intake with risk of psoriasis is limited.</p></div><div><h3>Objective</h3><p>To estimate the association between frequency of adding salt to foods and risk of psoriasis.</p></div><div><h3>Methods</h3><p>We conducted a prospective cohort study of 433,788 participants from the UK Biobank. Hazard ratios (HRs) and their 95 % confidence intervals (CIs) for risk of psoriasis in relation to frequency of adding salt to foods were estimated using multivariable Cox proportional hazards models. We further evaluated the joint association of adding salt to foods and genetic susceptibility with risk of psoriasis. We conducted a mediation analysis to assess how much of the effect of adding salt to foods on risk of psoriasis was mediated through several selected mediators.</p></div><div><h3>Results</h3><p>During a median of 14.0 years of follow-up, 4279 incident cases of psoriasis were identified. In the multivariable-adjusted model, a higher frequency of adding salt to foods was significantly associated with an increased risk of psoriasis (“always” versus “never/rarely” adding salt to foods, HR = 1.25, 95 % CI: 1.10, 1.41). The observed positive association was generally similar across subgroups. In the joint association analysis, we observed that participants with a high genetic risk (above the second tertile) and the highest frequency of adding salt to foods experienced 149 % higher risk of psoriasis, when compared with participants with a low genetic risk (below the first tertile) and the lowest frequency of adding salt to foods (HR = 2.49, 95 % CI: 2.05, 3.02). Mediation analysis revealed that 1.8 %–3.2 % of the positive association between frequency of adding salt and risk of psoriasis was statistically significantly mediated by obesity and inflammatory biomarkers such as C-reactive protein and systemic immune-inflammation index (all P values &lt; 0.004).</p></div><div><h3>Conclusions</h3><p>Our study demonstrated a positive association between frequency of adding salt to foods and risk of psoriasis. The positive association was independent of multiple other risk factors, and may be partially mediated through obesity and inflammation.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"147 ","pages":"Article 103259"},"PeriodicalIF":12.8,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186528","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":"Infectious and non-infectious precipitants of sarcoidosis.","authors":"Ozioma S Chioma, ZaDarreyal Wiggins, Samantha Rea, Wonder P Drake","doi":"10.1016/j.jaut.2024.103239","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103239","url":null,"abstract":"<p><p>Sarcoidosis is a chronic inflammatory disease that can affect any organ in the body. Its exact cause remains unknown, but it is believed to result from a combination of genetic and environmental factors. Some potential causes of sarcoidosis include genetics, environmental triggers, immune system dysfunction, the gut microbiome, sex, and race/ethnicity. Genetic mutations are associated with protection against disease progression or an increased susceptibility to more severe disease, while exposure to certain chemicals, bacteria, viruses, or allergens can trigger the formation of immune cell congregations (granulomas) in different organs. Dysfunction of the immune system, including autoimmune reactions, may also contribute. The gut microbiome and factors such as being female or having African American, Scandinavian, Irish, or Puerto Rican heritage are additional contributors to disease outcome. Recent research has suggested that certain drugs, such as anti-Programmed Death-1 (PD-1) and antibiotics such as tuberculosis (TB) drugs, may raise the risk of developing sarcoidosis. Hormone levels, particularly higher levels of estrogen and progesterone in women, have also been linked to an increased likelihood of sarcoidosis. The diagnosis of sarcoidosis involves a comprehensive assessment that includes medical history, physical examination, laboratory tests, and imaging studies. While there is no cure for sarcoidosis, the symptoms can often be effectively managed through various treatment options. Treatment may involve the use of medications, surgical interventions, or lifestyle changes. These disparate factors suggests that sarcoidosis has multiple positive and negative exacerbants on disease severity, some of which can be ameliorated and others which cannot.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":" ","pages":"103239"},"PeriodicalIF":12.8,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141183717","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":"Cannabinoid receptor 2 selective agonist alleviates systemic sclerosis by inhibiting Th2 differentiation through JAK/SOCS3 signaling","authors":"Na Tian ,&nbsp;Hao Cheng ,&nbsp;Yu Du ,&nbsp;Xiaoxia Wang ,&nbsp;Yi Lei ,&nbsp;Xinnan Liu ,&nbsp;Miao Chen ,&nbsp;Zhan Xu ,&nbsp;Lingbiao Wang ,&nbsp;Hanlin Yin ,&nbsp;Rong Fu ,&nbsp;Dan Li ,&nbsp;Penghui Zhou ,&nbsp;Liangjing Lu ,&nbsp;Zhinan Yin ,&nbsp;Sheng-Ming Dai ,&nbsp;Bin Li","doi":"10.1016/j.jaut.2024.103233","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103233","url":null,"abstract":"<div><p>Systemic sclerosis (SSc) poses a significant challenge in autoimmunology, characterized by the development of debilitating fibrosis of skin and internal organs. The pivotal role of dysregulated T cells, notably the skewed polarization toward Th2 cells, has been implicated in the vascular damage and progressive fibrosis observed in SSc. In this study, we explored the underlying mechanisms by which cannabinoid receptor 2 (CB2) highly selective agonist HU-308 restores the imbalance of T cells to alleviate SSc. Using a bleomycin-induced SSc (BLM-SSc) mouse model, we demonstrated that HU-308 effectively attenuates skin and lung fibrosis by specifically activating CB2 on CD4⁺ T cells to inhibit the polarization of Th2 cells in BLM-SSc mice, which was validated by Cnr2-specific-deficient mice. Different from classical signaling downstream of G protein-coupled receptors (GPCRs), HU-308 facilitates the expression of SOCS3 protein and subsequently impedes the IL2/STAT5 signaling pathway during Th2 differentiation. The deficiency of SOCS3 partially mitigated the impact of HU-308. Analysis of a cohort comprising 80 SSc patients and 82 healthy controls revealed an abnormal elevation in the Th2/Th1 ratio in SSc patients. The proportion of Th2 cells showed a significant positive correlation with mRSS score and positivity of anti-Scl-70. Administration of HU-308 to PBMCs and peripheral CD4⁺ T cells from SSc patients led to the upregulation of SOCS3, which effectively suppressed the aberrantly activated STAT5 signaling pathway and the proportion of CD4⁺IL4⁺ T cells. In conclusion, our findings unveil a novel mechanism by which the CB2 agonist HU-308 ameliorates fibrosis in SSc by targeting and reducing Th2 responses. These insights provide a foundation for future therapeutic approaches in SSc by modulating Th2 responses.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"147 ","pages":"Article 103233"},"PeriodicalIF":12.8,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141097785","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":"JAK inhibitors in refractory juvenile rheumatic diseases: Efficacy, tolerance and type-I interferon profiling, a single center retrospective study","authors":"Marie Solignac ,&nbsp;Natalia Cabrera ,&nbsp;Marine Fouillet-Desjonqueres ,&nbsp;Agnes Duquesne ,&nbsp;Audrey Laurent ,&nbsp;Anne-Perrine Foray ,&nbsp;Sebastien Viel ,&nbsp;Franck Zekre ,&nbsp;Alexandre Belot","doi":"10.1016/j.jaut.2024.103248","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103248","url":null,"abstract":"<div><h3>Objectives</h3><p><em>–</em> Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases.</p><p>This study aimed to describe the safety and effectiveness of JAKi in these diseases, with a focus on longitudinal interferon-stimulated genes (ISG) assessment.</p></div><div><h3>Methods</h3><p><em>–</em> We present a single-center retrospective study of children with refractory pediatric rheumatic diseases including connective tissue diseases, monogenic type I interferonopathies or juvenile idiopathic arthritis, receiving JAKi. According to physicians’ assessment, treatment effectiveness was classified at 12 months as a complete response in the total absence of disease activity, partial response in case of significant (&gt;50%) but incomplete improvement or no response in the case of non-response or improvement of less than 50% of the clinical and biological parameters. ISG were monitored longitudinally using Nanostring technology.</p></div><div><h3>Results</h3><p><em>-</em> 22 children were retrospectively included in this study, treated either by baricitinib or ruxolitinib. Complete response was achieved at 12 months in 9/22 (41%) patients. 6/22 (27%) patients were non-responders and treatment had been discontinued in five of them. Within the interferon (IFN)-related diseases group, ISG-score was significantly reduced 12 months after JAKi onset (p = 0.0068). At 12 months, daily glucocorticoid doses had been reduced with a median dose of 0.16 mg/kg/day (IQR 0.11; 0.33) (p = 0.0425). 7/22 (32%) patients had experienced side effects, infections being the most common. Increase of the body mass index was also recorded in children in the first 6 months of treatment.</p></div><div><h3>Conclusion</h3><p><em>–</em> JAKi represent a promising treatment of immune-mediated pediatric diseases, enabling to decrease type-I IFN transcriptomic signature in responding patients, especially in the context of juvenile dermatomyositis. JAKi represent steroid-sparing drugs but they induce metabolic changes linked to weight gain, posing a concern in the treatment of young patients and teenagers. More data are required to define the efficacy and safety of JAKi in the management of refractory pediatric rheumatic diseases.</p></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"147 ","pages":"Article 103248"},"PeriodicalIF":12.8,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0896841124000829/pdfft?md5=e99a7e46acc50951a7d761dfe499727f&pid=1-s2.0-S0896841124000829-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141095543","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}