Journal of autoimmunity最新文献

{"title":"Selective disruption of Traf1/cIAP2 interaction attenuates inflammatory responses and rheumatoid arthritis","authors":"Yitian Tang ,&nbsp;Fatemah Aleithan ,&nbsp;Sahib Singh Madahar ,&nbsp;Ali Mirzaesmaeili ,&nbsp;Sunpreet Saran ,&nbsp;Jialing Tang ,&nbsp;Safoura Zangiabadi ,&nbsp;Robert Inman ,&nbsp;Gary Sweeney ,&nbsp;Ali A. Abdul-Sater","doi":"10.1016/j.jaut.2025.103377","DOIUrl":"10.1016/j.jaut.2025.103377","url":null,"abstract":"<div><h3>Objectives</h3><div>Tumor necrosis factor receptor-associated factor 1 (TRAF1) is an immune signaling adapter protein linked to increased susceptibility to rheumatoid arthritis (RA). TRAF1 has dual roles in regulating NF-κB and MAPK signaling: it promotes signaling through its association with cellular inhibitor of apoptosis 2 (cIAP2) downstream of certain tumor necrosis factor receptor (TNFR) family members but inhibits Toll-like receptor (TLR) signaling by limiting linear ubiquitination of key signaling proteins. In this study, we investigated whether selectively targeting TRAF1/cIAP2 interaction would lower inflammation and reduce severity of RA.</div></div><div><h3>Methods</h3><div>We employed CRISPR/Cas9-mediated mediated gene editing to modify TRAF1 and specifically abrogate its interaction with cIAP2 in human macrophage cell lines and in mice. Biochemical studies were then employed to assess inflammatory signaling and cytokine production in gene edited macrophages. The collagen antibody-induced arthritis (CAIA) model of RA was used to trigger joint inflammation in mice.</div></div><div><h3>Results</h3><div>We identify a critical mutation in TRAF1 (V203A in humans, V196A in mice) that disrupts its interaction with cIAP2, leading to a significant reduction in TLR signaling and downstream inflammation in human and murine macrophages. We demonstrate that TRAF1 is recruited to the TLR4 complex and is indispensable for the recruitment of cIAP2, facilitating TAK1 phosphorylation and the activation of NF-κB and MAPK signaling pathways. Remarkably, mice harboring the TRAF1 V196A mutation are protected from LPS-induced septic shock and exhibit markedly reduced joint inflammation and disease severity in the CAIA model of RA.</div></div><div><h3>Conclusion</h3><div>These findings reveal a previously unrecognized and crucial role for the TRAF1/cIAP2 axis in promoting inflammation and offer a promising foundation for the development of novel therapeutic strategies for inflammatory conditions, such as RA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"152 ","pages":"Article 103377"},"PeriodicalIF":7.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364801","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":"LAMP3-mediated epithelial-mesenchymal transition promotes the invasion and excessive proliferation of fibroblast-like synoviocytes in rheumatoid arthritis","authors":"Wenxian Zhou ,&nbsp;Hui Cheng ,&nbsp;Chenghu Fan ,&nbsp;Xin Zhou ,&nbsp;Wenyu Chen ,&nbsp;Chenglong Xie ,&nbsp;Yuezheng Hu ,&nbsp;Yue Chen ,&nbsp;Xiaobing Wang ,&nbsp;Jinyu Wu","doi":"10.1016/j.jaut.2025.103359","DOIUrl":"10.1016/j.jaut.2025.103359","url":null,"abstract":"<div><h3>Objective</h3><div>The aim of this study was to explore the functional role of LAMP3-mediated epithelial-mesenchymal transition (EMT) in fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) patients and to evaluate its potential as a therapeutic target.</div></div><div><h3>Methodology</h3><div>Changes in EMT and LAMP3 were investigated in the synovial tissue and FLSs of RA patients. In vitro experiments were performed using the EMT inhibitor C19, siRNA, and lentivirus to examine the impact of EMT and LAMP3 on RA-FLSs and the underlying mechanisms involved. Finally, C19 was administered to mice with collagen-induced arthritis (CIA) to validate the therapeutic efficacy of C19 in treating arthritis.</div></div><div><h3>Results</h3><div>Compared with patients with osteoarthritis (OA), RA patients exhibited increased EMT and increased expression of LAMP3 in the synovium. The results from the <em>in vitro</em> experiments demonstrated that inhibiting EMT effectively reduced the excessive proliferation, anti-senescent properties, migration, and invasive behavior of RA-FLSs, as well as the secretion of MMP1, MMP3, and MMP13. Additionally, regulating the expression of LAMP3 not only affected the EMT pathway but also impacted the excessive proliferation and invasive behavior of RA-FLSs. In the CIA model, administration of the EMT inhibitor C19 significantly alleviated the progression of arthritis.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate the inhibitory impact of EMT on arthritis and suggest that inhibiting EMT or LAMP3 may be a promising novel therapeutic approach for treating RA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103359"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970959","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":"Glycobiology of psoriasis: A review","authors":"Yinuo Yang ,&nbsp;Xin Zhou ,&nbsp;Wenhui Wang ,&nbsp;Hui Dai","doi":"10.1016/j.jaut.2025.103361","DOIUrl":"10.1016/j.jaut.2025.103361","url":null,"abstract":"<div><div>Psoriasis is a chronic inflammatory skin disease with etiologies related to genetics, immunity, and the environment. It is characterized by excessive proliferation of keratinocytes and infiltration of inflammatory immune cells. Glycosylation is a post-translational modification of proteins that plays important roles in cell adhesion, signal transduction, and immune cell activation. Abnormal glycosylation is associated with inflammation, tumors, autoimmunity, and several diseases. Glycan profiles and glycosylation-related enzymes are altered in patients with psoriasis. Specific glycan structures, such as glycosaminoglycans and gangliosides, inhibit the development of psoriasis through various pathways. Lectins are glycan-binding proteins that are widely involved in the pathogenesis of psoriasis. The differential serum, epidermal, and dermal expression of galectins in patients with psoriasis distinguishes psoriasis from other nonspecific psoriasis-like dermatitis. This article summarizes relevant literature on psoriasis-related glycans to help clarify the potential molecular mechanisms of psoriasis and identify novel biomarkers and targets for the treatment of psoriasis.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103361"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983619","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":"Immunobiology of bile and cholangiocytes","authors":"Yang Li ,&nbsp;Patrick SC. Leung ,&nbsp;Weici Zhang ,&nbsp;Shucheng Zhang ,&nbsp;Zhenning Liu ,&nbsp;Mark Kurth ,&nbsp;Andrew D. Patterson ,&nbsp;M. Eric Gershwin ,&nbsp;Junmin Song","doi":"10.1016/j.jaut.2025.103376","DOIUrl":"10.1016/j.jaut.2025.103376","url":null,"abstract":"<div><div>The biliary tract is now recognized as an immune organ, and within the biliary tract, both bile and cholangiocytes play a key role in maintaining immune defense and homeostasis. First, immunoreactive proteins such as secretory IgA provide local antimicrobial effects. Second, bile acids (BAs) protect the biliary tree from immune-related injury through receptor signaling, mainly via the membrane-bound receptor TGR5 on cholangiocytes. Third, the biliary microbiota, similar to the intestinal microbiota, contributes to sustaining a stable physiobiological microenvironment. Fourth, cholangiocytes actively modulate the expression/release of adhesion molecules and cytokines/chemokines and are involved in antigen presentation; additionally, cholangiocyte senescence and apoptosis also influence immune responses. Conversely, aberrant bile composition, altered BA profiles, imbalances in the biliary microbiota, and cholangiocyte dysfunction are associated with immune-mediated cholangiopathies, including primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia. While current therapeutic agents that modulate BA homeostasis and receptor signaling have shown promise in preclinical and clinical studies, future research on biliary/intestinal microbiota and cholangiocyte function should focus on developing novel therapeutic strategies for treating cholangiopathies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103376"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074688","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":"Familial patterns of alopecia areata: A systematic review and meta-analysis","authors":"Yuwei Huang ,&nbsp;Eunjin Jee ,&nbsp;Minkyu Kim ,&nbsp;Xu Liu ,&nbsp;Xian Jiang","doi":"10.1016/j.jaut.2025.103378","DOIUrl":"10.1016/j.jaut.2025.103378","url":null,"abstract":"<div><h3>Background</h3><div>Alopecia Areata (AA) is a T cell-mediated autoimmune disease characterized by sudden hair loss. It is associated with a significant familial predisposition and comorbidities such as thyroid disease, diabetes, atopic dermatitis, and vitiligo. This study aims to systematically review and meta-analyze the prevalence of familial AA and its associated comorbidities to better understand the hereditary nature of the disease.</div></div><div><h3>Methods</h3><div>A systematic review and meta-analysis were conducted following the PRISMA guidelines. Relevant studies were identified from databases including EMBASE, Cochrane Library, PubMed, and Web of Science up to October 15, 2023. Studies were included if they reported on AA patients with a confirmed diagnosis and a family history of AA or related comorbidities. Data extraction and quality assessment were performed by two independent reviewers, with discrepancies resolved by a third reviewer. Pooled prevalence estimates were calculated using a random effects model.</div></div><div><h3>Results</h3><div>The meta-analysis included 67 studies, encompassing 24,226 AA patients and their relatives. The prevalence of a family history of alopecia areata (AA) was found to be 17.6 %, indicating that 17.6 % of individuals with AA have a positive family history of the condition. (CI: 14.9 %–20.6 %, I² = 96 %). The prevalence among relatives was 0.90 % (CI: 0.55 %–1.47 %, I² = 98 %), with the highest prevalence observed in first-degree relatives at 3.22 % (CI: 2.31 %–4.48 %, I² = 94 %). Comorbid conditions were present in 9.61 % (CI: 6.98 %–13.1 %, I² = 95 %) of family members across first-, second-, and third-degree relatives of individuals with alopecia areata have comorbid autoimmune or related conditions, including thyroid disease (4.7 %), diabetes (10.1 %), atopic dermatitis (18.9 %), vitiligo (5.5 %), and other autoimmune disease (12.1 %).</div></div><div><h3>Conclusion</h3><div>This systematic review and meta-analysis highlight the significant familial risk and comorbidities in family members of AA patients. The findings emphasize the need for comprehensive family monitoring, which includes regular health screenings for autoimmune and related conditions among relatives of AA patients, and genetic counseling to educate families on hereditary risks and to guide early intervention and monitoring strategies. It can lead to improved outcomes. In the future, large population-based studies focusing on second and third-degree relatives are needed to further elucidate these associations.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103378"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143272726","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":"CAR-T cell targeting three receptors on autoreactive B cells for systemic lupus erythematosus therapy","authors":"Vinayak Uppin ,&nbsp;Hunter Gibbons ,&nbsp;Marissa Troje ,&nbsp;Daniel Feinberg ,&nbsp;Beau R. Webber ,&nbsp;Branden S. Moriarity ,&nbsp;Reshmi Parameswaran","doi":"10.1016/j.jaut.2025.103369","DOIUrl":"10.1016/j.jaut.2025.103369","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell activation, autoantibody production, and nephritis. B cell activating factor (BAFF) overexpression enhances autoreactive B-cell survival, driving autoimmunity. BAFF specific belimumab and CD20 specific rituximab antibodies are used for SLE therapy but are not curative, highlighting the need for alternative B cell depletion therapies. Here, we use BAFF ligand based chimeric antigen receptor T (CAR-T) cells targeting BAFFr, BCMA and TACI expressed on mature B cells and plasma cells. BAFF CAR-T cells efficiently killed B cells after co-culture with peripheral blood mononuclear cells (PBMCs) from SLE patients and in a patient derived SLE xenograft humanized mouse model developed by injecting patient PBMCs into immunocompromised mice. We also generated murine CD8⁺ T cells expressing human BAFF CAR to test their therapeutic efficacy in spontaneous (MRL/lpr) and pristane induced mouse models of SLE. In both models, BAFF CAR-T cells mediated persistent elimination of mature B cells, resulting in a decrease in the production of autoantibodies (IgM, IgG, Anti-ANA, and Anti-dsDNA IgG) and proteinuria along with prolonged survival. Adoptive transfer of B cells from control MRL/lpr lupus mice to previously BAFF CAR-T treated MRL/lpr lupus mice showed continued depletion of B cells and prolonged survival. Potential advantages of BAFF CAR-T therapy include avoiding B cell aplasia as BAFF receptors are not expressed by early B cells and preventing the escape of long-lived plasma cells post BAFF CAR-T therapy as they express receptors of BAFF. These data demonstrate the potential for a cellular immunotherapy based approach to induce remission of SLE pathogenesis using BAFF-CAR-T therapy.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103369"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006066","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":"Pulmonary and serum cytokine profiles of patients with anti-ARS and anti-MDA5 antibodies","authors":"Kazuhiro Kurasawa ,&nbsp;Satoko Arai ,&nbsp;Yumeko Taniguchi-Namiki ,&nbsp;Sara Komatsu ,&nbsp;Aya Shimizu ,&nbsp;Anna Hasegawa ,&nbsp;Tomoka Hiyama ,&nbsp;Tomoyuki Miyao ,&nbsp;Ayae Tanaka ,&nbsp;Takayoshi Owada ,&nbsp;Hirokuni Hirata ,&nbsp;Yasutsugu Fukushima ,&nbsp;Masafumi Arima ,&nbsp;Reika Maezawa ,&nbsp;Kei Ikeda","doi":"10.1016/j.jaut.2025.103374","DOIUrl":"10.1016/j.jaut.2025.103374","url":null,"abstract":"<div><div>The present study aimed to determine the pulmonary cytokine profiles of patients with anti-RNA synthetase (ARS) and anti-melanoma differentiation-associated protein 5 (MDA5) antibodies. The study included patients with ARS and MDA5 whose serum or bronchoalveolar fluid (BALF) was available. Sandwich enzyme-linked immunoassay microarray multiplex assay was used to measure 18 cytokine levels in serum and BALF. The cytokine patterns were investigated using factor and cluster analyses. Pulmonary cytokine production was examined using the BALF/Seum cytokine ratio. Forty participants were enrolled in the study: 19 with ARS and 21 with MDA5. All patients had interstitial lung disease (ILD). BALF was collected from 10 patients with ARS and 6 with MDA5. Serum type 1 IFN, IP-10, MCP-1, and TNF-α were elevated in both ARS and MDA5. IL-6, IL-10, and IL-15 were elevated in MDA5. Serum cytokine patterns differed between ARS and MDA5. In BALF, IFN-α, IP-10, MCP-1, and ferritin were increased in both ARS and MDA5. Higher levels of IFN-α, IL-6, and ferritin were observed in MDA5. One patient with severe MDA5-ILD showed higher levels of multiple cytokines, including IL-6 and IFN-α. BALF cytokine patterns were similar in ARS and MDA5 cases except the one with severe MDA5-ILD. IL-6, IP-10, IL-15, MCP-1, and ferritin were produced in the lungs in ARS and MDA5 and IFN-α in MDA5. In conclusion, IFN-α and pulmonary macrophage activation play important roles in ILD development in both ARS and MDA5-ILD. MDA5-ILD could be characterized by higher production of multiple cytokines and macrophage activation, particularly in severe cases.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103374"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065977","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":"Identification of clonally expanded T-cell receptor sequences in giant cell arteritis","authors":"Anna Weber ,&nbsp;Michal Zulcinski ,&nbsp;Lubna Haroon-Rashid ,&nbsp;Beth Kuszlewicz ,&nbsp;Alice Driessen ,&nbsp;Darren Newton ,&nbsp;Ann W. Morgan ,&nbsp;María Rodríguez Martínez","doi":"10.1016/j.jaut.2025.103372","DOIUrl":"10.1016/j.jaut.2025.103372","url":null,"abstract":"<div><h3>Background</h3><div>Arterial wall inflammation in giant cell arteritis (GCA) is characterized by T-cell infiltration and granuloma formation. There have been limited studies investigating the diversity of the T-cell receptor (TCR) repertoire in GCA patients. Here we aim to identify disease-relevant TCRs.</div></div><div><h3>Methods</h3><div>We sequenced the TCRβ repertoires in peripheral blood and biopsies from 72 GCA patients and compared them to repertoires of 60 age-matched controls. Applying K-nearest neighbours classification based on tcrdist3, an established TCR similarity measure, we identified GCA-associated TCRs across multiple model hyperparameters and experimental replicates.</div></div><div><h3>Results</h3><div>We observed that species richness and Shannon diversity were significantly lower (P = 0.0003 and P = 0.004, respectively) in GCA peripheral blood TCR repertoires compared with age-matched controls. 1526 TCRs were identified that were consistently associated with GCA, 63 TCRs were also detected in TAB repertoires. Identical GCA-associated TCRs were observed in paired blood and tissue samples from 21/30 GCA cases. 57 % of GCA-associated TCRs were fitted into 10 clusters, which displayed distinct TCR sequences and TCR V and J segment usage. TRBV20-1∗01, TRBV4-3∗01, TRBV4-2∗01 and TRBV4-1∗01 segments were over-represented and occurred at least 10 % more often among GCA patients than age-matched controls. Only 27/1526 TCR sequences had matches reported in public databases, reducing the likelihood that these targeted common infectious agents.</div></div><div><h3>Conclusions</h3><div>Our data provide evidence of circulating T-cell clonal expansions in GCA patients. Certain TCR sequence patterns were over-represented in GCA subjects. As more TCR sequences directed at human antigens become available, further analysis may ultimately reveal whether these TCRs bind a common target antigen.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103372"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143154997","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":"The impact of gut microbiome on immune and metabolic homeostasis in type 1 diabetes: Clinical insights for prevention and treatment strategies","authors":"Jiaqi Li,&nbsp;Zhiguo Xie,&nbsp;Lin Yang,&nbsp;Keyu Guo,&nbsp;Zhiguang Zhou","doi":"10.1016/j.jaut.2025.103371","DOIUrl":"10.1016/j.jaut.2025.103371","url":null,"abstract":"<div><div>Type 1 diabetes (T1D) is a complex disease triggered by a combination of genetic and environmental factors, where abnormal autoimmune responses lead to progressive damage of the pancreatic β cells and severe glucose metabolism disorder. Recent studies have increasingly highlighted the close link between gut microbiota dysbiosis and the development of T1D. This review delves into existing population studies to explore the intricate interactions between the gut microbiota and the immune and metabolic homeostasis in T1D. It summarizes how changes in the structure and function of the gut microbiota are closely associated with the onset and progression of T1D across its natural course and clinical stages. More importantly, based on evidence accumulated from clinical observations and trials, we pioneer the discussion on gut microbiota-based T1D prevention and treatment strategies, this not only enriches our understanding of the complex pathological mechanisms of T1D but also provides potential directions for developing novel prevention and treatment strategies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103371"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065978","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":"Janus kinase inhibition prevents autoimmune diabetes in LEW.1WR1 rats","authors":"Adediwura Arowosegbe,&nbsp;Zhiru Guo,&nbsp;Emma Vanderleeden,&nbsp;Alan G. Derr,&nbsp;Jennifer P. Wang","doi":"10.1016/j.jaut.2025.103358","DOIUrl":"10.1016/j.jaut.2025.103358","url":null,"abstract":"<div><div>Numerous studies highlight the essential role of type I interferon (IFN) responses in type 1 diabetes. The absence of type I IFN signaling is associated with a partial reduction of autoimmune diabetes incidence in LEW.1WR1 rats. We sought to delineate type I IFN-independent mechanisms that drive diabetes using type I IFN α/β receptor (IFNAR) knockout rats. Rats were treated with polyinosinic:polycytidylic acid plus Kilham rat virus to induce diabetes. Single-cell RNA-sequencing of islets and cytokine measurements in blood and spleen from prediabetic <em>Ifnar1</em>^−/− rats were employed to identify factors driving insulitis in the global absence of IFNAR signaling. Islet immune cells were enriched for <em>Ccl4, Ccl5,</em> and <em>Ifng</em>. In addition, interleukin-1 (IL-1) was increased in spleen, and IFN-γ was increased in serum from prediabetic <em>Ifnar1</em>^−/− rats. Based on these findings, rats were treated with a C-C chemokine receptor type 5 inhibitor, an IL-1 receptor antagonist, or a nucleotide-binding oligomerization domain-like receptor family pyrin-domain containing 3 inhibitor, none of which prevented diabetes. The Janus kinase inhibitor ruxolitinib, which blocks both type I and II interferon-driven signaling, completely prevented diabetes, but only when given for a sustained period starting from the time of induction. The tyrosine kinase 2 inhibitor deucravacitinib also prevented diabetes to a significant degree. We conclude that type I and II IFNs act in concert as the main drivers of autoimmune diabetes and that inhibition of downstream signaling events for both is required for disease prevention.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103358"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006102","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}