Journal of autoimmunity最新文献

{"title":"Neutrophil extracellular traps induce trophoblasts pyroptosis via enhancing NLRP3 lactylation in SLE pregnancies","authors":"Haoyue Hu ,&nbsp;You Peng ,&nbsp;Chi Chiu Wang ,&nbsp;Jun Chen ,&nbsp;Xiao Yu ,&nbsp;Xiaoyan Chen ,&nbsp;Haotong Ouyang ,&nbsp;Qin Huang ,&nbsp;Jing Ma ,&nbsp;Qian Yin ,&nbsp;Lien Ma ,&nbsp;Ziling Ding ,&nbsp;Minyi Zhang ,&nbsp;Hao Ren ,&nbsp;Jiaman Zheng ,&nbsp;Wenqian Chen ,&nbsp;Zixin Tao ,&nbsp;Ruiyan Liu ,&nbsp;Lu Chen ,&nbsp;Xuefei Wang ,&nbsp;Mei Zhong","doi":"10.1016/j.jaut.2025.103411","DOIUrl":"10.1016/j.jaut.2025.103411","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder primarily affecting women during the reproductive years, often complicating pregnancy outcomes with elevated levels of neutrophil extracellular traps (NETs) infiltration. However, potential impacts of NETs on placental trophoblasts in SLE and the underlying molecular mechanisms remain unclear. To address this, transcriptome sequencing was conducted on placentas collected from seven pregnant women with SLE and six healthy pregnant controls to identify SLE-specific placental features. The effects of NETs were further assessed in MRL/lpr lupus-prone mice and pristane-induced lupus (PIL) mice, focusing on pregnancy outcomes and placental pathology. <em>In vitro,</em> trophoblasts were stimulated with NETs derived from patients with SLE, followed by molecular analyses such as transcriptomic, cellular energy metabolism assays and liquid chromatography-tandem mass spectrometry to explore the effects and mechanisms of NETs. Results showed elevated NETs were observed in the placentas of both patients with SLE and lupus mouse models, accompanied by activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Treatment with DNase I significantly improved pregnancy outcomes in MRL/lpr mice, while the use of peptidyl arginine deiminase 4 (PAD4)-deficient mice was beneficial on the pregnancy outcomes of PIL mice. Furthermore, SLE-derived NETs activated pyroptosis in trophoblasts by promoting glycolysis and subsequent lactylation of NLRP3. These findings highlight that NETs contribute to placental damage in SLE by inducing the lactylation of the NLRP3 inflammasome in trophoblasts, demonstrating the therapeutic potential of inhibiting NETs to improve placental function.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103411"},"PeriodicalIF":7.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759447","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":"Exploring the correlation between UVB sensitivity and SLE activity: Insights into UVB-driven pathogenesis in lupus erythematosus","authors":"Jiayu He ,&nbsp;Yuanning Guo ,&nbsp;Jiamin Chen ,&nbsp;Jinhua Xu ,&nbsp;Xiaohua Zhu","doi":"10.1016/j.jaut.2025.103393","DOIUrl":"10.1016/j.jaut.2025.103393","url":null,"abstract":"<div><div>Lupus erythematosus (LE) comprises various autoimmune inflammatory diseases, with significant overlap between cutaneous LE (CLE) and systemic LE (SLE). A key feature of both CLE and SLE is UV photosensitivity, particularly in UV-exposure-related skin inflammation. Despite this, reliable and objective UVB photosensitivity indicators closely correlating with LE activity have yet to be identified, and the underlying cellular and molecular mechanisms linking UVB sensitivity with LE onset and progression remain unclear.</div><div>We discovered that ultraviolet B minimal erythema dose (UVB-MED), a quantitative photosensitivity measure, is a significant and independent risk factor for SLE activity, demonstrating a negative correlation with SLEDAI (r = −0.58, <em>P</em> &lt; 0.0001). Comprehensive transcriptomic analyses of large-scale CLE and SLE samples (5918 in discovery and 7242 in validation datasets) revealed more pronounced and extensive UVB-response gene dysregulation in skin tissues compared to blood. Additionally, 14 lupus activity-correlated, UVB-response genes (UVBACGs) were identified, including eight type I interferon-stimulated genes (IRF7, ISG20, ISG15, IFI44, IFITM1, MX1, LY6E, OASL) and others (JUN, PTTG1, HLA-F, CAV1, HOPX, RPL3), with dysregulation evident in skin, blood, and affected organs (e.g., kidney and synovium). Immunocytes serve as the primary carriers of this dysregulation. Conventional LE therapies and type I interferon-targeted therapies were found to be associated with these genes and can potentially regulate them, thereby contributing to therapeutic effects.</div><div>These findings highlight the role of UVB in triggering autoimmune inflammation in the skin, which may subsequently spread to systemic inflammation via immune cells and factors. UVBACGs play a critical role in this process and may serve as targets for precise therapies, providing insight into the link between UVB photosensitivity and LE pathogenesis.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103393"},"PeriodicalIF":7.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697827","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":"Preventing the antigen-presenting function of retinal microglia blocks autoimmune neuroinflammation by dendritic cell-primed CD4+ T cells","authors":"Shintaro Shirahama ,&nbsp;Yoko Okunuki ,&nbsp;May Y. Lee ,&nbsp;Margarete M. Karg ,&nbsp;Nasrin Refaian ,&nbsp;Drenushe Krasniqi ,&nbsp;Kip M. Connor ,&nbsp;Meredith S. Gregory-Ksander ,&nbsp;Bruce R. Ksander","doi":"10.1016/j.jaut.2025.103417","DOIUrl":"10.1016/j.jaut.2025.103417","url":null,"abstract":"<div><div>Autoimmune uveitis is a major cause of blindness and experimental autoimmune uveitis (EAU) is mediated by interphotoreceptor retinoid-binding protein specific effector CD4⁺ T cells that infiltrate the retina. At least two MHC Class II (MHC II) antigen-presenting cell (APC) events are required for uveitis to develop. The first occurs in the secondary lymphoid organs when dendritic cells (DCs) activate and expand effector CD4⁺ T cells that enter the circulation and migrate systemically. The second APC event occurs when DC-primed effector CD4⁺ T cells infiltrate the retina and are restimulated by the relevant autoantigen. Importantly, if this second restimulation does not occur, then uveitis does not develop. However, it is still unclear which cell type(s) function as APCs within the retina. There are two candidate MHC II⁺ cell types-resident microglia and infiltrating DCs. We used the inducible Cre-lox approach to develop mouse strains in which MHC II was knocked out specifically on microglia using either the <em>P2ry12</em> or <em>Tmem119</em> gene to drive recombination. We also used <em>Itgax</em> (CD11c encoding gene) to drive recombination in DCs. Using this approach, we uncovered that the second APC event was mediated by MHC II⁺ microglia and not infiltrating MHC II⁺ DCs. Therefore, microglia are an important therapeutic target that can prevent and/or diminish uveitis even in the presence of circulating retinal autoantigen-specific effector CD4⁺ T cells.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103417"},"PeriodicalIF":7.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834429","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":"Integrated stress response inhibition restores hsa-miR-145-5p levels after IFN-β stimulation in salivary gland epithelial cells. Association between cellular stress and miRNA biogenesis in Sjögren's disease","authors":"Isabel Castro ,&nbsp;Patricia Carvajal ,&nbsp;Sergio Aguilera ,&nbsp;María-José Barrera ,&nbsp;Soledad Matus ,&nbsp;Sergio González ,&nbsp;Claudio Molina ,&nbsp;María-Julieta González","doi":"10.1016/j.jaut.2025.103412","DOIUrl":"10.1016/j.jaut.2025.103412","url":null,"abstract":"<div><div>Labial salivary glands (LSG) from Sjögren's disease (SjD) patients are characterized by increased levels of pro-inflammatory cytokines, such as type I interferons (IFN-I). These LSG also show activation of the integrated stress response (ISR) with overexpression of protein kinase R (PKR), a known IFN-stimulated gene. <em>In vitro</em>, IFN-I stimulation reproduces the downregulation of hsa-miR-145-5p, which is associated with TLR4 overexpression observed in LSG of SjD patients. MicroRNA levels depend on its biogenesis, which is a multi-step process involving several protein complexes. It is not known whether altered miRNA biogenesis is associated with the activation of the ISR induced by IFN-I in LSG from SjD. The aim of this study was to characterize the expression and localization of components of the miRNA biogenesis machinery in LSG of SjD patients, to assess the effect of pro-inflammatory cytokines on these components, and to test whether inhibition of the IFN-β-induced ISR restores the levels of hsa-miR-145-5p. In LSG from 12 SjD patients and 11 non-SjD sicca controls, we determined mRNA fold changes, relative protein levels, and the localization of the ISR and miRNA biogenesis machinery components by RT-qPCR, Western blot, and immunofluorescence, respectively. Pro-inflammatory cytokines, the ISR inhibitor ISRIB, and the PKR inhibitor C16 were used for <em>in vitro</em> assays. In LSG from SjD patients, PKR and its activator PACT colocalized in the cytoplasm, whereas the PKR inhibitor TRBP was observed in the nuclei. IFN-β activates PKR, increases p-eIF2α and ATF4 levels, and increases PACT and AGO2 detection in stress granules. C16 inhibits PKR phosphorylation but increases ATF4 by activating GCN2. ISRIB restores levels of hsa-miR-145-5p and its target TLR4 mRNA upon IFN-β stimulation. These findings suggest an association between inflammation, cellular stress, and miRNA biogenesis, where modulation of the ISR emerges as a potential strategy to restore cellular homeostasis in LSG from SjD patients.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103412"},"PeriodicalIF":7.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748148","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":"Evaluation of minor labial salivary gland focus score in Sjögren's disease using deep learning: a tool for more efficient diagnosis and future tissue biomarker discovery","authors":"Konstantinos N. Panagiotopoulos ,&nbsp;Nikos Tsiknakis ,&nbsp;Dimitrios I. Zaridis ,&nbsp;Clio P. Mavragani ,&nbsp;Athanasios G. Tzioufas ,&nbsp;Dimitrios I. Fotiadis ,&nbsp;Andreas V. Goules","doi":"10.1016/j.jaut.2025.103418","DOIUrl":"10.1016/j.jaut.2025.103418","url":null,"abstract":"<div><h3>Background</h3><div>Sjögren's Disease (SjD) is histopathologically characterized by focal sialadenitis in minor labial salivary gland biopsies (mLSGB), which is evaluated by utilizing the focus score (FS). Focus score ≥1 identification is a critical step of the diagnostic approach and SjD classification. Nonetheless, during mLSGB analysis, FS reporting is neglected in a staggering 17 %, and a degree of inter-observer variability is introduced, even among specialized university centers. As the unmet need for reliable FS reporting is displayed, leveraging artificial intelligence in mLSGB evaluation shows encouraging potential and mandates to be investigated.</div></div><div><h3>Methods</h3><div>Minor LSGBs stained only with hematoxylin and eosin (H&amp;E) during evaluation of individuals with a clinical suspicion of SjD, were randomly chosen from our archive. All mLSGBs were scanned digitally as whole slide images (WSI) and the final dataset was partitioned into a training (70 %) and a test set (30 %). An attention-based deep learning binary classification model was employed for evaluation of mLSGBs positivity (FS ≥ 1 or FS &lt; 1).</div></div><div><h3>Results</h3><div>The final dataset consisted of 271 mLSGBs, with 153 (56 %) having FS &lt; 1 and 118 (44 %) FS ≥ 1. In the FS ≥ 1 subset, 74 (63 %) were in the FS = 1–2 range, and the remaining biopsies had FS &gt; 2, following the expected FS distribution among the typical SjD population. Our model resulted in: AUC = 0.932 (0.881–0.984), sensitivity 87 % (0.733–0.944), specificity 84 % (0.71–0.915) and accuracy 85.2 % (0.763–0.912), achieving better performance from previous works.</div></div><div><h3>Conclusion</h3><div>Artificial intelligence models may overcome the intra-observer biases and inter-observer variability in FS evaluation, reinforcing the diagnosis and biomarker discovery in SjD.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103418"},"PeriodicalIF":7.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855064","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":"T-bet+CD11c+ age-associated B cells resist BLyS- and CD20-targeted ablation in murine lupus models","authors":"James J. Knox,&nbsp;Jean L. Scholz,&nbsp;Hannah Futeran,&nbsp;Sofia Cataliotti,&nbsp;Michael P. Cancro","doi":"10.1016/j.jaut.2025.103410","DOIUrl":"10.1016/j.jaut.2025.103410","url":null,"abstract":"<div><h3>Objective</h3><div>B cell ablation strategies show promise for treating humoral autoimmune diseases, but their impact on pathogenic tissue-localized T-bet⁺CD11c⁺ age-associated B cells (ABCs) is poorly defined. We assessed whether mAb-mediated B cell depletion impacts ABCs and other splenic B cell subsets in two mouse models of lupus.</div></div><div><h3>Methods</h3><div>Following disease onset, we injected NZBxNZWF1 mice (NZBWF1; n = 72) or bm12 chronic graft versus host disease mice (cGVHD; n = 59) with 0.2 mg or 1 mg of anti-BLyS (10F4), anti-CD20 (18B12), combined treatment, or saline. Spleens were harvested after two weeks and B cell subset representation was analyzed via flow cytometry.</div></div><div><h3>Results</h3><div>In the NZBWF1 model, lymphopenia and resistance to 10F4 and 18B12 that arose concomitant with disease onset complicated interpretation, as ablative activity was partial and variable in the follicular (FO) and marginal zone (MZ) pools. Conversely, the T-bet⁺CD11c⁺ ABC pool was unchanged or enlarged versus controls and was entirely refractory to antibody treatments. In the cGVHD model, both 10F4 and 18B12 treatments ablated nearly all FO B cells. MZ B cells were profoundly ablated by 10F4 but spared by 18B12 treatment, whereas 10F4 treatment spared a small, undefined subset of splenic B cells that was ablated by 18B12. In contrast, T-bet⁺CD11c⁺ ABCs were minimally impacted by either reagent alone or combined, regardless of dose.</div></div><div><h3>Conclusion</h3><div>The spleen-resident T-bet⁺CD11c⁺ ABC pool resists anti-BLyS and anti-CD20 ablative treatment. These findings have implications for antibody-mediated ablative strategies in patients with autoimmune diseases.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103410"},"PeriodicalIF":7.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734951","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":"Treatment of mixed connective tissue disease: A multicenter retrospective study","authors":"Kevin Chevalier ,&nbsp;Benjamin Thoreau ,&nbsp;Marc Michel ,&nbsp;Bertrand Godeau ,&nbsp;Christian Agard ,&nbsp;Thomas Papo ,&nbsp;Karim Sacre ,&nbsp;Raphaèle Seror ,&nbsp;Xavier Mariette ,&nbsp;Patrice Cacoub ,&nbsp;Ygal Benhamou ,&nbsp;Hervé Levesque ,&nbsp;Cécile Goujard ,&nbsp;Olivier Lambotte ,&nbsp;Bernard Bonnotte ,&nbsp;Maxime Samson ,&nbsp;Félix Ackermann ,&nbsp;Jean Schmidt ,&nbsp;Pierre Duhaut ,&nbsp;Kahn Jean-Emmanuel ,&nbsp;Luc Mouthon","doi":"10.1016/j.jaut.2025.103420","DOIUrl":"10.1016/j.jaut.2025.103420","url":null,"abstract":"<div><h3>Introduction</h3><div>Mixed connective tissue disease (MCTD) is a rare systemic disorder that belongs to connective tissue diseases (CTD). Few studies are available on MCTD treatment.</div></div><div><h3>Methods</h3><div>We conducted an observational study within the French MCTD cohort. Data were collected at diagnosis, during follow-up, and at the last follow-up (LFU). We studied three treatment groups i) no treatment, ii) hydroxychloroquine (HCQ) and/or glucocorticoids (GC) and iii) disease-modifying antirheumatic drugs (DMARDs)/immunosuppressant (IS).</div></div><div><h3>Results</h3><div>Three hundred and fifteen patients were included and followed for 96 [40–156] months. At MCTD diagnosis, 52 (16.5 %) patients were treatment-free, while 224 (71.1 %) received GC and/or HCQ and 39 (12.4 %) received DMARDs and/or IS. During follow-up, 10 (3.2 %) patients remained treatment-free, and 77 (24.4 %) were GC-free. Most patients (n = 271; 85.8 %) received HCQ, and 161 (51.1 %) were treated with DMARDs and/or IS. DMARDs and/or IS, including anti-B cell therapeutics, were more frequently prescribed in patients with musculoskeletal involvement (p &lt; 0.0001), interstitial lung disease (ILD, p &lt; 0.0001) and/or pulmonary arterial hypertension (PAH, p &lt; 0.01). Patients in clinical remission and those who did not evolve to a differentiated CTD (MCTD-dCTD) received significantly less frequently DMARDs and/or IS (including anti-B cell therapeutics; p &lt; 0.0001 for both). Patients who received HCQ at MCTD diagnosis appeared to develop less frequently ILD or PAH (p &lt; 0.05).</div></div><div><h3>Conclusion</h3><div>HCQ and GC were the cornerstones of MCTD treatment and were sufficient to control disease manifestations in nearly half of the patients, reflecting the good prognosis of this disease. DMARDs and IS were used for musculoskeletal involvement, PAH/ILD, and in MCTD-dCTD patients.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103420"},"PeriodicalIF":7.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834430","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":"Systemic immune characteristics predicting toxicity to immune checkpoint inhibitors in patients with advanced breast cancer","authors":"Yalong Qi ,&nbsp;Hewei Ge ,&nbsp;Xiaoying Sun ,&nbsp;Yuhan Wei ,&nbsp;Jingtong Zhai ,&nbsp;Haili Qian ,&nbsp;Hongnan Mo ,&nbsp;Fei Ma","doi":"10.1016/j.jaut.2025.103423","DOIUrl":"10.1016/j.jaut.2025.103423","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for cancer. However, frequent and sometimes life-threatening immune-related adverse events (irAEs) are associated with ICI treatment. Therefore, it is imperative to establish a model for predicting the risk of irAEs to identify high-risk groups, enable more accurate clinical risk‒benefit analysis for ICI treatment and decrease the incidence of irAEs. However, no ideal model for predicting irAEs has been applied in clinical practice. The aim of this study was to analyze the systemic immune characteristics of patients with irAEs and establish a model for predicting the risk of irAEs.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We conducted a study to monitor irAEs in patients with advanced breast cancer undergoing immunotherapy during and following the treatment course. Peripheral blood mononuclear cells (PBMCs) were collected before and after two cycles of therapy. Mass cytometry time-of-flight (CyTOF) was employed to identify baseline and posttreatment immune cell subpopulations, and the relationships between the proportions of cells in these subpopulations and the occurrence of irAEs were explored. Additionally, we conducted subgroup analyses stratified by the anatomic location and time of onset of irAEs. Furthermore, we developed a logistic regression model to predict the risk of irAEs and validated this model using two independent validation cohorts from the Gene Expression Omnibus (GEO) database (accession numbers GSE189125 and GSE186143).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;By analyzing 106 blood samples and samples from two independent validation cohorts (n = 16 and 60 patients), we found that high proportions of CXCR3&lt;sup&gt;+&lt;/sup&gt;CCR6&lt;sup&gt;+&lt;/sup&gt;CD4&lt;sup&gt;+&lt;/sup&gt; T cells and CD38&lt;sup&gt;+&lt;/sup&gt;CD86&lt;sup&gt;+&lt;/sup&gt;CXCR3&lt;sup&gt;+&lt;/sup&gt;CCR6&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt; T cells and a low proportion of CXCR3&lt;sup&gt;low&lt;/sup&gt;CD56&lt;sup&gt;dim&lt;/sup&gt; natural killer (NK) cells at baseline were significantly correlated with the incidence of irAEs (&lt;em&gt;P&lt;/em&gt; = 0.0029, &lt;em&gt;P&lt;/em&gt; &lt; 0.001, and &lt;em&gt;P&lt;/em&gt; = 0.0017, respectively). In the subgroup analysis, we observed consistent results in patients with immune-related pneumonitis (ir-pneumonitis) and immune-related thyroiditis (ir-thyroiditis). In the early irAE group, the baseline proportion of CXCR3&lt;sup&gt;+&lt;/sup&gt;CCR6&lt;sup&gt;+&lt;/sup&gt;CD4&lt;sup&gt;+&lt;/sup&gt; T cells was greater than that in the late irAE group (&lt;em&gt;P&lt;/em&gt; = 0.011). An analysis of PBMCs before and after ICI treatment revealed thatthe dynamic changes in the proportions of naïve CD4&lt;sup&gt;+&lt;/sup&gt; T cells and CXCR3&lt;sup&gt;low&lt;/sup&gt;CD56&lt;sup&gt;dim&lt;/sup&gt; NK cells were closely related to irAE occurrence. Finally, we ultimately developed a model for predicting the risk of irAEs, which yielded an area under the receiver operating characteristic curve (AUROC) of 0.79 in the training cohort and an AUROC of 0.75 in the single-cell validation cohort (GSE189125).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Concl","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103423"},"PeriodicalIF":7.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860273","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":"Human regulatory B cells suppress autoimmune disease primarily via interleukin-37","authors":"Luman Wang ,&nbsp;Maria-Ioanna Christodoulou ,&nbsp;Zheng Jin ,&nbsp;Yanmei Ma ,&nbsp;Munnaf Hossen ,&nbsp;Yuan Ji ,&nbsp;Wenjun Wang ,&nbsp;Xueqi Wang ,&nbsp;Eryi Wang ,&nbsp;Rongfei Wei ,&nbsp;Xiaojun Xiao ,&nbsp;Xiaoyu Liu ,&nbsp;Ping-Chang Yang ,&nbsp;Shaojun Xing ,&nbsp;Bingni Chen ,&nbsp;Kaifan Wang ,&nbsp;Jim Yi Huang ,&nbsp;Aysin Tulunay-Virlan ,&nbsp;Iain B. McInnes ,&nbsp;Jing Li ,&nbsp;Damo Xu","doi":"10.1016/j.jaut.2025.103415","DOIUrl":"10.1016/j.jaut.2025.103415","url":null,"abstract":"<div><div>Regulatory B cells (Bregs) are crucial for maintaining homeostasis and controlling inflammation. Although interleukin (IL)-10 has been traditionally suggested as the primary suppressive mechanism of Bregs in both mice and humans, the key functional differences between Bregs in these two species, particularly in the context of disease, is still largely unresolved. IL-37, the latest described immunosuppressive cytokine, is produced in humans but not in mice. Herein we identified the characteristics and functions of IL-37-producing Bregs, that naturally exist in human and can be induced by recombinant IL-37 (rIL-37) and/or Toll-like receptor 9 agonist CpG via different mechanisms. rIL-37 alone is sufficient to prompt IL-37, but not IL-10, production and proliferation of Bregs, whereas CpG elicits IL-37 expression in Bregs independently of IL-10, but dependent on HIF-1α which binds on the enhancer/promoter of the IL-37 gene. Functionally, IL-37⁺ Bregs exhibit superior anti-inflammatory efficacy than IL-37^- Bregs in vitro, as well as in psoriasis and colitis models. However, the frequency of IL-37⁺ Bregs is reduced in patients with psoriasis. Thus, IL-37⁺ Bregs hold significant therapeutic potential for treating various inflammatory disorders, including psoriasis and colitis.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103415"},"PeriodicalIF":7.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838557","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":"Exploring glucagon-like peptide-1 receptor agonists as potential disease-modifying agents in autoimmune diseases","authors":"Yuanyuan Yang ,&nbsp;Wencong Liu ,&nbsp;Zechang Zhang ,&nbsp;Yujia zhang ,&nbsp;Xuebin Wang ,&nbsp;Jing Wang ,&nbsp;Huaifang Cai ,&nbsp;Yichan Liu ,&nbsp;Ran Meng ,&nbsp;Yuqi Fu ,&nbsp;Hongmin Luo ,&nbsp;Lei Yang ,&nbsp;Wenxuan Liu","doi":"10.1016/j.jaut.2025.103414","DOIUrl":"10.1016/j.jaut.2025.103414","url":null,"abstract":"<div><h3>Background</h3><div>Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging with therapeutic agents for the treatment of two of the most prevalent metabolic disorders: diabetes and obesity. However, the causal relationship between GLP-1R agonists and autoimmune diseases is still unclear.</div></div><div><h3>Methods</h3><div>The available cis-eQTLs for drug target genes (GLP-1Rs) were used as proxies for exposure to GLP-1R agonists. Obesity and type 2 diabetes mellitus (T2DM) were used as positive controls to ensure the reliability of the genetic instrument. Mendelian randomization (MR) was performed to reveal the causal association of genetic proxy GLP-1R agonists with 18 autoimmune diseases from the IEU OpenGwas database and FinnGen database. Finally, the results of the two databases were analyzed via meta-analysis.</div></div><div><h3>Results</h3><div>A total of 22 significant cis-eQTL single-nucleotide polymorphisms were included as genetic instruments. Positive control analysis revealed that GLP-1R agonists were significantly associated with obesity (OR = 0.826, <em>p</em> = 0.021) and T2DM (OR = 0.886, <em>p</em> &lt; 0.001), which is consistent with the meta-analysis. MR analysis revealed that increased expression of the GLP-1R gene has a significant protective effect on type 1 diabetes mellitus (T1DM), hypothyroidism, primary biliary cholangitis (PBC) and rheumatoid arthritis (RA). However, the MR analysis suggested that increased expression of GLP-1R agonists may increase the risk of Graves' disease (GD), ulcerative colitis (UC) and psoriasis. Our findings were consistent with those of the meta-analysis.</div></div><div><h3>Conclusions</h3><div>This study provides new insights into potential adjuvant treatments for autoimmune diseases from the perspective of genetic variation and provides evidence for the safety of GLP-1R agonists.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103414"},"PeriodicalIF":7.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739157","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}