Annals of the Rheumatic Diseases最新文献

{"title":"Myeloid dendritic cell subsets characterise muscle in patients with inclusion body myositis and correlate with the IFN-γ pathway and effector T cell markers.","authors":"Raphael A Kirou, Iago Pinal-Fernandez, Maria Casal-Dominguez, Katherine Pak, Chiseko Ikenaga, Christopher Nelke, Sven Wischnewski, Corinna Preusse, Stefania Del Orso, Faiza Naz, Shamima Islam, Gustavo Gutierrez-Cruz, Thomas E Lloyd, Lucas Schirmer, Tobias Ruck, Werner Stenzel, Albert Selva-O'Callaghan, Jose C Milisenda, Andrew L Mammen","doi":"10.1016/j.ard.2026.03.001","DOIUrl":"https://doi.org/10.1016/j.ard.2026.03.001","url":null,"abstract":"<p><strong>Objectives: </strong>Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy characterised by type 1 inflammation, driven by muscle-infiltrating KLRG1+ and TBX21+ cytotoxic T cells. However, the cellular sources of the stimuli that trigger this effector response in the muscle of patients with IBM remain unclear. Given their role as antigen-presenting cells, we hypothesised that these may be myeloid dendritic cells (mDCs), which have previously been reported in skeletal muscle of patients with IBM. We used immunohistochemistry, immunofluorescence, single-nucleus RNA-sequencing (snRNA-seq) and bulk RNA-sequencing (RNA-seq) data from skeletal muscle of patients with IBM, other myositis, and controls to identify mDCs and characterise their contribution to IBM inflammation.</p><p><strong>Methods: </strong>We first analysed snRNA-seq data from 3 datasets to identify, quantify, and characterise 3 mDC subsets: type 1 conventional dendritic (cDC1) cells, type 2 conventional dendritic (cDC2) cells, and mature immunoregulatory dendritic (mregDC) cells. We then analysed RNA-seq data from 2 datasets to correlate specific markers of these subsets with markers of IBM disease activity. We used immunohistochemistry and immunofluorescence to confirm mDC presence.</p><p><strong>Results: </strong>All 3 mDC subsets, and especially cDC1 cells, are relatively increased in the muscle of patients with IBM and correlate strongly with IBM-specific inflammatory markers, including KLRG1 and TBX21. In particular, cDC1 cells specifically express the KLRG1 ligands, CDH1 and CDH2, and, along with mregDC cells, IL12B, representing possible juxtacrine and paracrine signals for effector T cells in IBM.</p><p><strong>Conclusions: </strong>Skeletal muscle of patients with IBM is specifically characterised by mDC subsets that correlate with markers of cytotoxic T cells and type 1 inflammation.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832791","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":"A phase 2, randomised, placebo-controlled study of guselkumab in adults with new-onset or relapsing giant cell arteritis.","authors":"Jean-Paul Makhzoum, Maria C Cid, Maxime Samson, Joerg Henes, Verena Schönau, Georgina Espigol-Frigole, Carolyn Ross, Mark A Ahlman, Ming-Chun Hsu, Shu Li, Pauline Verdijk, Linda Okonkwo, Peter C Grayson, Daniel Blockmans","doi":"10.1016/j.ard.2026.01.009","DOIUrl":"10.1016/j.ard.2026.01.009","url":null,"abstract":"<p><strong>Objectives: </strong>Guselkumab, a monoclonal antibody, selectively targets the p19 subunit of interleukin-23. This randomised, double-blind, placebo-controlled, phase 2 study evaluated guselkumab vs placebo for the treatment of giant cell arteritis (GCA).</p><p><strong>Methods: </strong>Patients ≥50 years of age with new-onset or relapsing GCA were randomised 2:1 to guselkumab or placebo. Both arms received background glucocorticoid (GC) therapy, with a protocol-defined taper through week 26. The primary endpoint was the proportion of patients achieving GC-free remission at week 28.</p><p><strong>Results: </strong>Thirty-five patients were randomised to receive guselkumab and 18 to receive placebo. All patients were White, 70% were female, and the mean age was 71.5 years; 60% had new-onset and 40% had relapsing GCA. At week 28, 40% (14/35) and 33% (6/18) of patients in the guselkumab and placebo groups, respectively, achieved GC-free remission (P = .64), whereas 31% (11/35) and 39% (7/18) had experienced a GCA flare or discontinued due to worsening GCA. Median time to first GCA flare through week 28 was not estimable (NE) in the guselkumab group (90% CI: 27.7-NE) and 29.7 weeks (90% CI: 20.1-NE) in the placebo group (P = .64). Through week 60, 97% (34/35) and 94% (17/18) of patients in the guselkumab and placebo groups, respectively, had adverse events (AEs); the most common AEs, aside from worsening of GCA (49% and 56%, respectively), were COVID-19 infection (23% and 28%) and headache (17% and 39%).</p><p><strong>Conclusions: </strong>The study's primary endpoint (GC-free remission) was not met; results do not support the use of guselkumab in the treatment of GCA.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"911-920"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193932","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":"Mosunetuzumab, a CD20xCD3 bispecific T-cell engager, in granulomatosis with polyangiitis.","authors":"Ayla Nadja Stütz, Laura-Marie Lahu, Sandra Jaschinski, Christina Düsing, Nebile Güzel, Daniel Schwarz, Jörg H W Distler, Wolfgang Merkt","doi":"10.1016/j.ard.2025.10.026","DOIUrl":"10.1016/j.ard.2025.10.026","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"958-961"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572744","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":"Heterogeneous responses of IM19 anti-CD19 CAR T-cell therapy in refractory systemic lupus erythematosus: an open-label pilot study and a mini-review.","authors":"Jinxia Zhao, Xiaoying Zhang, Yime Zhang, Xinyi Li, Hui Wei, Yinji Jin, Rui Liu, Zhaohua Li, Wei Guo, Zhenqing Wang, Yue Guo, Yunxia Xia, Yang Yu, Haijing Liu, Lin Zeng, Qiang Shu, Jinlian Sun, Yang Tian, Yanping Ding, Ting He, Xin'an Lu, Lin Sun, Rong Mu","doi":"10.1016/j.ard.2025.12.014","DOIUrl":"10.1016/j.ard.2025.12.014","url":null,"abstract":"<p><strong>Objectives: </strong>This study aims to evaluate the efficacy and safety of IM19, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell, in patients with refractory systemic lupus erythematosus (SLE), with a particular focus on lupus nephritis (LN).</p><p><strong>Methods: </strong>This is an open-label, single-arm clinical trial. IM19 was administered following lymphodepletion. Repeated renal biopsies were performed at day 180. Single-cell RNA sequencing on peripheral blood mononuclear cells was performed pre- and 180-day post-CAR-T infusion. A literature search on the efficacy of CAR T-cell therapy in LN in PubMed database was conducted.</p><p><strong>Results: </strong>Six patients with refractory SLE and renal involvement were enrolled. IM19 therapy was well tolerant, with mild cytokine release syndrome occurring in 4 patients. The median Systemic Lupus Erythematosus Disease Activity Index-2000 score decreased from 12 (range, 10-24) to 4 (range, 2-8) at day 90, and remained stable at 5 (range, 2-6) at day 180. The renal responses were heterogeneous with 2 complete responders, 2 partial responders, and 2 nonresponders. Repeated renal biopsies showed no B-cell infiltration, but dominant chronic changes and podocytopathies post-CAR-T therapy. A mini-review demonstrated that the renal complete response rate of CAR-T therapy was 72.4%, and advanced age was associated with suboptimal response. Single-cell analysis confirmed B-cell reconstitution in 3/6 patients.</p><p><strong>Conclusions: </strong>IM19 CAR T-cell therapy demonstrated a favourable safety profile and clinically meaningful systemic improvement. Responses to CAR-T therapy in LN were variable. Chronic renal manifestations, podocytopathy, and ageing were associated with suboptimal therapeutic outcome.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"836-847"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123262","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":"Untargeted breathomics identifies metabolic signatures of immune activity, intestinal integrity, and fatigue in systemic lupus erythematosus.","authors":"Ioannis Parodis, Martina Iacubino, Lorenzo Rocco, Dionysis Nikolopoulos, Leonardo Palazzo, Liam Grimmett, Matt Kerr, Chiara Bellocchi, Barbara Vigone, Alessandro Santaniello, Guillermo Barturen, Alexandre E Voskuyl, Marta E Alarcón-Riquelme, Lorenzo Beretta","doi":"10.1016/j.ard.2025.12.005","DOIUrl":"10.1016/j.ard.2025.12.005","url":null,"abstract":"<p><strong>Objectives: </strong>Systemic lupus erythematosus (SLE) is a complex autoimmune disease with pronounced clinical heterogeneity and symptom burden. Despite growing knowledge of SLE biology, sensitive noninvasive biomarkers for monitoring disease activity remain lacking. This study aimed to characterise the breath metabolome in SLE and to explore associations between volatile organic compounds (VOCs) and clinical features, including disease activity and fatigue.</p><p><strong>Methods: </strong>Exhaled breath was collected from 30 SLE patients and 30 matched healthy controls using the ReCIVA Breath Sampler and analysed by thermal desorption gas chromatography-mass spectrometry. VOCs were identified using high-resolution libraries and classified by confidence levels. Associations with clinical and patient-reported outcomes were evaluated, including disease activity indices, fatigue scores, Definition Of Remission In SLE remission, and Lupus Low Disease Activity State.</p><p><strong>Results: </strong>Of 1433 detected VOCs, 539 exhibited levels over background and were considered breath-derived. Distinct breathomic signatures discriminated patients from controls and stratified patients by SLE activity and fatigue burden. Five VOC clusters were identified. Methyl acetate was inversely associated with disease activity and fatigue, suggesting a role in immune homeostasis. A cluster of branched alkenes and alcohols was associated with active disease and greater fatigue, aligning with oxidative stress and lipid peroxidation. Nitrogen-containing heterocycles displayed U-shaped patterns across disease states, potentially reflecting varying intestinal permeability.</p><p><strong>Conclusions: </strong>This is the first study to characterise the breath metabolome in SLE. VOC signatures reflected immunometabolic perturbations, oxidative stress, and gut barrier integrity. Breathomics may provide a noninvasive means to monitor disease activity and symptom burden in SLE.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"848-857"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896117","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":"Microbial signatures in psoriatic arthritis distinguish disease phenotypes and newly diagnosed inflammatory bowel disease independent of faecal calprotectin.","authors":"Alba Boix-Amorós, Kevin Bu, Rebecca B Blank, Adam Cantor, Ana Gutiérrez-Casbas, Iago Rodríguez-Lago, Ignacio Marin-Jimenez, Jesus Sanz, Jordi Gratacos Masmitja, Elisa Trujillo, María Carmen Muñoz, María Luz García Vivar, Marta Carrillo, María Vanesa Hernández Hernández, Xavier Calvet, Marta Arévalo Salaet, Marta Izquierdo Romero, Anahy Brandy García, Sandra Pérez, Jose Francisco García Llorente, Yago Gonzalez-Lama, Carolina Merino Argumánez, Zulema Plaza, Marta Domínguez, Juan D Cañete, Jose Federico Diaz-Gonzalez, Jose U Scher, Jose C Clemente","doi":"10.1016/j.ard.2026.01.018","DOIUrl":"10.1016/j.ard.2026.01.018","url":null,"abstract":"<p><strong>Objectives: </strong>There is growing evidence of microbial involvement in immune-mediated inflammatory diseases, including psoriatic arthritis (PsA) and inflammatory bowel disease (IBD). However, it remains unclear whether different PsA phenotypes exhibit distinct microbial profiles. Furthermore, up to 4% of patients with PsA have comorbid IBD, which often remains undiagnosed. We hypothesised that the gut microbiome distinguishes PsA subphenotypes and serves as a biomarker of IBD in patients with PsA independent of faecal calprotectin (fCAL).</p><p><strong>Methods: </strong>We obtained samples from 192 patients with axial or peripheral PsA and no prior diagnosis of IBD enrolled in the EISER study. Patients with elevated fCAL and subclinical IBD symptoms underwent colonoscopy with intestinal biopsy. Stool samples were used to measure fCAL, and gut microbiome was characterised using shotgun metagenomics. Serum samples were used for cytokine profiling.</p><p><strong>Results: </strong>Axial PsA had lower alpha diversity and loss of several commensals compared with peripheral PsA, as well as a depletion of microbial biotin and arginine metabolism and higher levels of IL-23, IL-17F, and IL-8. Five subjects had newly diagnosed IBD which was characterised by a depletion of tryptophan and vitamin B6 metabolism. They also showed significant enrichment of several taxa compared to non-IBD and with a larger effect size than fCAL.</p><p><strong>Conclusions: </strong>Our results identify a distinct microbiome and immune profile in axial PsA, with lower microbiome diversity, a depletion of commensals and protective microbial mechanisms, and higher levels of some proinflammatory cytokines. In patients with newly diagnosed IBD, we identified microbial taxa associated with the condition yet independent of fCAL, the current clinical standard.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"806-817"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321287","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":"Dimerization as a key feature of autoreactive IgA antibody responses.","authors":"Anouk G van Mourik, Jim B D Keijser, Myrthe A M van Delft, Sanne Reijm, Alice Bacon, Theo Rispens, Nivine E W Levarht, Rayman T N Tjokrodirijo, Peter A van Veelen, Leendert A Trouw, René E M Toes, Karin A van Schie, Nienke Oskam, Diane van der Woude","doi":"10.1016/j.ard.2025.11.003","DOIUrl":"10.1016/j.ard.2025.11.003","url":null,"abstract":"<p><strong>Objectives: </strong>The presence of immunoglobulin A (IgA) autoantibodies has been described in many autoimmune diseases, and some of its characteristics, such as IgA dimerization, are considered a sign of a mucosal origin. However, limited information is available about the (patho)physiological conditions leading to the development of monomeric vs dimeric (autoreactive) IgA in humans. Therefore, we investigated IgA dimerization in rheumatic autoimmune diseases with a possible mucosal origin, as well as after vaccination.</p><p><strong>Methods: </strong>Plasma of patients with rheumatic disease (rheumatoid arthritis [RA], systemic sclerosis [SSc], anti-neutrophil cytoplasmic antibody associated vasculitis [AAV], systemic lupus erythematosus [SLE]), SARS-CoV-2 vaccinated healthy individuals, and healthy controls was used for size exclusion chromatography (SEC). Enzyme-linked immunosorbent assays were performed on SEC fractions to determine the size of IgA. Results were confirmed using western blot and tandem mass spectrometry.</p><p><strong>Results: </strong>The proportion of dimeric IgA was increased for autoantibodies compared to total IgA. This was most evident in RA, AAV, and SLE (dimeric autoreactive IgA ≈ 60%-80% vs total IgA ≈ 20%, SLE ≈ 60% total IgA), but not in SSc. Intramuscular vaccination against SARS-CoV-2 also led to an increased proportion of dimeric anti-spike IgA shortly after vaccination, irrespective of previous mucosal exposure.</p><p><strong>Conclusions: </strong>These findings indicate that dimeric (autoreactive) IgA responses are associated with newly emerging antigen-specific immune activation, where production temporarily shifts to dimeric IgA. Mucosal triggering is not necessarily always involved in these IgA immune responses. These findings provide key insights into the circumstances for IgA dimerization and suggest that dimeric IgA could serve as a marker for immunological disease activity in autoimmunity.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"797-805"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145628227","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":"Response to correspondence on 'ChatGPT vs rheumatologists: cross-sectional study on accuracy and patient perception of AI-generated information for psoriatic arthritis' by Xie et al.","authors":"Giulio Forte, Daniele Mauro, Francesco Ciccia","doi":"10.1016/j.ard.2026.01.011","DOIUrl":"https://doi.org/10.1016/j.ard.2026.01.011","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":"85 5","pages":"e49-e50"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855741","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":"Th9-arterial endothelial cell crosstalk promotes psoriatic atherosclerosis.","authors":"Ishita Baral, Yvonne Baumer, Aarohan Mukerjhee Burma, McKella Sylvester, Kyle Jones, Moses Mwesigwa Kitakule, Amit Dey, Justin Rodante, Cristhian A Gutierrez-Huerta, Bhavani Taramangalam, Julio Diaz Perez, Liang Guo, Alyssa Grogan, Tatsuya Shiraki, Aloke V Finn, Aran Son, Kyoungin Cho, Jaspal S Khillan, Marcus Y Chen, Tiffany M Powell-Wiley, Pamela A Frischmeyer-Guerrerio, Joshua D Milner, Nehal N Mehta, Guido H Falduto, Daniella M Schwartz","doi":"10.1016/j.ard.2025.11.008","DOIUrl":"10.1016/j.ard.2025.11.008","url":null,"abstract":"<p><strong>Objectives: </strong>Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death. Systemic autoimmune and inflammatory diseases are associated with increased ASCVD risk, severity, and mortality. The inflammatory cytokine interleukin 9 (IL-9) has been linked to murine atherogenesis, raising fundamental questions about the populations in which and the mechanisms by which IL-9 drives ASCVD.</p><p><strong>Methods: </strong>Circulating T helper subsets and coronary computed tomography angiography data were analysed in patients with psoriasis. Murine models of psoriatic atherogenesis (imiquimod-ApoE^-/-, IL-23-ApoE^-/-, and Card14^ΔE138-ApoE^-/-) were investigated using IL-9 blockade or global and endothelial-specific Il9r deletion. Primary human aortic endothelial cells were used to assess IL-9/STAT3-dependent endothelial responses.</p><p><strong>Results: </strong>Here, we found that expansion of IL-9-producing T helper cells (Th9) was significantly associated with high-risk radiographic ASCVD in patients with the autoimmune disease psoriasis. Th9 cells were poised to migrate to coronary vessels and were identified in human atherosclerotic plaque from individuals with psoriasis. In vivo, murine inflammatory atherogenesis was prevented by IL-9 blockade and by IL-9 receptor (IL-9R) deletion in endothelial cells. In human arterial endothelial cells, IL-9R/STAT3 signalling promoted endothelial dysfunction via diverse mechanisms including adhesion, activation, angiogenesis, and release of leukocyte chemoattractants.</p><p><strong>Conclusions: </strong>These findings suggest the Th9^high state may represent a novel psoriatic ASCVD endotype that could be targeted using precision approaches to prevent ASCVD in at-risk individuals.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"818-835"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751478","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":"A germline IκBα mutation outside the signal reception domain blocks nuclear translocation of NFκB1 and associates with autoinflammation-like features.","authors":"Abdulwahab Elsayed, Ignatius Ryan Adriawan, Faranaz Atschekzei, Natalia Dubrowinskaja, Manfred Anim, Fabian Hauck, Ulrich Baumann, Torsten Witte, Georgios Sogkas","doi":"10.1016/j.ard.2025.08.010","DOIUrl":"10.1016/j.ard.2025.08.010","url":null,"abstract":"<p><strong>Objectives: </strong>IκBα controls the canonical activation of NFκB. IκBα gain-of-function due to NFKBIA variants affecting the N-terminus of IκBα-especially residues 32 and 36-manifests with combined immunodeficiency. The role of NFKBIA variants affecting other IκBα domains has not been described.</p><p><strong>Methods: </strong>Variants in NFKBIA were identified using whole-exome sequencing. IκBα expression has been quantified by flow cytometry and Western blotting. Activation-induced IκBα degradation, NFκB1 activation, and nuclear translocation as well as inflammasome activity were evaluated.</p><p><strong>Results: </strong>The p.Gln228* variant in NFKBIA, identified in a family with a history of arthritis and psoriasis, did not affect induced degradation of IκBα. Its expression in HEK293T cells confirmed its truncating effect and revealed reduced NFκB activation. Similar to transfected HEK293T cells, peripheral blood mononuclear cells from patients harbouring the p.Gln228* variant displayed substantially reduced nuclear levels of NFκB1 p50. The latter findings suggest that the p.Gln228* variant causes a functional insufficiency of NFκB1. Similar to patients with NFκB1 haploinsufficiency, high serum levels of interleukin (IL)-18, as well as enhanced induced apoptosis-associated speck-like protein containing a caspase recruitment domain speck formation and IL-1β secretion in vitro, suggest enhanced inflammasome activation.</p><p><strong>Conclusions: </strong>NFKBIA variants not localising to the signal reception domain can affect IκBα function and consequently restrict the canonical activation of NFκB. In contrast to the phenotype of N-terminal variants, which is dominated by combined immunodeficiency, the here-reported C-terminal deletion of IκBα was identified in patients with autoinflammatory arthritis and psoriasis.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"932-941"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008081","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}