OBJECTIVESTo verify the pathogenesis of the OGFRL1 loss-of-function variant (c.30del, p. F10Ffs*110) identified in a CRMO patient and investigate the underlying mechanism.METHODSWhole exome sequencing and Sanger sequencing were performed to identify and confirm the variant. qPCR, ELISA, CBA, bulk RNA sequencing and single-cell RNA sequencing were conducted to detect the inflammatory signatures of the patient versus healthy controls. Collagen antibody-induced arthritis model was generated in Ogfrl1 knockout (KO) and wild-type (WT) mice and micro-CT scan was performed to investigate the pathogenicity of Ogfrl1 deficiency. In addition, osteoclast induction and differentiation in vitro was exerted to explore the underlying mechanism of Ogfrl1 deficiency.RESULTSThe patient exhibited upregulated MAPK and NF-κB signaling pathways, along with overproduction of proinflammatory cytokines. Compared to healthy controls, apparent activation of myeloid cells was observed, especially in monocytes, dendritic cells, and low-density granulocytes (LDGs) of the patient. In the collagen antibody-induced arthritis (CAIA) model, Ogfrl1 KO mice developed more severe and persistent arthritis and bone erosion than WT mice. Ogfrl1 KO mice were more prone to osteoclast differentiation versus WT mice. The patient responded well to TNF inhibitor therapy, with normalization of CRP, ESR, and SAA, and IL-6 levels, as well as improvement in osteolytic lesions.CONCLUSIONThis study identified OGFRL1 deficiency as a novel cause of CRMO, highlighted the previously unrecognized role of OGFRL1 in restraining inflammatory responses, and provided novel insights into the pathogenesis and treatment of this autoinflammatory disorder.
目的验证在CRMO患者中发现的OGFRL1功能丧失变异（c.30del, p. F10Ffs*110）的发病机制，并探讨其潜在机制。方法采用全外显子组测序和Sanger测序对变异进行鉴定和确认。采用qPCR、ELISA、CBA、散装RNA测序和单细胞RNA测序检测患者与健康对照组的炎症特征。在Ogfrl1敲除（KO）和野生型（WT）小鼠中建立胶原抗体诱导的关节炎模型，并通过微ct扫描研究Ogfrl1缺乏的致病性。此外，通过体外破骨细胞诱导和分化来探索Ogfrl1缺乏的潜在机制。结果患者表现出MAPK和NF-κB信号通路上调，同时促炎细胞因子过量产生。与健康对照相比，骨髓细胞明显活化，特别是在患者的单核细胞、树突状细胞和低密度粒细胞（LDGs）中。在胶原抗体诱导的关节炎（CAIA）模型中，Ogfrl1 KO小鼠比WT小鼠发生更严重和持续的关节炎和骨侵蚀。Ogfrl1 KO小鼠比WT小鼠更容易发生破骨细胞分化。患者对TNF抑制剂治疗反应良好，CRP、ESR、SAA和IL-6水平正常化，溶骨性病变改善。结论本研究确定了OGFRL1缺失是CRMO的一个新原因，突出了OGFRL1在抑制炎症反应中的作用，并为这种自身炎症性疾病的发病机制和治疗提供了新的见解。
{"title":"OGFRL1 deficiency causes CRMO via pathological osteoclastogenesis, with therapeutic response to TNF inhibitor.","authors":"Wen Xiong,Yusha Wang,Tingyan He,Jinjian Fu,Ying Luo,Jinbo Wang,Jun Wang,Xiaomin Yu,Qing Zhou,Jun Yang","doi":"10.1002/art.70057","DOIUrl":"https://doi.org/10.1002/art.70057","url":null,"abstract":"OBJECTIVESTo verify the pathogenesis of the OGFRL1 loss-of-function variant (c.30del, p. F10Ffs*110) identified in a CRMO patient and investigate the underlying mechanism.METHODSWhole exome sequencing and Sanger sequencing were performed to identify and confirm the variant. qPCR, ELISA, CBA, bulk RNA sequencing and single-cell RNA sequencing were conducted to detect the inflammatory signatures of the patient versus healthy controls. Collagen antibody-induced arthritis model was generated in Ogfrl1 knockout (KO) and wild-type (WT) mice and micro-CT scan was performed to investigate the pathogenicity of Ogfrl1 deficiency. In addition, osteoclast induction and differentiation in vitro was exerted to explore the underlying mechanism of Ogfrl1 deficiency.RESULTSThe patient exhibited upregulated MAPK and NF-κB signaling pathways, along with overproduction of proinflammatory cytokines. Compared to healthy controls, apparent activation of myeloid cells was observed, especially in monocytes, dendritic cells, and low-density granulocytes (LDGs) of the patient. In the collagen antibody-induced arthritis (CAIA) model, Ogfrl1 KO mice developed more severe and persistent arthritis and bone erosion than WT mice. Ogfrl1 KO mice were more prone to osteoclast differentiation versus WT mice. The patient responded well to TNF inhibitor therapy, with normalization of CRP, ESR, and SAA, and IL-6 levels, as well as improvement in osteolytic lesions.CONCLUSIONThis study identified OGFRL1 deficiency as a novel cause of CRMO, highlighted the previously unrecognized role of OGFRL1 in restraining inflammatory responses, and provided novel insights into the pathogenesis and treatment of this autoinflammatory disorder.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"95 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015158","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}
Corrado Campochiaro,Marie-Elise Truchetet,Madelon Vonk,Giacomo De Luca,Giovanna Cuomo,Lidia P Ananieva,Eric Hachulla,Vanessa Smith,Ana Maria Gheorghiu,Radim Becvar,Patricia Carreira,Nicolas Hunzelmann,Daniel E Furst,Vera Ortiz-Santamaria,Francesco Del Galdo,Marco Matucci-Cerinic,Anna-Maria Hoffmann-Vold,
BACKGROUNDThe treatment landscape for systemic sclerosis-associated interstitial lung disease (SSc-ILD) has evolved with increasing immunosuppressive (IST) and anti-fibrotic therapies available. However, their real-world use remains unclear.OBJECTIVESTo analyze treatment trends and the effect of IST and anti-fibrotic therapies on ILD progression using the EUSTAR database.METHODSWe included SSc-ILD patients meeting the 2013 ACR/EULAR criteria with high-resolution CT-confirmed ILD, pulmonary function, and therapy data, grouped into four time periods (≤2006, 2007-2011, 2012-2016, ≥2017). We analyzed IST initiation, switching, discontinuation, and combination therapy. ILD progression was defined as a decline in %FVC ≥5% or %DLCO ≥10% over 12 ± 3 months.RESULTSAmong 1,409 patients, IST use at first evaluation increased significantly from 13.6% (≤2006) to 57.4% (≥2017, p<0.001). Mycophenolate mofetil emerged as the most prescribed IST (7% to 57%, p<0.001). Combination therapy rose from 17.9% to 26.9% (p<0.001), while ILD progression rates declined from 21.3% (2007-2011) to 12.1% (≥2017, p<0.001). In the ≥2017 cohort, logistic regression showed shorter disease duration (Odds ratio (OR) 0.991, 95%CI 0.987-0.996, p <0.001) and myositis (OR 9.9, 95% CI 1.94-51.76, p=0.006) were associated with therapy initiation, while switching was higher in patients with a higher mRSS (OR 1.03, 95%CI 1.00-1.06, p=0.035) and in patients with arthritis (OR 3.03, 95% CI 1.55-5.94, p=0.001). Lastly, combination therapy was associated with younger age, higher dyspnea class and arthritis.CONCLUSIONSOur findings reveal a significant evolution in clinical practice. However, continued disease progression emphasizes the need for more effective therapeutic approaches.
{"title":"Impact of evolving treatment patterns on interstitial lung disease progression in systemic sclerosis using the EUSTAR database.","authors":"Corrado Campochiaro,Marie-Elise Truchetet,Madelon Vonk,Giacomo De Luca,Giovanna Cuomo,Lidia P Ananieva,Eric Hachulla,Vanessa Smith,Ana Maria Gheorghiu,Radim Becvar,Patricia Carreira,Nicolas Hunzelmann,Daniel E Furst,Vera Ortiz-Santamaria,Francesco Del Galdo,Marco Matucci-Cerinic,Anna-Maria Hoffmann-Vold, ","doi":"10.1002/art.70043","DOIUrl":"https://doi.org/10.1002/art.70043","url":null,"abstract":"BACKGROUNDThe treatment landscape for systemic sclerosis-associated interstitial lung disease (SSc-ILD) has evolved with increasing immunosuppressive (IST) and anti-fibrotic therapies available. However, their real-world use remains unclear.OBJECTIVESTo analyze treatment trends and the effect of IST and anti-fibrotic therapies on ILD progression using the EUSTAR database.METHODSWe included SSc-ILD patients meeting the 2013 ACR/EULAR criteria with high-resolution CT-confirmed ILD, pulmonary function, and therapy data, grouped into four time periods (≤2006, 2007-2011, 2012-2016, ≥2017). We analyzed IST initiation, switching, discontinuation, and combination therapy. ILD progression was defined as a decline in %FVC ≥5% or %DLCO ≥10% over 12 ± 3 months.RESULTSAmong 1,409 patients, IST use at first evaluation increased significantly from 13.6% (≤2006) to 57.4% (≥2017, p<0.001). Mycophenolate mofetil emerged as the most prescribed IST (7% to 57%, p<0.001). Combination therapy rose from 17.9% to 26.9% (p<0.001), while ILD progression rates declined from 21.3% (2007-2011) to 12.1% (≥2017, p<0.001). In the ≥2017 cohort, logistic regression showed shorter disease duration (Odds ratio (OR) 0.991, 95%CI 0.987-0.996, p <0.001) and myositis (OR 9.9, 95% CI 1.94-51.76, p=0.006) were associated with therapy initiation, while switching was higher in patients with a higher mRSS (OR 1.03, 95%CI 1.00-1.06, p=0.035) and in patients with arthritis (OR 3.03, 95% CI 1.55-5.94, p=0.001). Lastly, combination therapy was associated with younger age, higher dyspnea class and arthritis.CONCLUSIONSOur findings reveal a significant evolution in clinical practice. However, continued disease progression emphasizes the need for more effective therapeutic approaches.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"66 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015161","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":"Comment on: \"Longitudinal Associations Between Baseline Sarcopenia and Knee Osteoarthritis Progression and Risk of Knee Replacement\" - Intramuscular Fat Infiltration: A Hidden Covariate in the Sarcopenia-Knee Osteoarthritis Association? Leveraging OAI MRI Data for Adjustment.","authors":"Huihui Wu,Zhi Wang,Liang Guo","doi":"10.1002/art.70059","DOIUrl":"https://doi.org/10.1002/art.70059","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"29 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005467","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}
Gulzada Kulzhanova, Alexis Klee, Mina Botros, Victoria L Hansen, John Reuter, Eliya Tazreena Tashbib, Eloise Fadial, Benjamin F Ricciardi, Brian Giordano, Chia-Lung Wu
Objectives: Femoroacetabular impingement (FAI) and synovitis have been recognized as essential factors for developing osteoarthritis (OA) in the hip joints. However, little is known about altered synovial cellular compositions, their associated transcriptomic profiles, and cell-cell interactions in FAI and hip OA.
Methods: Synovial samples from a sex-matched cohort of FAI and hip OA patients (n = 6/condition) were analyzed using integrative single-cell RNA sequencing and spatial transcriptomics.
Results: Compared to FAI, epiregulin (EREG)-enriched lining synovial fibroblast-like synoviocytes (FLS) were significantly increased in hip OA. EREG+ FLS are pro-inflammatory due to elevated expression of CXCL1, IL8, and MMPs. Pseudotime analysis predicts that EREG+ FLS are derived from DPP4+PI16+ sublining FLS, likely regulated by NFIX and REL, as well as ELK3 and ETV6 transcription factors under FAI or OA conditions, respectively. Importantly, the only putative cell-cell interaction is fibroblast growth factor 2 (FGF2) - syndecan 4 (SDC4) communication between COL1A1+IGFBP5+ fibrotic macrophages (MΦ) and EREG+ FLS. This interaction may induce expression of IL6, IL8, and MMP1 in hip OA synovium. The gene ontology (GO) analysis of activated genes downstream of FGF2-SDC4 signaling revealed that inflammation and angiogenesis were upregulated in hip OA, while positive gene transcription and skeletal muscle differentiation were dominant in FAI. Moreover, we also found that EREG+CCL20+MMP3hi lining FLS along with most MΦ and monocyte populations are unique to hip OA patients compared to knee OA and RA patients.
Conclusion: The findings of this study offer a groundwork in tailoring novel targets and therapies for FAI and hip OA patients.
{"title":"Integrative single cell RNA-sequencing and spatial transcriptomics uncovers distinct macrophage-fibroblast cross-talk in human hip synovium between patients with femoroacetabular impingement and osteoarthritis.","authors":"Gulzada Kulzhanova, Alexis Klee, Mina Botros, Victoria L Hansen, John Reuter, Eliya Tazreena Tashbib, Eloise Fadial, Benjamin F Ricciardi, Brian Giordano, Chia-Lung Wu","doi":"10.1002/art.70033","DOIUrl":"https://doi.org/10.1002/art.70033","url":null,"abstract":"<p><strong>Objectives: </strong>Femoroacetabular impingement (FAI) and synovitis have been recognized as essential factors for developing osteoarthritis (OA) in the hip joints. However, little is known about altered synovial cellular compositions, their associated transcriptomic profiles, and cell-cell interactions in FAI and hip OA.</p><p><strong>Methods: </strong>Synovial samples from a sex-matched cohort of FAI and hip OA patients (n = 6/condition) were analyzed using integrative single-cell RNA sequencing and spatial transcriptomics.</p><p><strong>Results: </strong>Compared to FAI, epiregulin (EREG)-enriched lining synovial fibroblast-like synoviocytes (FLS) were significantly increased in hip OA. EREG<sup>+</sup> FLS are pro-inflammatory due to elevated expression of CXCL1, IL8, and MMPs. Pseudotime analysis predicts that EREG<sup>+</sup> FLS are derived from DPP4<sup>+</sup>PI16<sup>+</sup> sublining FLS, likely regulated by NFIX and REL, as well as ELK3 and ETV6 transcription factors under FAI or OA conditions, respectively. Importantly, the only putative cell-cell interaction is fibroblast growth factor 2 (FGF2) - syndecan 4 (SDC4) communication between COL1A1<sup>+</sup>IGFBP5<sup>+</sup> fibrotic macrophages (MΦ) and EREG<sup>+</sup> FLS. This interaction may induce expression of IL6, IL8, and MMP1 in hip OA synovium. The gene ontology (GO) analysis of activated genes downstream of FGF2-SDC4 signaling revealed that inflammation and angiogenesis were upregulated in hip OA, while positive gene transcription and skeletal muscle differentiation were dominant in FAI. Moreover, we also found that EREG<sup>+</sup>CCL20<sup>+</sup>MMP3<sup>hi</sup> lining FLS along with most MΦ and monocyte populations are unique to hip OA patients compared to knee OA and RA patients.</p><p><strong>Conclusion: </strong>The findings of this study offer a groundwork in tailoring novel targets and therapies for FAI and hip OA patients.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145950982","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}
Anna H Wu,Chiuchen Tseng,Song-Yi Park,Daniel O Stram,Kami White,Jun Wu,Cheryl Vigen,Veronica W Setiawan,Xian Yu,Steven Gazal,Christopher Haiman,Lynne Wilkens,Loïc Le Marchan,Iona Cheng,William Stohl
OBJECTIVETo evaluate the effects of ambient air pollution on rheumatoid arthritis (RA) incidence in a racially/ethnically diverse population.METHODSThis analysis included 42,152 California Multiethnic Cohort (MEC) participants, ages 65 or older (>70% African American and Latino adults) who were enrolled in the Fee-for-Service component of Medicare (2001-2018). We employed multivariable Cox proportional hazards regression to examine the associations of time-varying air pollutants based on spatiotemporal models with RA incidence (n=2,027) after adjusting for demographics, neighborhood socioeconomic status (nSES), smoking, work and other exposures.RESULTSRA incidence increased with exposure to fine particulate matter (PM) with diameter ≤2.5 μm (PM2.5) (hazard ratios (HR) [95% CI] per 2 μg/m3 =1.20 [1.16-1.23]) and nitrogen dioxide (NO2) HR per 10 μg/m3=1.44 [1.35-1.52]). Air pollutant levels and risk associations were higher in African American and Latino than in Japanese American and White adults (Pheterogeneity<0.05). The RA-PM2.5 association was higher in men (1.23 [1.15-1.32]) than in women (1.17 [1.12-1.21] Pheterogeneity=0.06). RA associations with PM2.5 (and NO2) did not differ by demographics, smoking, or other lifestyle factors but the HR associated with PM2.5 was higher among those with high-risk work (longest occupation in labor/craftsman work and exposed to ≥10 years in one or more of 13 industries) (1.29[1.18-1.41]) than those without high-risk work exposures (1.16 [1.12-1.21] Pheterogeneity=0.04).CONCLUSIONExposure to PM and gaseous pollution associates with increased RA incidence after age 65, particularly among African American and Latino adults. Further characterization of air pollution's contribution to racial and ethnic disparities in RA risk is warranted.
{"title":"Late-Onset Rheumatoid Arthritis and Air Pollution in the Multiethnic Cohort.","authors":"Anna H Wu,Chiuchen Tseng,Song-Yi Park,Daniel O Stram,Kami White,Jun Wu,Cheryl Vigen,Veronica W Setiawan,Xian Yu,Steven Gazal,Christopher Haiman,Lynne Wilkens,Loïc Le Marchan,Iona Cheng,William Stohl","doi":"10.1002/art.70054","DOIUrl":"https://doi.org/10.1002/art.70054","url":null,"abstract":"OBJECTIVETo evaluate the effects of ambient air pollution on rheumatoid arthritis (RA) incidence in a racially/ethnically diverse population.METHODSThis analysis included 42,152 California Multiethnic Cohort (MEC) participants, ages 65 or older (>70% African American and Latino adults) who were enrolled in the Fee-for-Service component of Medicare (2001-2018). We employed multivariable Cox proportional hazards regression to examine the associations of time-varying air pollutants based on spatiotemporal models with RA incidence (n=2,027) after adjusting for demographics, neighborhood socioeconomic status (nSES), smoking, work and other exposures.RESULTSRA incidence increased with exposure to fine particulate matter (PM) with diameter ≤2.5 μm (PM2.5) (hazard ratios (HR) [95% CI] per 2 μg/m3 =1.20 [1.16-1.23]) and nitrogen dioxide (NO2) HR per 10 μg/m3=1.44 [1.35-1.52]). Air pollutant levels and risk associations were higher in African American and Latino than in Japanese American and White adults (Pheterogeneity<0.05). The RA-PM2.5 association was higher in men (1.23 [1.15-1.32]) than in women (1.17 [1.12-1.21] Pheterogeneity=0.06). RA associations with PM2.5 (and NO2) did not differ by demographics, smoking, or other lifestyle factors but the HR associated with PM2.5 was higher among those with high-risk work (longest occupation in labor/craftsman work and exposed to ≥10 years in one or more of 13 industries) (1.29[1.18-1.41]) than those without high-risk work exposures (1.16 [1.12-1.21] Pheterogeneity=0.04).CONCLUSIONExposure to PM and gaseous pollution associates with increased RA incidence after age 65, particularly among African American and Latino adults. Further characterization of air pollution's contribution to racial and ethnic disparities in RA risk is warranted.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"39 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949804","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}
OBJECTIVESThis study investigated the role of IL-17 in Giant Cell Arteritis (GCA), which has remained uncertain despite previous research suggesting a contribution of Th17 cells to the disease.METHODSTemporal artery biopsies (TABs) were cultured ex vivo in MATRIGEL® with IL-17, secukinumab, or control IgG, and subsequently analyzed using bulk RNA-sequencing and RT-qPCR. Positive-TABs with GCA features were compared to negative-TABs or used to obtain in vitro cultures of myofibroblasts (MFs). Confocal microscopy analyzed IL-17 receptor expression. MFs and peripheral blood mononuclear cells co-cultures were used to study T-cell polarization.RESULTSTranscriptomic analysis showed that secukinumab treatment of positive TABs reduced expression of genes linked to vascular inflammation, notably IL6. RT-qPCR analysis confirmed that secukinumab decreased mRNA encoding IL-6, CCL20, and GM-CSF in positive-TABs, while IL-17 upregulated them in negative-TABs. No changes were observed regarding the expression of genes related to vascular remodeling. IL-17 receptor chains were expressed on MFs, and their expression was enhanced by IFN-γ. RT-qPCR and Luminex® analyses confirmed IL-17-driven upregulation of IL-6, CCL20, CCL2, GM-CSF, and VEGF in MFs, which was reversed by secukinumab. Addition of IFN-γ to the culture increased the expression level of IL-17 receptor chains, resulting in a synergistic effect. Additionally, IL-17 pre-treated MFs promoted Th17 polarization.CONCLUSIONSIL-17 exacerbates vascular inflammation in GCA by activating MFs and synergizing with IFN-γ to increase production of pro-inflammatory cytokines (IL-6, GM-CSF), chemokines (CCL20, CCL2), and angiogenic factors (VEGF, indicating that IL-17 is a key contributor to disease pathogenesis.
{"title":"In synergy with interferon-gamma, interleukin-17 activates vascular stromal cells towards a pro-inflammatory profile in giant cell arteritis.","authors":"Hélène Greigert,André Ramon,Claudie Cladiere,Baptiste Lamarthée,Corentin Richard,Marion Ciudad,Alexis Varin,Noémie Herrmann,Roman Praliaud,Guillaume Brenac,Jérôme Razanamahery,Louis Arnould,Pierre-Henry Gabrielle,Catherine Creuzot-Garcher,Georges Tarris,Laurent Martin,Sylvain Audia,Romain Boidot,Bernard Bonnotte,Maxime Samson","doi":"10.1002/art.70051","DOIUrl":"https://doi.org/10.1002/art.70051","url":null,"abstract":"OBJECTIVESThis study investigated the role of IL-17 in Giant Cell Arteritis (GCA), which has remained uncertain despite previous research suggesting a contribution of Th17 cells to the disease.METHODSTemporal artery biopsies (TABs) were cultured ex vivo in MATRIGEL® with IL-17, secukinumab, or control IgG, and subsequently analyzed using bulk RNA-sequencing and RT-qPCR. Positive-TABs with GCA features were compared to negative-TABs or used to obtain in vitro cultures of myofibroblasts (MFs). Confocal microscopy analyzed IL-17 receptor expression. MFs and peripheral blood mononuclear cells co-cultures were used to study T-cell polarization.RESULTSTranscriptomic analysis showed that secukinumab treatment of positive TABs reduced expression of genes linked to vascular inflammation, notably IL6. RT-qPCR analysis confirmed that secukinumab decreased mRNA encoding IL-6, CCL20, and GM-CSF in positive-TABs, while IL-17 upregulated them in negative-TABs. No changes were observed regarding the expression of genes related to vascular remodeling. IL-17 receptor chains were expressed on MFs, and their expression was enhanced by IFN-γ. RT-qPCR and Luminex® analyses confirmed IL-17-driven upregulation of IL-6, CCL20, CCL2, GM-CSF, and VEGF in MFs, which was reversed by secukinumab. Addition of IFN-γ to the culture increased the expression level of IL-17 receptor chains, resulting in a synergistic effect. Additionally, IL-17 pre-treated MFs promoted Th17 polarization.CONCLUSIONSIL-17 exacerbates vascular inflammation in GCA by activating MFs and synergizing with IFN-γ to increase production of pro-inflammatory cytokines (IL-6, GM-CSF), chemokines (CCL20, CCL2), and angiogenic factors (VEGF, indicating that IL-17 is a key contributor to disease pathogenesis.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"27 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949785","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}
Luz P Blanco, Binod Regmi, Carmelo Carmona-Rivera, Yudong Liu, Xiantao Wang, Philip M Carlucci, Monica M Jackson, Zerai Manna, Sarfaraz Hasni, Markus Hafner, Hong-Wei Sun, Mariana J Kaplan
Objective: Neutrophil dysfunction is a hallmark of systemic lupus erythematosus (SLE), but its molecular basis remains unclear. This study explores transcriptional and post-transcriptional changes in low-density granulocytes (LDGs), a proinflammatory neutrophil subset expanded in SLE, focusing on NADPH oxidase (Nox) function and minor intron splicing.
Methods: LDGs and normal-density neutrophils (NDGs) were isolated from SLE patients and healthy controls (HCs). CYBA (P22phox) expression was evaluated at transcript and protein levels. Nox activity was measured using luminol assays. Bulk RNA sequencing and rMATS software were used to assess alternative splicing, particularly of U12-type intron-containing genes.
Results: CYBA expression was reduced in SLE LDGs (n=11) compared to SLE NDGs and HCs (n=6), with levels resembling those in chronic granulomatous disease neutrophils. SLE LDGs exhibited impaired Nox activity (n=7 SLE, n=12 HC). CYBA is a U12 intron-containing gene, and transcriptomic analysis revealed broad downregulation of this gene class in SLE LDGs, suggesting minor spliceosome dysfunction. rMATS analysis showed increased U12-type intron retention and widespread splicing defects-including exon skipping and mutually exclusive exon use-in genes such as GBP5, MAEA and STX10. These abnormalities were validated in an independent long-read RNA-seq dataset from SLE PBMCs. Importantly, splicing disruptions correlated with disease activity and autoantibody profiles.
Conclusion: Impaired U12-dependent splicing may contribute to neutrophil dysfunction in SLE, potentially via defective oxidative burst and altered immune regulation. These findings highlight the minor spliceosome as a novel player in lupus pathogenesis.
{"title":"Dysregulation of U12-Type Splicing in Lupus Neutrophils.","authors":"Luz P Blanco, Binod Regmi, Carmelo Carmona-Rivera, Yudong Liu, Xiantao Wang, Philip M Carlucci, Monica M Jackson, Zerai Manna, Sarfaraz Hasni, Markus Hafner, Hong-Wei Sun, Mariana J Kaplan","doi":"10.1002/art.70053","DOIUrl":"10.1002/art.70053","url":null,"abstract":"<p><strong>Objective: </strong>Neutrophil dysfunction is a hallmark of systemic lupus erythematosus (SLE), but its molecular basis remains unclear. This study explores transcriptional and post-transcriptional changes in low-density granulocytes (LDGs), a proinflammatory neutrophil subset expanded in SLE, focusing on NADPH oxidase (Nox) function and minor intron splicing.</p><p><strong>Methods: </strong>LDGs and normal-density neutrophils (NDGs) were isolated from SLE patients and healthy controls (HCs). CYBA (P22phox) expression was evaluated at transcript and protein levels. Nox activity was measured using luminol assays. Bulk RNA sequencing and rMATS software were used to assess alternative splicing, particularly of U12-type intron-containing genes.</p><p><strong>Results: </strong>CYBA expression was reduced in SLE LDGs (n=11) compared to SLE NDGs and HCs (n=6), with levels resembling those in chronic granulomatous disease neutrophils. SLE LDGs exhibited impaired Nox activity (n=7 SLE, n=12 HC). CYBA is a U12 intron-containing gene, and transcriptomic analysis revealed broad downregulation of this gene class in SLE LDGs, suggesting minor spliceosome dysfunction. rMATS analysis showed increased U12-type intron retention and widespread splicing defects-including exon skipping and mutually exclusive exon use-in genes such as GBP5, MAEA and STX10. These abnormalities were validated in an independent long-read RNA-seq dataset from SLE PBMCs. Importantly, splicing disruptions correlated with disease activity and autoantibody profiles.</p><p><strong>Conclusion: </strong>Impaired U12-dependent splicing may contribute to neutrophil dysfunction in SLE, potentially via defective oxidative burst and altered immune regulation. These findings highlight the minor spliceosome as a novel player in lupus pathogenesis.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145950942","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}
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