Wieke M. van Oostveen, Eva M. Hoekstra, E.W. Nivine Levarht, Ilana B. Kotliar, Thomas P. Sakmar, René E.M. Toes, Jeska K. de Vries‐Bouwstra, Laura H. Heitman, Cynthia M. Fehres
ObjectiveSystemic sclerosis (SSc) is a rare but severe autoimmune disease characterized by immune dysregulation, fibrosis, and vasculopathy. While previous studies have highlighted the presence of functional autoantibodies targeting the angiotensin II type 1 receptor (AT1R) and endothelin‐1 type A receptor (ETAR), leading to autoantibody‐mediated receptor stimulation and subsequent activation of endothelial cells (ECs), a comprehensive understanding of the direct interaction between these autoantibodies and their receptors is currently lacking. Moreover, existing data confirming the presence of these autoantibodies in SSc often rely on similar methodologies and assays. Our aim was to replicate previous findings and to investigate the functional effects of SSc patient‐derived IgG (SSc IgG) on AT1R‐ and ETAR signaling, the downstream EC response, as well as presence of AT1R‐binding autoantibodies in circulation.MethodsQuantitative PCR (qPCR) and cytokine ELISA, alongside a real‐time cell analyzer, were utilized to assess receptor‐specific functional characteristics of purified IgG from SSc patients (n=18). Additionally, a novel protein capture assay using solubilized epitope‐tagged AT1R was developed to detect AT1R‐binding autoantibodies in plasma samples from SSc patients (n=28) and healthy donors (n=14).ResultsNo evidence for EC activation in an AT1R‐ or ETAR‐dependent manner was revealed. Furthermore, stimulation with SSc IgG did not induce receptor activation nor alter GPCR signaling upon agonist stimulation in a model with receptor overexpression. Lastly, no AT1R‐binding autoantibodies were detected in plasma from SSc patients when using epitope‐tagged solubilized AT1R.ConclusionOverall, our study did not provide evidence to support the presence of AT1R‐ or ETAR‐activating autoantibodies in purified SSc IgG, nor AT1R‐binding autoantibodies in circulation of SSc patients.
{"title":"Absence of Functional Autoantibodies Targeting Angiotensin II Type 1 Receptor (AT1R) and Endothelin‐1 Type A Receptor (ETAR) in Circulation and Purified IgG from Patients with Systemic Sclerosis","authors":"Wieke M. van Oostveen, Eva M. Hoekstra, E.W. Nivine Levarht, Ilana B. Kotliar, Thomas P. Sakmar, René E.M. Toes, Jeska K. de Vries‐Bouwstra, Laura H. Heitman, Cynthia M. Fehres","doi":"10.1002/art.43099","DOIUrl":"https://doi.org/10.1002/art.43099","url":null,"abstract":"ObjectiveSystemic sclerosis (SSc) is a rare but severe autoimmune disease characterized by immune dysregulation, fibrosis, and vasculopathy. While previous studies have highlighted the presence of functional autoantibodies targeting the angiotensin II type 1 receptor (AT<jats:sub>1</jats:sub>R) and endothelin‐1 type A receptor (ET<jats:sub>A</jats:sub>R), leading to autoantibody‐mediated receptor stimulation and subsequent activation of endothelial cells (ECs), a comprehensive understanding of the direct interaction between these autoantibodies and their receptors is currently lacking. Moreover, existing data confirming the presence of these autoantibodies in SSc often rely on similar methodologies and assays. Our aim was to replicate previous findings and to investigate the functional effects of SSc patient‐derived IgG (SSc IgG) on AT<jats:sub>1</jats:sub>R‐ and ET<jats:sub>A</jats:sub>R signaling, the downstream EC response, as well as presence of AT<jats:sub>1</jats:sub>R‐binding autoantibodies in circulation.MethodsQuantitative PCR (qPCR) and cytokine ELISA, alongside a real‐time cell analyzer, were utilized to assess receptor‐specific functional characteristics of purified IgG from SSc patients (n=18). Additionally, a novel protein capture assay using solubilized epitope‐tagged AT<jats:sub>1</jats:sub>R was developed to detect AT<jats:sub>1</jats:sub>R‐binding autoantibodies in plasma samples from SSc patients (n=28) and healthy donors (n=14).ResultsNo evidence for EC activation in an AT<jats:sub>1</jats:sub>R‐ or ET<jats:sub>A</jats:sub>R‐dependent manner was revealed. Furthermore, stimulation with SSc IgG did not induce receptor activation nor alter GPCR signaling upon agonist stimulation in a model with receptor overexpression. Lastly, no AT<jats:sub>1</jats:sub>R‐binding autoantibodies were detected in plasma from SSc patients when using epitope‐tagged solubilized AT<jats:sub>1</jats:sub>R.ConclusionOverall, our study did not provide evidence to support the presence of AT<jats:sub>1</jats:sub>R‐ or ET<jats:sub>A</jats:sub>R‐activating autoantibodies in purified SSc IgG, nor AT<jats:sub>1</jats:sub>R‐binding autoantibodies in circulation of SSc patients.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"54 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887006","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":"Author Reply to Letter to the Editor","authors":"Wayne YW Lee, Rongliang Wong","doi":"10.1002/art.43100","DOIUrl":"https://doi.org/10.1002/art.43100","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"150 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887009","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}
Sara Chenguiti Fakhouri, Honglin Zhu, Yi-Nan Li, Moritz Ronicke, Aleix Rius Rigau, Clara Dees, Laura Konstantinidis, Ralf Schmid, Alexandru-Emil Matei, Markus Eckstein, Carol Geppert, Ingo Ludolph, Alexander Kreuter, Michael Sticherling, Carola Berking, Raymund E. Horch, Georg Schett, Jörg H.W. Distler, Christina Bergmann
Little is known on the mechanisms necessary to maintain the physiological adult human skin integrity. This study aims to quantitatively describe anatomical changes in systemic sclerosis (SSc)-skin compared to controls and investigate the underlying mechanisms.
{"title":"Disturbed spatial WNT activation – a potential driver of the reticularized skin phenotype in Systemic Sclerosis (SSc)","authors":"Sara Chenguiti Fakhouri, Honglin Zhu, Yi-Nan Li, Moritz Ronicke, Aleix Rius Rigau, Clara Dees, Laura Konstantinidis, Ralf Schmid, Alexandru-Emil Matei, Markus Eckstein, Carol Geppert, Ingo Ludolph, Alexander Kreuter, Michael Sticherling, Carola Berking, Raymund E. Horch, Georg Schett, Jörg H.W. Distler, Christina Bergmann","doi":"10.1002/art.43094","DOIUrl":"https://doi.org/10.1002/art.43094","url":null,"abstract":"Little is known on the mechanisms necessary to maintain the physiological adult human skin integrity. This study aims to quantitatively describe anatomical changes in systemic sclerosis (SSc)-skin compared to controls and investigate the underlying mechanisms.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"63 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887128","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: Targeting long non‐coding RNA H19 in Subchondral Bone Osteocytes Alleviates Cartilage Degradation in Osteoarthritis","authors":"An‐Fang Huang, Wang‐Dong Xu","doi":"10.1002/art.43101","DOIUrl":"https://doi.org/10.1002/art.43101","url":null,"abstract":"Click on the article title to read more.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"112 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874268","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}
Carmel B. Stober, Louise Ellis, Jane C. Goodall, Marc Veldhoen, J.S. Hill Gaston
ObjectiveGenetic associations and blockade of the interleukin‐23/IL‐17 axis with monoclonal antibodies support a role for this pathway in psoriatic arthritis (PsA). This study examines the requirement of IL‐23 for IL‐17 production, and the role of the metabolic microenvironment in the expansion of Th17‐derived cells in PsA.MethodsPsA patient synovial fluid or peripheral blood Th17 cell frequencies were evaluated by flow cytometry using CCR6, CD161 and T‐bet as phenotypic markers, and the cytokines IFN‐γ, GM‐CSF and IL‐17 assessed by flow cytometry and ELISA. The impact of IL‐23 and metabolic stress on T cell differentiation was investigated.ResultsPolyfunctional IL‐17pos CD4 (p<0.0001) & CD8 (p<0.0001), and GM‐CSFpos Th17‐derived (p<0.0001) cells were increased in inflamed joints of patients with PsA, with a proportional decrease in patient peripheral blood. We demonstrate IL‐23‐independent IL‐17 release by PsA patient CD4 T cells, where the absence of IL‐23 during Th17 differentiation reduced IL‐17 by 31±5.8%. Exogenous IL‐23 increased IL‐17, negatively regulated GM‐CSF and co‐operated with TGF‐β to augment IL‐17. Polyfunctional Th17 and Th17‐derived cells, but not Th1 cells, were expanded by metabolic stress in patients with PsA.ConclusionsWe confirmed the abundance of polyfunctional Type17 CD4 and CD8 cells in PsA inflamed joints. We demonstrate IL‐23‐independent expansion of Th17 cells, where IL‐23 negatively regulates GM‐CSF. This may account for therapeutic differences in IL‐17 and IL‐23 inhibition in PsA and the Spondyloarthritides. Polyfunctional IL‐17pos Th17, and Th17‐derived but not Th1 cells, were expanded by metabolic stress, where metabolic stress may itself represent a unique therapeutic target.
{"title":"Metabolic Stress expands Polyfunctional, Proinflammatory Th17 cells in Psoriatic Arthritis, where there is IL‐23‐independent IL‐17 production","authors":"Carmel B. Stober, Louise Ellis, Jane C. Goodall, Marc Veldhoen, J.S. Hill Gaston","doi":"10.1002/art.43095","DOIUrl":"https://doi.org/10.1002/art.43095","url":null,"abstract":"ObjectiveGenetic associations and blockade of the interleukin‐23/IL‐17 axis with monoclonal antibodies support a role for this pathway in psoriatic arthritis (PsA). This study examines the requirement of IL‐23 for IL‐17 production, and the role of the metabolic microenvironment in the expansion of Th<jats:sub>17</jats:sub>‐derived cells in PsA.MethodsPsA patient synovial fluid or peripheral blood Th<jats:sub>17</jats:sub> cell frequencies were evaluated by flow cytometry using CCR6, CD161 and T‐bet as phenotypic markers, and the cytokines IFN‐γ, GM‐CSF and IL‐17 assessed by flow cytometry and ELISA. The impact of IL‐23 and metabolic stress on T cell differentiation was investigated.ResultsPolyfunctional IL‐17<jats:sup>pos</jats:sup> CD4 (p<0.0001) & CD8 (p<0.0001), and GM‐CSF<jats:sup>pos</jats:sup> Th<jats:sub>17</jats:sub>‐derived (p<0.0001) cells were increased in inflamed joints of patients with PsA, with a proportional decrease in patient peripheral blood. We demonstrate IL‐23‐independent IL‐17 release by PsA patient CD4 T cells, where the absence of IL‐23 during Th<jats:sub>17</jats:sub> differentiation reduced IL‐17 by 31±5.8%. Exogenous IL‐23 increased IL‐17, negatively regulated GM‐CSF and co‐operated with TGF‐β to augment IL‐17. Polyfunctional Th<jats:sub>17</jats:sub> and Th<jats:sub>17</jats:sub>‐derived cells, but not Th<jats:sub>1</jats:sub> cells, were expanded by metabolic stress in patients with PsA.ConclusionsWe confirmed the abundance of polyfunctional Type<jats:sub>17</jats:sub> CD4 and CD8 cells in PsA inflamed joints. We demonstrate IL‐23‐independent expansion of Th<jats:sub>17</jats:sub> cells, where IL‐23 negatively regulates GM‐CSF. This may account for therapeutic differences in IL‐17 and IL‐23 inhibition in PsA and the Spondyloarthritides. Polyfunctional IL‐17<jats:sup>pos</jats:sup> Th<jats:sub>17</jats:sub>, and Th<jats:sub>17</jats:sub>‐derived but not Th<jats:sub>1</jats:sub> cells, were expanded by metabolic stress, where metabolic stress may itself represent a unique therapeutic target.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"48 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874317","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}
Marco A Alba, Sebastian Unizony, Kenneth J. Warrington, Giuseppe Murgia, Sergio Prieto‐González, Carlo Salvarani, Eric L. Matteson, Tanaz A Kermani
Giant cell arteritis (GCA) is a relapsing large‐vessel vasculitis with risk of serious ischemic manifestations including vision loss and vascular damage in the form of large‐artery stenosis, aneurysms and dissections. Approximately 50% of patients treated with glucocorticoid (GC) monotherapy and 30% of patients receiving adjunctive therapy with tocilizumab experience disease relapses, often during the first 2 years after diagnosis. Although most relapses in GCA do not involve life‐ or organ‐threatening presentations and can be controlled successfully, frequent relapses may lead to increased use of GC and consequent treatment‐related morbidity, in addition to risk of further vascular damage. Emerging data suggests that persistent disease activity may lead to increased vascular morbidity. Additionally, while tocilizumab decreases the frequency of relapses, more than 50% of patients relapse after discontinuation of therapy. Therefore, while interleukin‐6 blockade suppresses disease activity, it does not restore tolerance. In this article, we discuss the practical diagnosis and management of GCA relapses from an expert perspective. Current treatment options for GCA relapses, including those recommended by international guidelines, and novel potential therapies are reviewed.
{"title":"Expert Perspective: Management of Relapses in Giant Cell Arteritis","authors":"Marco A Alba, Sebastian Unizony, Kenneth J. Warrington, Giuseppe Murgia, Sergio Prieto‐González, Carlo Salvarani, Eric L. Matteson, Tanaz A Kermani","doi":"10.1002/art.43098","DOIUrl":"https://doi.org/10.1002/art.43098","url":null,"abstract":"Giant cell arteritis (GCA) is a relapsing large‐vessel vasculitis with risk of serious ischemic manifestations including vision loss and vascular damage in the form of large‐artery stenosis, aneurysms and dissections. Approximately 50% of patients treated with glucocorticoid (GC) monotherapy and 30% of patients receiving adjunctive therapy with tocilizumab experience disease relapses, often during the first 2 years after diagnosis. Although most relapses in GCA do not involve life‐ or organ‐threatening presentations and can be controlled successfully, frequent relapses may lead to increased use of GC and consequent treatment‐related morbidity, in addition to risk of further vascular damage. Emerging data suggests that persistent disease activity may lead to increased vascular morbidity. Additionally, while tocilizumab decreases the frequency of relapses, more than 50% of patients relapse after discontinuation of therapy. Therefore, while interleukin‐6 blockade suppresses disease activity, it does not restore tolerance. In this article, we discuss the practical diagnosis and management of GCA relapses from an expert perspective. Current treatment options for GCA relapses, including those recommended by international guidelines, and novel potential therapies are reviewed.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"201 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874320","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":"Transient perivascular inflammation of the carotid artery (TIPIC) syndrome","authors":"Neeharika Namineni, Sowmya Mahalingam, Abhijeet Danve","doi":"10.1002/art.43093","DOIUrl":"https://doi.org/10.1002/art.43093","url":null,"abstract":"Click on the article title to read more.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"61 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874318","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}
Holly T. Philpott, Trevor B. Birmingham, Garth Blackler, J. Daniel Klapak, Alexander J. Knights, Easton C. Farrell, Benoit Fiset, Logan A. Walsh, J. Robert Giffin, Edward M. Vasarhelyi, Steven J. MacDonald, Brent A. Lanting, Tristan Maerz, C. Thomas Appleton
Uncontrolled pain remains a major clinical challenge in the management of knee osteoarthritis (OA), the most common disabling joint disease. Worse pain is associated with synovial innate immune cell infiltration (synovitis), but the role of innate immune regulatory cells in pain is unknown. Our objective was to identify synovial innate immune cell subsets and pathophysiologic mechanisms associated with worse pain in patients with knee OA.
{"title":"Synovial innate immune exhaustion is associated with worse pain in knee osteoarthritis","authors":"Holly T. Philpott, Trevor B. Birmingham, Garth Blackler, J. Daniel Klapak, Alexander J. Knights, Easton C. Farrell, Benoit Fiset, Logan A. Walsh, J. Robert Giffin, Edward M. Vasarhelyi, Steven J. MacDonald, Brent A. Lanting, Tristan Maerz, C. Thomas Appleton","doi":"10.1002/art.43089","DOIUrl":"https://doi.org/10.1002/art.43089","url":null,"abstract":"Uncontrolled pain remains a major clinical challenge in the management of knee osteoarthritis (OA), the most common disabling joint disease. Worse pain is associated with synovial innate immune cell infiltration (synovitis), but the role of innate immune regulatory cells in pain is unknown. Our objective was to identify synovial innate immune cell subsets and pathophysiologic mechanisms associated with worse pain in patients with knee OA.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"53 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841779","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}
Faye AH Cooles, Gemma V Pedrola, Najib Naamane, Arthur G Pratt, Ben Barron‐Millar, Amy E Anderson, Catharien MU Hilkens, John Casement, Vincent Bondet, Darragh Duffy, Fan Zhang, Ruchi Shukla, John D Isaacs
ObjectivesEndogenous retroelements (EREs) stimulate type 1 interferon (IFN‐I) production but have not been explored as potential interferonogenic triggers in Rheumatoid Arthritis (RA). We investigated ERE expression in early RA (eRA), a period where IFN‐I is increased.MethodsERE expression (LTR5, LINE1, SINE) in disease modifying treatment naïve eRA whole blood and bulk synovial tissue was examined by RT‐PCR and Nanostring alongside IFN‐α activity. Circulating lymphocyte subsets, including B cell subsets, from eRA patients and early psoriatic arthritis (ePsA), were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single‐cell sequencing data was re‐interrogated to identify repeat elements, and associations explored.ResultsThere was significant co‐expression of all ERE classes and IFNA in eRA synovial tissue (n=22, p<0.0001) and significant positive associations between whole blood LINE1 expression (n=56) and circulating IFN‐α protein (p=0.018) and anti‐CCP titres (p<0.0001). ERE expression was highest in circulating eRA B‐cells, particularly naïve B‐cells compared with ePsA, with possible ERE regulation by SAMDH1 implicated and associations with IFNA again observed. Finally, in established RA synovium, LTRs, particularly ERVK, were most increased in RA compared with OA where, for all synovial subsets (monocytes, B‐cells, T‐cells and fibroblasts), ERE expression associated with increased IFN‐I signalling (p<0.001).ConclusionsPeripheral blood and synovial ERE expression is examined for the first time in eRA highlighting both a potential causal relationship between ERE and IFN‐I production and an intriguing association with anti‐CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.
目的内源性逆转录酶（EREs）可刺激 1 型干扰素（IFN-I）的产生，但尚未将其作为类风湿关节炎（RA）的潜在干扰素诱发因素进行研究。我们通过 RT-PCR 和 Nanostring 方法检测了早期类风湿关节炎（ERA）中ERE 的表达（LTR5、LINE1、SINE）以及 IFN-α 的活性。对来自 eRA 患者和早期银屑病关节炎（ePsA）的循环淋巴细胞亚群（包括 B 细胞亚群）进行了流式细胞仪分选和类似检测。结果在ERA滑膜组织中，所有ERE类别和IFNA都有显著的共表达（n=22，p<0.0001），全血LINE1表达（n=56）与循环IFN-α蛋白（p=0.018）和抗CCP滴度（p<0.0001）之间存在显著的正相关。与epsA相比，ERE在循环ERA B细胞，尤其是幼稚B细胞中的表达量最高，这可能与SAMDH1的ERE调控有关，并再次观察到与IFNA的关联。最后，在已建立的 RA 滑膜中，与 OA 相比，RA 的 LTR（尤其是 ERVK）增加最多，在所有滑膜亚群（单核细胞、B 细胞、T 细胞和成纤维细胞）中，ERE 的表达与 IFN-I 信号的增加有关（p<0.001）。这表明ERE可能有助于RA的病理生理学，并对未来的新型治疗策略产生影响。
{"title":"Endogenous retroelement activation is implicated in IFN‐α production and anti‐CCP autoantibody generation in early Rheumatoid Arthritis","authors":"Faye AH Cooles, Gemma V Pedrola, Najib Naamane, Arthur G Pratt, Ben Barron‐Millar, Amy E Anderson, Catharien MU Hilkens, John Casement, Vincent Bondet, Darragh Duffy, Fan Zhang, Ruchi Shukla, John D Isaacs","doi":"10.1002/art.43083","DOIUrl":"https://doi.org/10.1002/art.43083","url":null,"abstract":"ObjectivesEndogenous retroelements (EREs) stimulate type 1 interferon (IFN‐I) production but have not been explored as potential interferonogenic triggers in Rheumatoid Arthritis (RA). We investigated ERE expression in early RA (eRA), a period where IFN‐I is increased.MethodsERE expression (LTR5, LINE1, SINE) in disease modifying treatment naïve eRA whole blood and bulk synovial tissue was examined by RT‐PCR and Nanostring alongside IFN‐α activity. Circulating lymphocyte subsets, including B cell subsets, from eRA patients and early psoriatic arthritis (ePsA), were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single‐cell sequencing data was re‐interrogated to identify repeat elements, and associations explored.ResultsThere was significant co‐expression of all ERE classes and <jats:italic>IFNA</jats:italic> in eRA synovial tissue (n=22, p<0.0001) and significant positive associations between whole blood LINE1 expression (n=56) and circulating IFN‐α protein (p=0.018) and anti‐CCP titres (p<0.0001). ERE expression was highest in circulating eRA B‐cells, particularly naïve B‐cells compared with ePsA, with possible ERE regulation by SAMDH1 implicated and associations with <jats:italic>IFNA</jats:italic> again observed. Finally, in established RA synovium, LTRs, particularly ERVK, were most increased in RA compared with OA where, for all synovial subsets (monocytes, B‐cells, T‐cells and fibroblasts), ERE expression associated with increased IFN‐I signalling (p<0.001).ConclusionsPeripheral blood and synovial ERE expression is examined for the first time in eRA highlighting both a potential causal relationship between ERE and IFN‐I production and an intriguing association with anti‐CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"6 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832080","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":"Short‐term risk of cardiovascular events in people newly diagnosed with gout: comment on the article by Cipolletta et al.","authors":"Zichang Liu, Yanwei Zhu, Hui Zhao","doi":"10.1002/art.43091","DOIUrl":"https://doi.org/10.1002/art.43091","url":null,"abstract":"Click on the article title to read more.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"6 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825168","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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