According to a central tenet of classical immune theory, a healthy immune system must avoid self-reactive lymphocyte clones but we now know that B cells repertoire exhibit some level of autoreactivity. These autoreactive B cells are thought to rely on self-ligands for their clonal selection and survival. Here, we confirm that healthy mice exhibit self-reactive B cell clones that can be stimulated in vitro by agonists of toll-like receptor (TLR) 1/2, TLR4, TLR7 and TLR9 to secrete anti-LG3/perlecan. LG3/perlecan is an antigen packaged in exosome-like structures released by apoptotic endothelial cells (ApoExos) upon vascular injury. We demonstrate that the injection of ApoExos in healthy animals activates the IL-23/IL-17 pro-inflammatory and autoimmune axis, and produces several autoantibodies, including anti-LG3 autoantibodies and hallmark autoantibodies found in systemic lupus erythematosus. We also identify γδT cells as key mediators of the maturation of ApoExos-induced autoantibodies in healthy mice. Altogether we show that ApoExos released by apoptotic endothelial cells display immune-mediating functions that can stimulate the B cells in the normal repertoire to produce autoantibodies. Our work also identifies TLR activation and γδT cells as important modulators of the humoral autoimmune response induced by ApoExos.
根据经典免疫理论的核心原则,健康的免疫系统必须避免自我反应性淋巴细胞克隆,但我们现在知道,B 细胞复合物表现出一定程度的自我反应性。这些自反应性 B 细胞被认为依赖于自身配体进行克隆选择和存活。在这里,我们证实了健康小鼠表现出的自反应性 B 细胞克隆可在体外受到收费样受体(TLR)1/2、TLR4、TLR7 和 TLR9 激动剂的刺激而分泌抗 LG3/perlecan。LG3/perlecan是一种抗原,在血管损伤时由凋亡的内皮细胞(ApoExos)释放的类外泌体结构中包装。我们证明,在健康动物体内注射 ApoExos 会激活 IL-23/IL-17 促炎症和自身免疫轴,并产生多种自身抗体,包括抗 LG3 自身抗体和系统性红斑狼疮中的标志性自身抗体。我们还发现γδT细胞是ApoExos诱导的自身抗体在健康小鼠体内成熟的关键介质。总之,我们的研究表明,凋亡的内皮细胞释放的 ApoExos 具有免疫介导功能,可刺激正常细胞群中的 B 细胞产生自身抗体。我们的研究还发现 TLR 激活和 γδT 细胞是 ApoExos 诱导的体液自身免疫反应的重要调节因子。
{"title":"Vascular injury derived apoptotic exosome-like vesicles trigger autoimmunity","authors":"Sandrine Juillard , Annie Karakeussian-Rimbaud , Marie-Hélène Normand , Julie Turgeon , Charlotte Veilleux-Trinh , Alexa C. Robitaille , Joyce Rauch , Andrzej Chruscinski , Nathalie Grandvaux , Éric Boilard , Marie-Josée Hébert , Mélanie Dieudé","doi":"10.1016/j.jtauto.2024.100250","DOIUrl":"10.1016/j.jtauto.2024.100250","url":null,"abstract":"<div><p>According to a central tenet of classical immune theory, a healthy immune system must avoid self-reactive lymphocyte clones but we now know that B cells repertoire exhibit some level of autoreactivity. These autoreactive B cells are thought to rely on self-ligands for their clonal selection and survival. Here, we confirm that healthy mice exhibit self-reactive B cell clones that can be stimulated <em>in vitro</em> by agonists of toll-like receptor (TLR) 1/2, TLR4, TLR7 and TLR9 to secrete anti-LG3/perlecan. LG3/perlecan is an antigen packaged in exosome-like structures released by apoptotic endothelial cells (ApoExos) upon vascular injury. We demonstrate that the injection of ApoExos in healthy animals activates the IL-23/IL-17 pro-inflammatory and autoimmune axis, and produces several autoantibodies, including anti-LG3 autoantibodies and hallmark autoantibodies found in systemic lupus erythematosus. We also identify γδT cells as key mediators of the maturation of ApoExos-induced autoantibodies in healthy mice. Altogether we show that ApoExos released by apoptotic endothelial cells display immune-mediating functions that can stimulate the B cells in the normal repertoire to produce autoantibodies. Our work also identifies TLR activation and γδT cells as important modulators of the humoral autoimmune response induced by ApoExos.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"9 ","pages":"Article 100250"},"PeriodicalIF":4.7,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909024000200/pdfft?md5=10a63c2cb5c64a890726d7f77c3163c6&pid=1-s2.0-S2589909024000200-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-27DOI: 10.1016/j.jtauto.2024.100249
Bing Wang, Biqing Zhang, Min Wu, Ting Xu
Systemic lupus erythematosus (SLE) represents an autoimmune disorder that affects multiple systems. In the treatment of this condition, the focus primarily revolves around inflammation suppression and immunosuppression. Consequently, targeted therapy has emerged as a prevailing approach. Currently, the quest for highly sensitive and specifically effective targets has gained significant momentum in the context of SLE treatment. Lymphocyte activation gene-3 (LAG-3) stands out as a crucial inhibitory receptor that binds to pMHC-II, thereby effectively dampening autoimmune responses. Fibrinogen-like protein 1 (FGL1) serves as the principal immunosuppressive ligand for LAG-3, and their combined action demonstrates a potent immunosuppressive effect. This intricate mechanism paves the way for potential SLE treatment by targeting LAG-3 with FGL1. This work provides a comprehensive summary of LAG-3's role in the pathogenesis of SLE and elucidates the feasibility of leveraging FGL1 as a therapeutic approach for SLE management. It introduces a novel therapeutic target and opens up new avenues of therapeutic consideration in the clinical context of SLE treatment.
{"title":"Unlocking therapeutic potential: Targeting lymphocyte activation Gene-3 (LAG-3) with fibrinogen-like protein 1 (FGL1) in systemic lupus erythematosus","authors":"Bing Wang, Biqing Zhang, Min Wu, Ting Xu","doi":"10.1016/j.jtauto.2024.100249","DOIUrl":"10.1016/j.jtauto.2024.100249","url":null,"abstract":"<div><p>Systemic lupus erythematosus (SLE) represents an autoimmune disorder that affects multiple systems. In the treatment of this condition, the focus primarily revolves around inflammation suppression and immunosuppression. Consequently, targeted therapy has emerged as a prevailing approach. Currently, the quest for highly sensitive and specifically effective targets has gained significant momentum in the context of SLE treatment. Lymphocyte activation gene-3 (LAG-3) stands out as a crucial inhibitory receptor that binds to pMHC-II, thereby effectively dampening autoimmune responses. Fibrinogen-like protein 1 (FGL1) serves as the principal immunosuppressive ligand for LAG-3, and their combined action demonstrates a potent immunosuppressive effect. This intricate mechanism paves the way for potential SLE treatment by targeting LAG-3 with FGL1. This work provides a comprehensive summary of LAG-3's role in the pathogenesis of SLE and elucidates the feasibility of leveraging FGL1 as a therapeutic approach for SLE management. It introduces a novel therapeutic target and opens up new avenues of therapeutic consideration in the clinical context of SLE treatment.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"9 ","pages":"Article 100249"},"PeriodicalIF":4.7,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909024000194/pdfft?md5=9ede3dcb5f11d159f2702ec556ac9231&pid=1-s2.0-S2589909024000194-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141841524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-16DOI: 10.1016/j.jtauto.2024.100248
Jun Huang , Jia Tang , Chen Zhang, Tingting Liu, Zhiyong Deng, Lei Liu
Objective
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder with an unclear pathogenetic mechanism in the labial gland. This study aims to investigate the cellular and molecular mechanisms contributing to the development of this disease.
Methods
Single-cell RNA sequencing (scRNA-seq) was performed on 32,337 cells of labial glands from three pSS patients and three healthy individuals. We analyzed all cell subsets implicated in pSS pathogenesis.
Results
Our research revealed diminished differentiation among epithelial cells, concomitant with an enhancement of interferons (IFNs)-mediated signaling pathways. This indicates a cellular functional shift in reaction to inflammatory triggers. Moreover, we observed an augmentation in the population of myofibroblasts and endothelial cells, likely due to the intensified IFNs signaling, suggesting a possible reconfiguration of tissue structure and vascular networks in the impacted regions. Within the immune landscape, there was an apparent increase in immunosuppressive macrophages and dendritic cells (DCs), pointing to an adaptive immune mechanism aimed at modulating inflammation and averting excessive tissue harm. Elevated activation levels of CD4+T cells, along with a rise in regulatory T (Treg) cells, were noted, indicating a nuanced immune interplay designed to manage the inflammatory response. In the CD8+T cell subsests, we detected a notable increase in cells expressing granzyme K (GZMK), signaling an intensified cytotoxic activity. Additionally, the escalated presence of T cells with high levels of heat shock proteins (HSPs) suggests a cellular stress condition, possibly associated with persistent low-grade inflammation, mirroring the chronic aspect of the condition.
Conclusions
Our research identified distinct stromal and immune cell populations linked to pSS, revealing new potential targets for its management. The activation of myeloid, B, and T cells could contribute to pSS pathogenesis, providing important guidance for therapeutic approaches.
目的原发性斯约格伦综合征(pSS)是一种全身性自身免疫性疾病,唇腺的发病机制尚不清楚。本研究旨在探讨导致这种疾病发生的细胞和分子机制。方法对来自三名 pSS 患者和三名健康人的 32,337 个唇腺细胞进行了单细胞 RNA 测序(scRNA-seq)。我们分析了与 pSS 发病机制有关的所有细胞亚群。结果我们的研究发现,上皮细胞分化减弱,同时干扰素(IFNs)介导的信号通路增强。这表明细胞对炎症诱因的反应发生了功能性转变。此外,我们还观察到肌成纤维细胞和内皮细胞的数量增加,这可能是由于 IFNs 信号的增强,表明受影响区域的组织结构和血管网络可能发生了重组。在免疫环境中,免疫抑制巨噬细胞和树突状细胞(DCs)明显增加,这表明适应性免疫机制旨在调节炎症和避免对组织造成过度伤害。CD4+T细胞活化水平升高,调节性T细胞(Treg)增加,这表明免疫系统之间存在着微妙的相互作用,旨在控制炎症反应。在 CD8+T 细胞亚群中,我们检测到表达颗粒酶 K (GZMK) 的细胞明显增加,这表明细胞毒性活性增强。此外,热休克蛋白(HSPs)水平较高的 T 细胞的增加表明细胞处于应激状态,可能与持续的低度炎症有关,反映了病情的慢性方面。结论我们的研究发现了与 pSS 相关的不同基质和免疫细胞群,揭示了治疗 pSS 的新潜在靶点。髓系细胞、B 细胞和 T 细胞的活化可能有助于 pSS 的发病机制,为治疗方法提供了重要指导。
{"title":"Single-cell transcriptomic analysis uncovers heterogeneity in the labial gland microenvironment of primary Sjögren's syndrome","authors":"Jun Huang , Jia Tang , Chen Zhang, Tingting Liu, Zhiyong Deng, Lei Liu","doi":"10.1016/j.jtauto.2024.100248","DOIUrl":"10.1016/j.jtauto.2024.100248","url":null,"abstract":"<div><h3>Objective</h3><p>Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder with an unclear pathogenetic mechanism in the labial gland. This study aims to investigate the cellular and molecular mechanisms contributing to the development of this disease.</p></div><div><h3>Methods</h3><p>Single-cell RNA sequencing (scRNA-seq) was performed on 32,337 cells of labial glands from three pSS patients and three healthy individuals. We analyzed all cell subsets implicated in pSS pathogenesis.</p></div><div><h3>Results</h3><p>Our research revealed diminished differentiation among epithelial cells, concomitant with an enhancement of interferons (IFNs)-mediated signaling pathways. This indicates a cellular functional shift in reaction to inflammatory triggers. Moreover, we observed an augmentation in the population of myofibroblasts and endothelial cells, likely due to the intensified IFNs signaling, suggesting a possible reconfiguration of tissue structure and vascular networks in the impacted regions. Within the immune landscape, there was an apparent increase in immunosuppressive macrophages and dendritic cells (DCs), pointing to an adaptive immune mechanism aimed at modulating inflammation and averting excessive tissue harm. Elevated activation levels of CD4<sup>+</sup>T cells, along with a rise in regulatory T (Treg) cells, were noted, indicating a nuanced immune interplay designed to manage the inflammatory response. In the CD8<sup>+</sup>T cell subsests, we detected a notable increase in cells expressing granzyme K (GZMK), signaling an intensified cytotoxic activity. Additionally, the escalated presence of T cells with high levels of heat shock proteins (HSPs) suggests a cellular stress condition, possibly associated with persistent low-grade inflammation, mirroring the chronic aspect of the condition.</p></div><div><h3>Conclusions</h3><p>Our research identified distinct stromal and immune cell populations linked to pSS, revealing new potential targets for its management. The activation of myeloid, B, and T cells could contribute to pSS pathogenesis, providing important guidance for therapeutic approaches.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"9 ","pages":"Article 100248"},"PeriodicalIF":4.7,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909024000182/pdfft?md5=28c94a7aa08c4484edc759073e98b10c&pid=1-s2.0-S2589909024000182-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141701616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-22DOI: 10.1016/j.jtauto.2024.100247
Ilaria Maccora , Sara Soldovieri , Teodoro Oliverio , Salvatore de Masi , Edoardo Marrani , Ilaria Pagnini , Maria Vincenza Mastrolia , Gabriele Simonini
Objective
Since adalimumab approval in childhood chronic non-infectious uveitis (cNIU), the prognosis has been dramatically changed, but the 25 % failed to achieve inactivity. There is not accordance if it is better to switch to another anti-TNF or to swap to another category of biologic. Thus, we aim to summarize evidence regarding the best treatment of cNIU refractory to the first anti-TNF.
Methods
A systematic literature review and meta-analysis, according to PRISMA Guidelines, was performed(Jan2000-Aug2023). Studies investigating the efficacy of treatment in cNIU refractory to the first anti-TNF were considered for inclusion. The primary outcome was the improvement of intraocular inflammation according to SUN. A combined estimation of the proportion of children responding to switch or swap and for each drug was performed.
Results
23 articles were eligible, reporting 150 children of whom 109 switched anti-TNF (45 adalimumab, 49 infliximab, 9 golimumab) and 41 swapped to another biologics (31 abatacept, 8 tocilizumab and 1 rituximab). The proportion of responding children was 46 %(95 % CI 23-70) for switch and 38 %(95 % CI 8-73) for swap (χ20.02, p = 0.86). Instead analysing for each drug, the proportion of responding children was the 24 %(95 % CI 2-55) for adalimumab, 43 %(95 % CI 2-80) for abatacept, 79 %(95 % CI 61-93) for infliximab, 56 %(95 % CI 14-95) for golimumab and 96 %(95 % CI 58-100) for tocilizumab. We evaluated a superiority of tocilizumab and infliximab compared to the other drugs(χ2 27.5 p < 0.0001).
Conclusion
Although non-conclusive, this meta-analysis suggests that, after the first anti-TNF failure, tocilizumab and infliximab are the best available treatment for the management of cNIU.
目的自从阿达木单抗被批准用于儿童慢性非感染性葡萄膜炎(cNIU)以来,预后发生了巨大变化,但仍有25%的患者未能达到无效状态。目前尚不清楚是改用另一种抗肿瘤坏死因子(anti-TNF)更好,还是改用另一类生物制剂更好。因此,我们旨在总结有关对第一种抗肿瘤坏死因子(anti-TNF)治疗无效的 cNIU 的最佳治疗方法的证据。纳入考虑的研究对象是对首次抗肿瘤坏死因子治疗无效的 cNIU 进行疗效调查的研究。主要结果是眼内炎症的改善程度(根据 SUN 标准)。结果23篇文章符合条件,共报告了150名患儿,其中109名患儿换用了抗肿瘤坏死因子(45名阿达木单抗、49名英夫利昔单抗、9名戈利木单抗),41名患儿换用了其他生物制剂(31名阿帕他赛、8名托珠单抗和1名利妥昔单抗)。换药儿童的应答比例为 46%(95 % CI 23-70),换药儿童的应答比例为 38%(95 % CI 8-73)(χ20.02,P = 0.86)。如果对每种药物进行分析,阿达木单抗的应答儿童比例为 24%(95 % CI 2-55),阿帕他赛的应答儿童比例为 43%(95 % CI 2-80),英夫利西单抗的应答儿童比例为 79%(95 % CI 61-93),戈利木单抗的应答儿童比例为 56%(95 % CI 14-95),托珠单抗的应答儿童比例为 96%(95 % CI 58-100)。我们评估了托西珠单抗和英夫利昔单抗与其他药物相比的优越性(χ2 27.5 p < 0.0001)。结论尽管尚无定论,但这项荟萃分析表明,在首次抗肿瘤坏死因子治疗失败后,托西珠单抗和英夫利昔单抗是治疗 cNIU 的最佳药物。
{"title":"To switch or to swap? Evidence from a meta-analysis for the best treatment approach in childhood chronic uveitis resistant to the I anti-TNF","authors":"Ilaria Maccora , Sara Soldovieri , Teodoro Oliverio , Salvatore de Masi , Edoardo Marrani , Ilaria Pagnini , Maria Vincenza Mastrolia , Gabriele Simonini","doi":"10.1016/j.jtauto.2024.100247","DOIUrl":"https://doi.org/10.1016/j.jtauto.2024.100247","url":null,"abstract":"<div><h3>Objective</h3><p>Since adalimumab approval in childhood chronic non-infectious uveitis (cNIU), the prognosis has been dramatically changed, but the 25 % failed to achieve inactivity. There is not accordance if it is better to switch to another anti-TNF or to swap to another category of biologic. Thus, we aim to summarize evidence regarding the best treatment of cNIU refractory to the first anti-TNF.</p></div><div><h3>Methods</h3><p>A systematic literature review and meta-analysis, according to PRISMA Guidelines, was performed(Jan2000-Aug2023). Studies investigating the efficacy of treatment in cNIU refractory to the first anti-TNF were considered for inclusion. The primary outcome was the improvement of intraocular inflammation according to SUN. A combined estimation of the proportion of children responding to switch or swap and for each drug was performed.</p></div><div><h3>Results</h3><p>23 articles were eligible, reporting 150 children of whom 109 switched anti-TNF (45 adalimumab, 49 infliximab, 9 golimumab) and 41 swapped to another biologics (31 abatacept, 8 tocilizumab and 1 rituximab). The proportion of responding children was 46 %(95 % CI 23-70) for switch and 38 %(95 % CI 8-73) for swap (χ<sup>2</sup>0.02, p = 0.86). Instead analysing for each drug, the proportion of responding children was the 24 %(95 % CI 2-55) for adalimumab, 43 %(95 % CI 2-80) for abatacept, 79 %(95 % CI 61-93) for infliximab, 56 %(95 % CI 14-95) for golimumab and 96 %(95 % CI 58-100) for tocilizumab. We evaluated a superiority of tocilizumab and infliximab compared to the other drugs(χ<sup>2</sup> 27.5 p < 0.0001).</p></div><div><h3>Conclusion</h3><p>Although non-conclusive, this meta-analysis suggests that, after the first anti-TNF failure, tocilizumab and infliximab are the best available treatment for the management of cNIU.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"9 ","pages":"Article 100247"},"PeriodicalIF":4.7,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909024000170/pdfft?md5=0c91f958902d6a7d2c337e34d2d6fdd5&pid=1-s2.0-S2589909024000170-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141487571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lupus nephritis (LN) diagnosis and follow-up requires noninvasive biomarkers. Therefore, the added value of coupling the urinary soluble (s)CD163/creatinuria ratio with serological markers was evaluated in a real-world clinical practice. To this end, a monocentric and retrospective study was conducted in 139 SLE patients with biopsy-proven nephritis having an active LN (LN-A, n = 63 with a positive SLEDAI-renal score) or inactive (n = 76), as well as 98 non-renal SLE patients. The urinary sCD163/creatinuria ratio outperformed serological markers for predicting LN-A (AUC>0.972; p < 10−4 with a 100 % specificity threshold fixed at 320 ng/mmol), and for monitoring renal activity allowing prediction of impending flares and remissions in follow-up (AUC = 0.789, p < 10−4). LN-A patients with an elevated spot proteinuria/creatinuria ratio (p = 8 × 10−6) and sCD163/creatinuria ratio (p = 10−3) were at risk for developing end-stage kidney disease but sCD163/creatinuria ratio cannot substitute kidney biopsy to discriminate LN-A from other glomerulonephritis. Among serological markers (n = 14), anti-dsDNA and anti-C1q antibodies (Abs) (AUC>0.750 versus non-LN patients, and AUC>0.640 versus LN-IR patients) best predicted LN-A, and higher levels were retrieved in class III/IV proliferative LN-A. In multivariate logistic regression analysis, the urinary sCD163/creatinuria ratio remained the only statistically significant biomarker to predict LN-A (p < 0.001). In conclusion, and as compared to classical serological markers, the urinary sCD163/creatinuria ratio provides an additional parameter for monitoring LN patients.
{"title":"Urinary soluble CD163 is useful as “liquid biopsy” marker in lupus nephritis at both diagnosis and follow-up to predict impending flares","authors":"Yves Renaudineau , Dominique Chauveau , Stanislas Faguer , Antoine Huart , David Ribes , Gregory Pugnet , Laurent Sailler , Thibaut Jamme , Emmanuel Treiner , Françoise Fortenfant , Chloé Bost , Caroline Carlé , Julie Belliere","doi":"10.1016/j.jtauto.2024.100244","DOIUrl":"https://doi.org/10.1016/j.jtauto.2024.100244","url":null,"abstract":"<div><p>Lupus nephritis (LN) diagnosis and follow-up requires noninvasive biomarkers. Therefore, the added value of coupling the urinary soluble (s)CD163/creatinuria ratio with serological markers was evaluated in a real-world clinical practice. To this end, a monocentric and retrospective study was conducted in 139 SLE patients with biopsy-proven nephritis having an active LN (LN-A, n = 63 with a positive SLEDAI-renal score) or inactive (n = 76), as well as 98 non-renal SLE patients. The urinary sCD163/creatinuria ratio outperformed serological markers for predicting LN-A (AUC>0.972; p < 10<sup>−4</sup> with a 100 % specificity threshold fixed at 320 ng/mmol), and for monitoring renal activity allowing prediction of impending flares and remissions in follow-up (AUC = 0.789, p < 10<sup>−4</sup>). LN-A patients with an elevated spot proteinuria/creatinuria ratio (p = 8 × 10<sup>−6</sup>) and sCD163/creatinuria ratio (p = 10<sup>−3</sup>) were at risk for developing end-stage kidney disease but sCD163/creatinuria ratio cannot substitute kidney biopsy to discriminate LN-A from other glomerulonephritis. Among serological markers (n = 14), anti-dsDNA and anti-C1q antibodies (Abs) (AUC>0.750 versus non-LN patients, and AUC>0.640 versus LN-IR patients) best predicted LN-A, and higher levels were retrieved in class III/IV proliferative LN-A. In multivariate logistic regression analysis, the urinary sCD163/creatinuria ratio remained the only statistically significant biomarker to predict LN-A (p < 0.001). In conclusion, and as compared to classical serological markers, the urinary sCD163/creatinuria ratio provides an additional parameter for monitoring LN patients.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"9 ","pages":"Article 100244"},"PeriodicalIF":4.7,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909024000145/pdfft?md5=5f6c05181e41d12b1f58ed7baadf5037&pid=1-s2.0-S2589909024000145-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141438181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-20DOI: 10.1016/j.jtauto.2024.100246
Ellen D. Kaan , Tammo E. Brunekreef , Julia Drylewicz , Lucas L. van den Hoogen , Maarten van der Linden , Helen L. Leavis , Jacob M. van Laar , Michiel van der Vlist , Henny G. Otten , Maarten Limper
Objective
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a variety of disease symptoms and an unpredictable clinical course. To improve treatment outcome, stratification based on immunological manifestations commonly seen in patients with SLE such as autoantibodies, type I interferon (IFN) signature and neutrophil extracellular trap (NET) release may help. It is assumed that there is an association between these immunological phenomena, since NET release induces IFN production and IFN induces autoantibody formation via B-cell activation. Here we studied the association between autoantibodies, the IFN signature, NET release, and clinical manifestations in patients with SLE.
Methods
We performed principal component analysis (PCA) and hierarchical clustering of 57 SLE-related autoantibodies in 25 patients with SLE. We correlated each autoantibody to the IFN signature and NET inducing capacity.
Results
We observed two distinct clusters: one cluster contained mostly patients with a high IFN signature. Patients in this cluster often present with cutaneous lupus, and have higher anti-dsDNA concentrations. Another cluster contained a mix of patients with a high and low IFN signature. Patients with high and low NET inducing capacity were equally distributed between the clusters. Variance between the clusters is mainly driven by antibodies against histones, RibP2, RibP0, EphB2, RibP1, PCNA, dsDNA, and nucleosome. In addition, we found a trend towards increased concentrations of autoantibodies against EphB2, RibP1, and RNP70 in patients with an IFN signature. We found a negative correlation of NET inducing capacity with anti-FcER (r = −0.530; p = 0.007) and anti-PmScl100 (r = −0.445; p = 0.03).
Conclusion
We identified a subgroup of patients with an IFN signature that express increased concentrations of antibodies against DNA and RNA-binding proteins, which can be useful for further patient stratification and a more targeted therapy. We did not find positive associations between autoantibodies and NET inducing capacity. Our study further strengthens the evidence of a correlation between RNA-binding autoantibodies and the IFN signature.
{"title":"Association of autoantibodies with the IFN signature and NETosis in patients with systemic lupus erythematosus","authors":"Ellen D. Kaan , Tammo E. Brunekreef , Julia Drylewicz , Lucas L. van den Hoogen , Maarten van der Linden , Helen L. Leavis , Jacob M. van Laar , Michiel van der Vlist , Henny G. Otten , Maarten Limper","doi":"10.1016/j.jtauto.2024.100246","DOIUrl":"https://doi.org/10.1016/j.jtauto.2024.100246","url":null,"abstract":"<div><h3>Objective</h3><p>Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a variety of disease symptoms and an unpredictable clinical course. To improve treatment outcome, stratification based on immunological manifestations commonly seen in patients with SLE such as autoantibodies, type I interferon (IFN) signature and neutrophil extracellular trap (NET) release may help. It is assumed that there is an association between these immunological phenomena, since NET release induces IFN production and IFN induces autoantibody formation via B-cell activation. Here we studied the association between autoantibodies, the IFN signature, NET release, and clinical manifestations in patients with SLE.</p></div><div><h3>Methods</h3><p>We performed principal component analysis (PCA) and hierarchical clustering of 57 SLE-related autoantibodies in 25 patients with SLE. We correlated each autoantibody to the IFN signature and NET inducing capacity.</p></div><div><h3>Results</h3><p>We observed two distinct clusters: one cluster contained mostly patients with a high IFN signature. Patients in this cluster often present with cutaneous lupus, and have higher anti-dsDNA concentrations. Another cluster contained a mix of patients with a high and low IFN signature. Patients with high and low NET inducing capacity were equally distributed between the clusters. Variance between the clusters is mainly driven by antibodies against histones, RibP2, RibP0, EphB2, RibP1, PCNA, dsDNA, and nucleosome. In addition, we found a trend towards increased concentrations of autoantibodies against EphB2, RibP1, and RNP70 in patients with an IFN signature. We found a negative correlation of NET inducing capacity with anti-FcER (r = −0.530; p = 0.007) and anti-PmScl100 (r = −0.445; p = 0.03).</p></div><div><h3>Conclusion</h3><p>We identified a subgroup of patients with an IFN signature that express increased concentrations of antibodies against DNA and RNA-binding proteins, which can be useful for further patient stratification and a more targeted therapy. We did not find positive associations between autoantibodies and NET inducing capacity. Our study further strengthens the evidence of a correlation between RNA-binding autoantibodies and the IFN signature.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"9 ","pages":"Article 100246"},"PeriodicalIF":4.7,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909024000169/pdfft?md5=7ab271c4eddb80612212f613a866cdd3&pid=1-s2.0-S2589909024000169-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141444632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-06DOI: 10.1016/j.jtauto.2024.100243
Kalliopi Azariadis , Nikolaos K. Gatselis , Aggeliki Lyberopoulou , Pinelopi Arvaniti , Kalliopi Zachou , Stella Gabeta , George N. Dalekos
Background
Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148 M (rs738409 C/G) variant has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD).
Aim
Our aim was to investigate the significance of PNPLA3 I148 M variant in AIH.
Method
Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR).
Results
The I148 M variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with PNPLA3 genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the I148 M variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients.
Conclusions
The PNPLA3 I148 M variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the PNPLA3 I148 M variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.
{"title":"PNPLA3 I148 M genetic variant in autoimmune hepatitis characterises advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related mortality","authors":"Kalliopi Azariadis , Nikolaos K. Gatselis , Aggeliki Lyberopoulou , Pinelopi Arvaniti , Kalliopi Zachou , Stella Gabeta , George N. Dalekos","doi":"10.1016/j.jtauto.2024.100243","DOIUrl":"https://doi.org/10.1016/j.jtauto.2024.100243","url":null,"abstract":"<div><h3>Background</h3><p>Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (<em>PNPLA3</em>) <em>I148 M</em> (<em>rs7</em>38409 C/G) variant has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD).</p></div><div><h3>Aim</h3><p>Our aim was to investigate the significance of <em>PNPLA3 I148 M</em> variant in AIH.</p></div><div><h3>Method</h3><p>Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR).</p></div><div><h3>Results</h3><p>The <em>I148 M</em> variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with <em>PNPLA3</em> genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the <em>I148 M</em> variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients.</p></div><div><h3>Conclusions</h3><p>The <em>PNPLA3 I148 M</em> variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the <em>PNPLA3 I148 M</em> variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"9 ","pages":"Article 100243"},"PeriodicalIF":3.9,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909024000133/pdfft?md5=88106cddb30fad94504e751c77e514d0&pid=1-s2.0-S2589909024000133-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141325237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01DOI: 10.1016/j.jtauto.2024.100232
Bo Zhang , Xiaole Mei , Ming Zhao , Qianjin Lu
{"title":"The new era of immune skin diseases: Exploring advances in basic research and clinical translations","authors":"Bo Zhang , Xiaole Mei , Ming Zhao , Qianjin Lu","doi":"10.1016/j.jtauto.2024.100232","DOIUrl":"10.1016/j.jtauto.2024.100232","url":null,"abstract":"","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"8 ","pages":"Article 100232"},"PeriodicalIF":3.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909024000029/pdfft?md5=fe40277a1fbc700802b0cd52f1aac353&pid=1-s2.0-S2589909024000029-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139539963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01DOI: 10.1016/j.jtauto.2023.100224
Yves Renaudineau
{"title":"Editorial from the new editor-in-chief","authors":"Yves Renaudineau","doi":"10.1016/j.jtauto.2023.100224","DOIUrl":"10.1016/j.jtauto.2023.100224","url":null,"abstract":"","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"8 ","pages":"Article 100224"},"PeriodicalIF":3.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909023000370/pdfft?md5=ceca85d18551d4eb2075c6d003907f99&pid=1-s2.0-S2589909023000370-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138608307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-03DOI: 10.1016/j.jtauto.2024.100242
Pengyuan Liu , Huiyang Liu , Yali Sang , Lingyan Zhu , Peiyao Zhang , Chunyan Pang , Yongfu Wang , Li Bai
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammatory changes in the joints, the etiology of which is unclear. It is now well established that regulated cell death (RCD) and migration of neutrophils play an important role in the pathogenesis of RA. Tripterygium wilfordii Hook.f (TwHF) is a total saponin extracted from the root of Tripterygium wilfordii Hook.f, a plant of the family Wesleyanaceae, which has strong anti-inflammatory and immunomodulatory effects and has been used as a basic drug in the clinical treatment of RA. Despite the good efficacy of TwHF treatment, the mechanism of action of TwHF remains unclear. Several studies have demonstrated that the drug tripterygium glycosides, in which TwHF is the main ingredient, has achieved excellent efficacy in the clinical treatment of RA. Investigations have also found that TwHF can affect cellular RCD, cell migration, cell proliferation, and the apoptosis-related Hippo signaling pathway. In this study, we first analyzed the RCD and migration differences of neutrophils in patients with RA through network pharmacology and transcriptome analysis. Subsequently, we used electron microscopy, immunofluorescence, and other methods to identify the RCD phenotype of neutrophils. In collagen-induced arthritis (CIA) model, we demonstrated that Triptolide (the main active ingredient in TwHF) could alleviate the progression of arthritis by reducing the bone destruction and the infiltration of neutrophils. Furthermore, in vitro experiments showed that Triptolide induced neutrophil apoptosis, inhibited the formation of neutrophil extracellular traps (NETs), and impeded the neutrophil migration process in a Hippo pathway-dependent manner. Taken together, these findings indicate that Triptolide has potential for treating RA and provide theoretical support for the clinical application of TwHF, as a traditional Chinese medicine, in RA.
类风湿性关节炎(RA)是一种慢性自身免疫性疾病,以关节炎症性改变为特征,其病因尚不清楚。目前已经确定,调节性细胞死亡(RCD)和中性粒细胞迁移在类风湿性关节炎的发病机制中发挥着重要作用。威斯康辛科植物三尖杉(Tripterygium wilfordii Hook.f)(TwHF)是从其根部提取的一种总皂苷,具有很强的抗炎和免疫调节作用,已被用作临床治疗 RA 的基础药物。尽管TwHF治疗效果良好,但其作用机制仍不清楚。多项研究表明,以TwHF为主要成分的三叶皂苷类药物在临床治疗RA方面取得了很好的疗效。研究还发现,TwHF可影响细胞RCD、细胞迁移、细胞增殖以及与细胞凋亡相关的Hippo信号通路。在本研究中,我们首先通过网络药理学和转录组分析,分析了RA患者中性粒细胞的RCD和迁移差异。随后,我们利用电子显微镜、免疫荧光等方法确定了中性粒细胞的RCD表型。在胶原诱导的关节炎(CIA)模型中,我们证明了特利托利(Triptolide,TwHF 的主要活性成分)可以通过减少骨破坏和中性粒细胞的浸润来缓解关节炎的进展。此外,体外实验表明,曲托列特能诱导中性粒细胞凋亡,抑制中性粒细胞胞外捕获物(NET)的形成,并以依赖 Hippo 通路的方式阻碍中性粒细胞的迁移过程。综上所述,这些研究结果表明,雷公藤内酯具有治疗风湿性关节炎的潜力,并为风湿性关节炎的中药临床应用提供了理论支持。
{"title":"Triptolide regulates neutrophil function through the Hippo signaling pathway to alleviate rheumatoid arthritis disease progression","authors":"Pengyuan Liu , Huiyang Liu , Yali Sang , Lingyan Zhu , Peiyao Zhang , Chunyan Pang , Yongfu Wang , Li Bai","doi":"10.1016/j.jtauto.2024.100242","DOIUrl":"https://doi.org/10.1016/j.jtauto.2024.100242","url":null,"abstract":"<div><p>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammatory changes in the joints, the etiology of which is unclear. It is now well established that regulated cell death (RCD) and migration of neutrophils play an important role in the pathogenesis of RA. Tripterygium wilfordii Hook.f (TwHF) is a total saponin extracted from the root of Tripterygium wilfordii Hook.f, a plant of the family Wesleyanaceae, which has strong anti-inflammatory and immunomodulatory effects and has been used as a basic drug in the clinical treatment of RA. Despite the good efficacy of TwHF treatment, the mechanism of action of TwHF remains unclear. Several studies have demonstrated that the drug tripterygium glycosides, in which TwHF is the main ingredient, has achieved excellent efficacy in the clinical treatment of RA. Investigations have also found that TwHF can affect cellular RCD, cell migration, cell proliferation, and the apoptosis-related Hippo signaling pathway. In this study, we first analyzed the RCD and migration differences of neutrophils in patients with RA through network pharmacology and transcriptome analysis. Subsequently, we used electron microscopy, immunofluorescence, and other methods to identify the RCD phenotype of neutrophils. In collagen-induced arthritis (CIA) model, we demonstrated that Triptolide (the main active ingredient in TwHF) could alleviate the progression of arthritis by reducing the bone destruction and the infiltration of neutrophils. Furthermore, in vitro experiments showed that Triptolide induced neutrophil apoptosis, inhibited the formation of neutrophil extracellular traps (NETs), and impeded the neutrophil migration process in a Hippo pathway-dependent manner. Taken together, these findings indicate that Triptolide has potential for treating RA and provide theoretical support for the clinical application of TwHF, as a traditional Chinese medicine, in RA.</p></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"8 ","pages":"Article 100242"},"PeriodicalIF":3.9,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589909024000121/pdfft?md5=2ca56dddf1ab03029724871214bfa00d&pid=1-s2.0-S2589909024000121-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140894458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}