Journal of Translational Autoimmunity最新文献_第7页

Aberrant B cell receptor signaling responses in circulating double-negative 2 B cells from radiographic axial spondyloarthritis patients 轴性脊柱炎x线摄影患者循环双阴性B细胞异常B细胞受体信号反应

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-06-01 Epub Date: 2025-01-23 DOI: 10.1016/j.jtauto.2025.100270

Rick Wilbrink , Stefan F.H. Neys , Rudi W. Hendriks , Anneke Spoorenberg , Frans G.M. Kroese , Odilia B.J. Corneth , Gwenny M.P.J. Verstappen

Objective

Radiographic axial spondyloarthritis (r-axSpA) is a chronic rheumatic disease in which innate immune cells and T cells are thought to play a major role. However, recent studies also hint at B cell involvement. Here, we performed an in-depth analysis on alterations within the B-cell compartment from r-axSpA patients.

Methods

We performed immune gene expression profiling on total peripheral blood B cells from 8 r-axSpA patients and 8 healthy controls (HCs). Next, we explored B cell subset distribution and B-cell receptor (BCR) signaling responses in circulating B cells from 28 r-axSpA patients and 15 HCs, by measuring spleen tyrosine kinase, phosphoinositide 3-kinase and extracellular signal regulated kinase 1/2 phosphorylation upon α-Ig stimulation using phosphoflow cytometry.

Results

Immune gene expression profiling indicated an elevated pathway score for BCR signaling in total B cells from r-axSpA patients compared with HCs. Flow cytometric analysis revealed an increase in frequency of both total and double-negative 2 (DN2) B cells in r-axSpA patients compared with HCs. In r-axSpA patients, DN2 B cells displayed an isotype shift towards IgA. Remarkably, where DN2 B cells from HCs were hyporesponsive, these cells displayed significant proximal BCR signaling responses in r-axSpA patients. Enhanced BCR signaling responses were also observed in the transitional and naïve B cell population from r-axSpA patients compared with HCs. The enhanced BCR signaling responses in DN2 B cells correlated with clinical disease parameters.

Conclusion

In r-axSpA patients, circulating DN2 B cells are expanded and, together with transitional and naïve B cells, display significantly enhanced BCR signaling responses upon stimulation. Together, our data suggest B cell involvement in the pathogenesis of r-axSpA.

目的影像学中轴性脊柱炎（r-axSpA）是一种慢性风湿性疾病，先天免疫细胞和T细胞被认为在其中起主要作用。然而，最近的研究也暗示了B细胞的参与。在这里，我们对r-axSpA患者的b细胞室内的变化进行了深入分析。方法对8例r-axSpA患者和8例健康对照（hc）外周血总B细胞进行免疫基因表达谱分析。接下来，我们通过使用磷酸流式细胞术检测α-Ig刺激下脾脏酪氨酸激酶、磷酸肌肽3激酶和细胞外信号调节激酶1/2磷酸化，探讨了28例r-axSpA患者和15例hcc患者循环B细胞的B细胞亚群分布和B细胞受体（BCR）信号传导反应。结果免疫基因表达谱显示，与hc相比，r-axSpA患者总B细胞中BCR信号通路评分升高。流式细胞术分析显示，与hc相比，r-axSpA患者的总B细胞和双负2 (DN2) B细胞的频率均有所增加。在r-axSpA患者中，dn2b细胞表现出向IgA的同型转移。值得注意的是，当来自hc的DN2 B细胞反应低下时，这些细胞在r-axSpA患者中表现出显著的近端BCR信号反应。与hc相比，r-axSpA患者的过渡性和naïve B细胞群也观察到增强的BCR信号反应。DN2 B细胞BCR信号反应的增强与临床疾病参数相关。结论在r-axSpA患者中，循环DN2 B细胞扩增，并与过渡性和naïve B细胞一起，在刺激下表现出明显增强的BCR信号反应。总之，我们的数据表明B细胞参与了r-axSpA的发病机制。

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引用次数: 0

Understanding the role of immune-mediated inflammatory disease related cytokines interleukin 17 and 23 in pregnancy: A systematic review 了解免疫介导炎性疾病相关细胞因子白介素17和23在妊娠中的作用：一项系统综述

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-06-01 Epub Date: 2025-02-07 DOI: 10.1016/j.jtauto.2025.100279

Aniek Plug , Liana Barenbrug , Bart G.J. Moerings , Elke M.G. de Jong , Renate G. van der Molen

Background

Pregnancy requires a careful immune balance between tolerance for the semi-allogenic fetus and protection against pathogens. Women with immune-mediated inflammatory diseases (IMIDs), where the interleukin (IL)-23/IL-17 axis plays an important role, often experience changes in disease severity during pregnancy. These changes and the association between disease flares and pregnancy complications, suggests a role for IL-17 and IL-23 in pregnancy.

Methods

We systemically searched PubMed, EMBASE, and Web of Science (March 2024), to assess the role of IL-17 and IL-23 in pregnancy-related in vitro assays, animal or human studies.

Results

Eighty articles (8 in vitro, 11 animal and 61 human studies) were included. Seventy-one studies reported on IL-17 and 16 studies on IL-23. In vitro trophoblast proliferation, migration and invasion was increased in the presence of IL-17, but impaired with IL-23. IL-17 levels were increased in animal models for pregnancy complications. In humans, IL-17 levels seemed to be increased in pregnant women versus non-pregnant women. Additionally, elevated IL-17 levels were associated with pregnancy complications. Although similar trends were found for IL-23, data were limited.

Conclusions

We identified a large, but heterogenic, body of evidence for a significant role of IL-17 in all stages of pregnancy: while an excessive increase seemed to be associated with complications. The limited number of studies prevents firm conclusions on the role of IL-23. Future research is needed to find biomarkers for patients with IMIDs to predict the effect of possible disease flares on pregnancy, and the effect of therapeutic inhibition of IL-17 or IL-23.

背景：怀孕需要在对半同种异体胎儿的耐受和对病原体的保护之间保持谨慎的免疫平衡。白细胞介素(IL)-23/IL-17轴起着重要作用，患有免疫介导性炎症性疾病（IMIDs）的妇女在怀孕期间经常经历疾病严重程度的变化。这些变化以及疾病发作和妊娠并发症之间的关联提示IL-17和IL-23在妊娠中的作用。方法系统检索PubMed、EMBASE和Web of Science（2024年3月），评估IL-17和IL-23在妊娠相关体外实验、动物或人体研究中的作用。结果共纳入论文80篇，其中体外研究8篇，动物研究11篇，人体研究61篇。关于IL-17和IL-23的研究分别有71项和16项。IL-17的存在增加了体外滋养细胞的增殖、迁移和侵袭，而IL-23的存在则削弱了滋养细胞的增殖、迁移和侵袭。妊娠并发症动物模型中IL-17水平升高。在人类中，孕妇的IL-17水平似乎比非孕妇高。此外，IL-17水平升高与妊娠并发症有关。虽然IL-23也有类似的趋势，但数据有限。结论：我们发现了大量但异质性的证据，证明IL-17在妊娠的所有阶段都有重要作用，而过度增加似乎与并发症有关。由于研究数量有限，无法对IL-23的作用得出明确的结论。未来的研究需要寻找IMIDs患者的生物标志物，以预测可能的疾病发作对妊娠的影响，以及治疗性抑制IL-17或IL-23的效果。

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引用次数: 0

NETosis: A key player in autoimmunity, COVID-19, and long COVID NETosis：自身免疫、COVID-19和长COVID的关键参与者

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-06-01 Epub Date: 2025-02-21 DOI: 10.1016/j.jtauto.2025.100280

Diana M. Monsalve , Yeny Acosta-Ampudia , Nicolás Guerrero Acosta , Mariana Celis-Andrade , Ali Şahin , Ahsen Morva Yilmaz , Yehuda Shoenfeld , Carolina Ramírez-Santana

NETosis, the process through which neutrophils release neutrophil extracellular traps (NETs), has emerged as a crucial mechanism in host defense and the pathogenesis of autoimmune responses. During the SARS-CoV-2 pandemic, this process received significant attention due to the central role of neutrophil recruitment and activation in infection control. However, elevated neutrophil levels and dysregulated NET formation have been linked to coagulopathy and endothelial damage, correlating with disease severity and poor prognosis in COVID-19. Moreover, it is known that SARS-CoV-2 can induce persistent low-grade systemic inflammation, known as long COVID, although the underlying causes remain unclear. It has been increasingly acknowledged that excessive NETosis and NET generation contribute to further pathophysiological abnormalities following SARS-CoV-2 infection. This review provides an updated overview of the role of NETosis in autoimmune diseases, but also the relationship between COVID-19 and long COVID with autoimmunity (e.g., latent and overt autoimmunity, molecular mimicry, epitope spreading) and NETosis (e.g., immune responses, NET markers). Finally, we discuss potential therapeutic strategies targeting dysregulated NETosis to mitigate the severe complications of COVID-19 and long COVID.

NETosis是中性粒细胞释放中性粒细胞胞外陷阱（NETs）的过程，已成为宿主防御和自身免疫反应发病机制的重要机制。在SARS-CoV-2大流行期间，由于中性粒细胞募集和激活在感染控制中的核心作用，这一过程受到了极大的关注。然而，中性粒细胞水平升高和NET形成失调与凝血功能障碍和内皮损伤有关，与COVID-19的疾病严重程度和不良预后相关。此外，众所周知，SARS-CoV-2可以诱导持续的低度全身性炎症，即长冠状病毒，尽管根本原因尚不清楚。人们越来越多地认识到，过度的NETosis和NET生成有助于SARS-CoV-2感染后进一步的病理生理异常。本文综述了NETosis在自身免疫性疾病中的作用，以及COVID-19和长型COVID与自身免疫（如潜伏性和显性自身免疫、分子模仿、表位扩散）和NETosis（如免疫反应、NET标记物）之间的关系。最后，我们讨论了针对NETosis失调的潜在治疗策略，以减轻COVID-19和长期COVID的严重并发症。

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引用次数: 0

A placebo-controlled Phase 2 trial of E6011, anti-human fractalkine monoclonal antibody, in primary biliary cholangitis 抗人fractalkine单克隆抗体E6011治疗原发性胆管炎的安慰剂对照2期试验

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-06-01 Epub Date: 2025-03-20 DOI: 10.1016/j.jtauto.2025.100283

Atsushi Tanaka , Masanori Abe , Tadashi Namisaki , Shinji Shimoda , Mikio Zeniya , Akio Ido , Hitoshi Yoshiji , Hiromasa Ohira , Kenichi Harada , Yuko Kakuda , Atsushi Umeda , Yuki Kamiya , Yukari Higashine , Seiichiro Hojo , Toshio Imai , Tetsu Kawano , Yasuni Nakanuma , Hirohito Tsubouchi

Background

While ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC), the autoimmune nature of PBC underscores the need for treatments targeting immunological pathways that may achieve a cure. E6011, a novel humanized anti-fractalkine monoclonal antibody, has emerged as a potential therapeutic option for PBC. We conducted a randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of E6011 in patients with PBC with an incomplete response to UDCA.

Methods

The study was composed of 12-week Double-Blind Phase (placebo, E6011 10 mg/kg/month, 15 mg/kg/month, or 10 mg/kg/every other week [eow]) followed by a 52-week Open-Label Phase. The primary endpoint was the percent change in alkaline phosphatase (ALP) at Week 12.

Results

A total of 29 patients were enrolled. Histological evaluation at screening revealed that 83 % of the enrolled patients were classified as Stage 4 according to the Nakanuma Classification. The mean percent changes in ALP at Week 12 were +0.45 % in the placebo, +0.65 % in the 10 mg/kg/month, +1.23 % in the 15 mg/kg/month and +1.19 % in the 10 mg/kg/eow, with no observed trends toward ALP reduction in the E6011 treatment. Based on the interim analysis, the study was discontinued due to a lack of the efficacy. E6011 was generally safe and well tolerated.

Conclusion

This study of E6011 failed to meet the primary endpoint in patients with PBC with an incomplete response to UDCA. The advanced histological severity present in more than 80 % of patients at baseline may have contributed to these findings.

背景尽管熊去氧胆酸（UDCA）仍是治疗原发性胆汁性胆管炎（PBC）的一线疗法，但 PBC 的自身免疫性质突出表明，需要针对免疫途径的治疗方法来实现治愈。E6011是一种新型人源化抗小动脉粥样硬化单克隆抗体，已成为PBC的潜在治疗方案。我们进行了一项随机、安慰剂对照、双盲研究，以评估 E6011 在对 UDCA 反应不完全的 PBC 患者中的疗效和安全性。主要终点是第12周时碱性磷酸酶（ALP）的变化百分比。筛查时的组织学评估显示，根据中沼分类法，83%的入组患者被划分为4期。第12周时，安慰剂的ALP平均变化率为+0.45%，10 mg/kg/月为+0.65%，15 mg/kg/月为+1.23%，10 mg/kg/ow为+1.19%，E6011治疗未观察到ALP下降趋势。根据中期分析，该研究因缺乏疗效而终止。E6011总体上安全且耐受性良好。结论这项E6011研究未能在对UDCA反应不完全的PBC患者中达到主要终点。80%以上的患者在基线时组织学严重程度已达到晚期，这可能是导致上述结果的原因之一。

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引用次数: 0

Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patients 类风湿性关节炎患者瓜氨酸化cle12a自身抗体的鉴定

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-06-01 Epub Date: 2025-04-15 DOI: 10.1016/j.jtauto.2025.100287

Lillian Barra , Sheri Saunders , Mathias Mangion , Guillaume Paré , Halim Maaroufi , Alain Garnier , Ewa Cairns , Maria J. Fernandes

Objective

Rheumatoid arthritis is an autoimmune disease characterized by anti-citrullinated protein antibodies (ACPA). The pathogenic and protective roles of ACPA of distinct specificities are emerging and remains poorly understood. Thus, it is crucial to define the range of ACPA specificities and determine their contribution to disease and their potential clinical relevance. Since extracellular citrullination occurs in RA, we investigated whether autoantibodies in RA patients bind a citrullinated form of the cell-surface receptor CLEC12A that is expressed on neutrophils, the most abundant leukocyte in inflamed joints.

Methods

We generated a FLAG-tagged, recombinant form of the extracellular portion of human CLEC12A. After purification, the tag was removed prior to citrullination by PAD2 that was confirmed by mass spectrometry. We developed an ELISA for citrullinated CLEC12A to screen for seropositivity in sera of 68 RA patients and 36 healthy controls. Potential associations between these autoantibodies and clinical variables were determined.

Results

In our cohort, 40 % of RA patients were positive for anti-citrullinated CLEC12A autoantibodies. Those seropositive patients were younger than RA patients that tested negative for these autoantibodies (p = 0.0058). Most patients had antibodies to multiple citrullinated and homocitrullinated antigens; 17 % of patients negative for other ACPA were positive for anti-citrullinated CLEC12A autoantibodies.

Conclusion

This is the first report of seropositivity towards citrullinated CLEC12A in RA patients. A validation cohort will confirm our findings and identify additional correlations between these autoantibodies and clinical parameters. Citrullination may be a mechanism through which CLEC12A's inhibitory function is altered to exacerbate inflammation in RA. Identifying citrullinated neoantigens advances our understanding of the diverse molecular mechanisms that contribute to RA pathogenesis.

目的类风湿性关节炎是一种以抗瓜氨酸蛋白抗体（ACPA）为特征的自身免疫性疾病。具有不同特异性的 ACPA 的致病和保护作用正在逐渐显现，但人们对其了解甚少。因此，明确 ACPA 的特异性范围并确定它们对疾病的贡献及其潜在的临床意义至关重要。由于细胞外瓜氨酸化发生在RA中，我们研究了RA患者的自身抗体是否与细胞表面受体CLEC12A的瓜氨酸化形式结合，CLEC12A表达在中性粒细胞上，中性粒细胞是发炎关节中最多的白细胞。纯化后，在通过 PAD2 进行瓜氨酸化之前去除标签，并通过质谱法进行确认。我们开发了一种瓜氨酸化 CLEC12A 酶联免疫吸附试验（ELISA），以筛查 68 名 RA 患者和 36 名健康对照者血清中的血清阳性反应。结果在我们的队列中，40%的 RA 患者抗瓜氨酸化 CLEC12A 自身抗体呈阳性。这些血清阳性患者比这些自身抗体检测阴性的 RA 患者更年轻（p = 0.0058）。大多数患者体内存在多种瓜氨酸化和同型瓜氨酸化抗原抗体；17%其他ACPA检测阴性的患者体内抗瓜氨酸化CLEC12A自身抗体呈阳性。验证队列将证实我们的研究结果，并确定这些自身抗体与临床参数之间的其他相关性。瓜氨酸化可能是CLEC12A的抑制功能发生改变从而加剧RA炎症的一种机制。鉴定瓜氨酸化新抗原有助于我们了解导致RA发病机制的多种分子机制。

{"title":"Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patients","authors":"Lillian Barra , Sheri Saunders , Mathias Mangion , Guillaume Paré , Halim Maaroufi , Alain Garnier , Ewa Cairns , Maria J. Fernandes","doi":"10.1016/j.jtauto.2025.100287","DOIUrl":"10.1016/j.jtauto.2025.100287","url":null,"abstract":"<div><h3>Objective</h3><div>Rheumatoid arthritis is an autoimmune disease characterized by anti-citrullinated protein antibodies (ACPA). The pathogenic and protective roles of ACPA of distinct specificities are emerging and remains poorly understood. Thus, it is crucial to define the range of ACPA specificities and determine their contribution to disease and their potential clinical relevance. Since extracellular citrullination occurs in RA, we investigated whether autoantibodies in RA patients bind a citrullinated form of the cell-surface receptor CLEC12A that is expressed on neutrophils, the most abundant leukocyte in inflamed joints.</div></div><div><h3>Methods</h3><div>We generated a FLAG-tagged, recombinant form of the extracellular portion of human CLEC12A. After purification, the tag was removed prior to citrullination by PAD2 that was confirmed by mass spectrometry. We developed an ELISA for citrullinated CLEC12A to screen for seropositivity in sera of 68 RA patients and 36 healthy controls. Potential associations between these autoantibodies and clinical variables were determined.</div></div><div><h3>Results</h3><div>In our cohort, 40 % of RA patients were positive for anti-citrullinated CLEC12A autoantibodies. Those seropositive patients were younger than RA patients that tested negative for these autoantibodies (p = 0.0058). Most patients had antibodies to multiple citrullinated and homocitrullinated antigens; 17 % of patients negative for other ACPA were positive for anti-citrullinated CLEC12A autoantibodies.</div></div><div><h3>Conclusion</h3><div>This is the first report of seropositivity towards citrullinated CLEC12A in RA patients. A validation cohort will confirm our findings and identify additional correlations between these autoantibodies and clinical parameters. Citrullination may be a mechanism through which CLEC12A's inhibitory function is altered to exacerbate inflammation in RA. Identifying citrullinated neoantigens advances our understanding of the diverse molecular mechanisms that contribute to RA pathogenesis.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100287"},"PeriodicalIF":4.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Iron metabolism in rheumatic diseases 风湿病中的铁代谢。

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-06-01 Epub Date: 2025-01-04 DOI: 10.1016/j.jtauto.2025.100267

Aliakbar Givian , Amin Azizan , Ahmadreza Jamshidi , Mahdi Mahmoudi , Elham Farhadi

Iron is a crucial element for living organism in terms of oxygen transport, hematopoiesis, enzymatic activity, mitochondrial respiratory chain function and also immune system function. The human being has evolved a mechanism to regulate body iron. In some rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematous (SLE), systemic sclerosis (SSc), ankylosing spondylitis (AS), and gout, this balanced iron regulation is impaired. Altered iron homeostasis can contribute to disease progression through ROS production, fibrosis, inflammation, abnormal bone homeostasis, NETosis and cell senescence. In this review, we have focused on the iron metabolism in rheumatic disease and its role in disease progression.

铁是生物体在氧运输、造血、酶活性、线粒体呼吸链功能和免疫系统功能方面的关键元素。人类已经进化出一种调节体内铁的机制。在一些风湿性疾病中，如类风湿关节炎（RA）、系统性红斑狼疮（SLE）、系统性硬化症（SSc）、强直性脊柱炎（as）和痛风，这种平衡的铁调节受到损害。铁稳态改变可通过ROS生成、纤维化、炎症、骨稳态异常、NETosis和细胞衰老等途径促进疾病进展。在这篇综述中，我们主要关注风湿性疾病中的铁代谢及其在疾病进展中的作用。

引用次数: 0

Tofacitinib downregulates JAK1 and JAK3 on human intestinal monocytes and macrophages without affecting dendritic cells phenotype or function 托法替尼下调人肠道单核细胞和巨噬细胞的JAK1和JAK3，而不影响树突状细胞的表型或功能

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-06-01 Epub Date: 2025-01-22 DOI: 10.1016/j.jtauto.2025.100271

Elisa Arribas-Rodríguez , Ángel De Prado , Beatriz de Andrés , Benito Velayos , Jesús Barrio , Alejandro Romero , Francisco Javier García-Alonso , Álvaro Martín-Muñoz , José A. Garrote , Eduardo Arranz , Luis Fernández-Salazar , David Bernardo

Background

Ulcerative colitis (UC) is an inflammatory disorder of the gastrointestinal tract. Although Tofacitinib, which inhibits the JAK1 and JAK3 signalling pathway, is approved to treat patients with UC, its specific mechanism of action remain elusive. Given the central role that conventional dendritic cells (cDC) elicit in gut homeostasis, we hypothesised that Tofacitinib acts modulating cDC function in UC.

Methods

Human biopsies were obtained from colon of controls, and patients with UC (active and quiescent). Lamina propria mononuclear cells (LPMC) were ex-vivo cultured in the presence/absence of Tofacitinib. The specific effect elicited over human intestinal cDC, monocytes and macrophages was assessed by flow cytometry. cDC were also enriched following Tofacitinib conditioning in order to assess its effect over naïve T-cells.

Results

Several human intestinal cDC, monocyte and macrophage subsets can be found in the human colon, with these cells being more similar between controls and patients with qUC referred to patients with aUC. Following ex-vivo culture, Tofacitinib downregulated JAK1 expression on intestinal monocytes from patients with both active and quiescent UC. As for macrophages, JAK1 was decreased on patients with active UC while JAK was downregulated on macrophages from patients with quiescent disease. Tofacitinib did not modulate the phenotype or function of human intestinal cDC.

Conclussion

Tofacitinib does not modulate the phenotype and function of human intestinal cDC in UC. On the contrary, it displays a differential capacity to modulate intestinal monocyte and macrophage phenotype. Future studies should address whether it also translates into a differential function of these cells.

背景溃疡性结肠炎（UC）是一种胃肠道炎症性疾病。尽管抑制JAK1和JAK3信号通路的Tofacitinib被批准用于治疗UC患者，但其具体的作用机制尚不清楚。鉴于传统树突状细胞（cDC）在肠道稳态中所起的核心作用，我们假设托法替尼在UC中调节cDC功能。方法对对照组和UC患者（活动性和静止性）进行结肠活检。在有或没有托法替尼的情况下，体外培养固有层单个核细胞（LPMC）。流式细胞术检测其对人肠道cDC、单核细胞和巨噬细胞的特异性作用。cDC也在托法替尼调理后富集，以评估其对naïve t细胞的影响。结果在人类结肠中可发现多种人类肠道cDC、单核细胞和巨噬细胞亚群，且这些细胞在对照组和qUC患者（即aUC患者）之间更为相似。在体外培养后，托法替尼下调了活性和静止UC患者肠道单核细胞中JAK1的表达。在巨噬细胞中，活动性UC患者的JAK1表达降低，而静止性UC患者的巨噬细胞中JAK1表达下调。托法替尼不调节人肠道cDC的表型或功能。结论托法替尼对UC患者肠道cDC的表型和功能无调节作用。相反，它在调节肠道单核细胞和巨噬细胞表型方面表现出不同的能力。未来的研究应该解决它是否也转化为这些细胞的差异功能。

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引用次数: 0

A comparative study of different assays for autoantibodies detection in patients with autoimmune gastritis 不同方法检测自身免疫性胃炎患者自身抗体的比较研究

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-06-01 Epub Date: 2025-05-24 DOI: 10.1016/j.jtauto.2025.100294

Małgorzata Osmola , Caroline Hémont , Marcin Romańczyk , Amaury Druet , Nicolas Chapelle , Tamara Matysiak-Budnik , Marco Vincenzo Lenti , Jérôme C. Martin

Objective

Autoimmune gastritis (AIG) is an important health problem and a risk factor for gastric neoplasms. This study assessed the diagnostic performance of different assays for anti-parietal cell antibodies (APCA) and anti-intrinsic factor antibodies (AIFA) in patients with histologically confirmed AIG.

Methods

This prospective, multicenter study included 50 AIG patients and 93 controls. The diagnostic performance of fluorescent enzyme immunoassay (FEIA) and immunoblot was evaluated for the detection of both APCA and AIFA, while indirect immunofluorescence (IIF) was assessed for APCA only.

Results

Overall, AIFA detection using FEIA demonstrated slightly better performance (specificity [Sp] 100 %, positive predictive value [PPV] 100 %, negative predictive value [NPV] 75 %) compared to immunoblot (Sp 98.9 %, PPV 94.1 %, NPV 73 %). However, both methods showed low sensitivity (Se): 38 % for FEIA and 32 % for immunoblot. When the FEIA cut-off was adjusted using ROC curve analysis, Se increased to 50 %, while maintaining high Sp (98.9 %). For APCA detection, Se was similar across all methods (∼80 %), but Sp varied: immunoblot showed lower Sp (89.3 %) compared to IIF (98.8 %) and FEIA (95.7 %). PPV was highest for IIF (97.5 %), followed by FEIA (89.9 %) and immunoblot (89.3 %). NPV was lowest for immunoblot (80 %), while IIF and FEIA showed comparable values (89.5 % and 90.9 %, respectively). Adjusting the FEIA cut-off for APCA increased Sp to 98.9 % without reducing Se (76 %). Combining AIFA and APCA testing improved diagnostic performance, yielding a sensitivity of 90 % and specificity of 95.7 %.

Conclusions

FEIA offers superior diagnostic accuracy for APCA and AIFA testing in AIG. The highest diagnostic yield for AIG is observed when both APCA and AIFA are assessed. This approach could be clinically applicable in the screening for AIG and diagnostic process of AIG.

目的自身免疫性胃炎（AIG）是重要的健康问题，也是胃肿瘤发生的危险因素之一。本研究评估了抗壁细胞抗体（APCA）和抗内因子抗体（AIFA）的不同检测方法对组织学证实的AIG患者的诊断效果。方法本前瞻性、多中心研究纳入50例AIG患者和93例对照组。采用荧光酶免疫分析法（FEIA）和免疫印迹法（immunoblot）检测APCA和AIFA，采用间接免疫荧光法（indirect immunofluorescence， IIF）检测APCA。结果总体而言，FEIA检测AIFA的特异性[Sp] 100%，阳性预测值[PPV] 100%，阴性预测值[NPV] 75%，优于免疫印迹（Sp 98.9%, PPV 94.1%, NPV 73%）。然而，两种方法都显示出低灵敏度（Se）： FEIA为38%，免疫印迹为32%。当使用ROC曲线分析调整FEIA截止时，Se增加到50%，同时保持较高的Sp（98.9%）。对于APCA检测，所有方法的Se相似（~ 80%），但Sp不同：免疫印迹显示Sp（89.3%）低于IIF（98.8%）和FEIA（95.7%）。IIF的PPV最高（97.5%），其次是FEIA（89.9%）和免疫印迹（89.3%）。免疫印迹的NPV最低（80%），而IIF和FEIA的NPV值相当（分别为89.5%和90.9%）。调整FEIA的APCA截止值将Sp增加到98.9%，而不降低Se（76%）。结合AIFA和APCA检测提高了诊断性能，敏感性为90%，特异性为95.7%。结论feia对AIG的APCA和AIFA检测具有较高的诊断准确性。当同时评估APCA和AIFA时，观察到AIG的最高诊断率。该方法在临床上可用于AIG的筛查和诊断过程。

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引用次数: 0

Autoantibodies in systemic sclerosis: From disease bystanders to pathogenic players 系统性硬化症的自身抗体：从疾病旁观者到致病参与者

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-06-01 Epub Date: 2025-01-21 DOI: 10.1016/j.jtauto.2025.100272

Aurélien Chepy , Aurore Collet , David Launay , Sylvain Dubucquoi , Vincent Sobanski

Autoantibodies (Aab) are recognized as key indicators in the diagnosis, classification, and monitoring of systemic autoimmune diseases (AID). Recent studies have expanded knowledge through the discovery of new antigenic targets, advanced methods for measuring Aab levels, and understanding their possible pathogenic roles in AID. This narrative review uses systemic sclerosis (SSc) as an example to highlight the importance of Aab associated with HEp-2 immunofluorescence assay positivity (traditionally referred as antinuclear antibodies [ANA]), exploring recent developments in the field. Firstly, we outline the various types of ANA found in SSc and their links with specific disease features. Newly discovered antibodies shed light on SSc cases where Aab had previously gone unidentified. Secondly, we emphasize the necessity for novel quantitative techniques to track Aab levels over time by gathering data regarding the timing of Aab occurrence relative to SSc symptoms and the relationships between Aab concentrations and disease severity. Finally, we discuss the experimental findings suggesting a potential direct role of Aab in the development of SSc. The advancements surrounding Aab provide insights into new disease mechanisms and may lead to innovative diagnostic and treatment approaches.

自身抗体（Aab）被认为是诊断、分类和监测全身性自身免疫性疾病（AID）的关键指标。最近的研究通过发现新的抗原靶点、测量Aab水平的先进方法以及了解其在AID中可能的致病作用，扩大了知识范围。本文以系统性硬化症（SSc）为例，强调Aab与HEp-2免疫荧光检测阳性（传统上称为抗核抗体[ANA]）相关的重要性，探讨该领域的最新进展。首先，我们概述了在SSc中发现的各种类型的ANA及其与特定疾病特征的联系。新发现的抗体揭示了Aab以前未被识别的SSc病例。其次，我们强调需要新的定量技术，通过收集与SSc症状相关的Aab发生时间以及Aab浓度与疾病严重程度之间的关系的数据来跟踪Aab水平随时间的变化。最后，我们讨论了提示Aab在SSc发展中的潜在直接作用的实验结果。围绕Aab的进展提供了新的疾病机制的见解，并可能导致创新的诊断和治疗方法。

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引用次数: 0

Large soluble CD18 complexes with exclusive ICAM-1-binding properties are shed during immune cell migration in inflammation 具有特异性icam -1结合特性的大型可溶性CD18复合物在炎症免疫细胞迁移过程中脱落。

IF 4.7 Q2 IMMUNOLOGY

Journal of Translational Autoimmunity

Pub Date : 2025-06-01 Epub Date: 2025-01-05 DOI: 10.1016/j.jtauto.2025.100266

Alexey Ferapontov , Anders Mellemkjær , Helen M. McGettrick , Thomas Vorup-Jensen , Tue W. Kragstrup , Kristian Juul-Madsen

The family of heterodimeric CD11/CD18 integrins facilitate leukocyte adhesion and migration in a wide range of normal physiologic responses, as well as in the pathology of inflammatory diseases. Soluble CD18 (sCD18) is found mainly in complexes with hydrodynamic radii of 5 and 7.2 nm, suggesting a compositional difference. Earlier work reported that the complexes include at least part of the CD11a or CD11b chains containing the intercellular adhesion molecule (ICAM)-1 binding domain, and that sCD18 is capable of quantitatively competing with the cell membrane-bound form for ICAM-1 binding. However, it is not clear if the size differences between the sCD18 complexes reflect any functional variance regarding shedding from the cell membrane or binding to ICAM-1. Here, we show evidence that sCD18 found in serum regulates release of the proinflammatory cytokine monocyte chemoattractant protein-1 (MCP-1/CCL2) from fibroblast-like synovial cells. Further, only large sCD18 complexes are capable of binding to ICAM-1. Migrating neutrophils shed large, but not small, sCD18 complexes. Together, these observations explain results measured from patients with rheumatoid arthritis (RA), where large sCD18 complexes dominated in local inflammatory processes involving neutrophil influx into zones of inflammation. Our data points to a previously unappreciated aspect of sCD18 integrin biology as regulators of inflammation in the context of migrating leukocyte. Surprisingly, this regulation is tied to sCD18 complex size, opening new opportunities for therapeutic intervention in serious inflammatory diseases such as arthritis.

异二聚体CD11/CD18整合素家族在广泛的正常生理反应以及炎症性疾病的病理中促进白细胞的粘附和迁移。可溶性CD18 （sCD18）主要存在于水动力半径为5 nm和7.2 nm的配合物中，表明其组成存在差异。早期的研究报道，这些复合物包括至少部分含有细胞间粘附分子(ICAM)-1结合域的CD11a或CD11b链，并且sCD18能够在数量上与细胞膜结合形式竞争ICAM-1结合。然而，尚不清楚sCD18复合物之间的大小差异是否反映了在细胞膜脱落或与ICAM-1结合方面的任何功能差异。在这里，我们展示了血清中发现的sCD18调节促炎细胞因子单核细胞趋化蛋白-1 （MCP-1/CCL2）从成纤维细胞样滑膜细胞释放的证据。此外，只有大的sCD18复合物能够与ICAM-1结合。迁移的中性粒细胞脱落大而不小的sCD18复合物。总之，这些观察结果解释了从类风湿性关节炎（RA）患者中测量的结果，其中大型sCD18复合物在局部炎症过程中占主导地位，涉及中性粒细胞流入炎症区。我们的数据指出了sCD18整合素生物学在迁移白细胞背景下作为炎症调节剂的一个以前未被认识的方面。令人惊讶的是，这种调节与sCD18复合物的大小有关，为关节炎等严重炎症性疾病的治疗干预开辟了新的机会。

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