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Stem cell-based therapy for systemic lupus erythematous 干细胞疗法治疗系统性红斑狼疮
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2024-04-26 DOI: 10.1016/j.jtauto.2024.100241
Maryam Zare Moghaddam , Mohammad Javad Mousavi , Somayeh Ghotloo

Systemic lupus erythematosus (SLE), an autoimmune disease, is among the most prevalent rheumatic autoimmune disorders. It affects autologous connective tissues caused by the breakdown of self-tolerance mechanisms. During the last two decades, stem cell therapy has been increasingly considered as a therapeutic option in various diseases, including parkinson's disease, alzheimer, stroke, spinal cord injury, multiple sclerosis, inflammatory bowel disease, liver disease, diabete, heart disease, bone disease, renal disease, respiratory diseases, and hematological abnormalities such as anemia. This is due to the unique properties of stem cells that divide and differentiate to the specialized cells in the damaged tissues. Moreover, they impose immunomodulatory properties affecting the diseases caused by immunological abnormalities such as rheumatic autoimmune disorders.

In the present manuscript, efficacy of stem cell therapy with two main types of stem cells, including mesenchymal stem cell (MSC), and hematopoietic stem cells (HSC) in animal models or human patients of SLE, has been reviewed. Taken together, MSC and HSC therapies improved the disease activity, and severity in kidney, lung, liver, and bone (improvement in the clinical manifestation). In addition, a change in the immunological parameters occurred (improvement in immunological parameters). The level of autoantibodies, including antinuclear antibody (ANA), and anti-double-stranded deoxyribonucleic acid antibodies (dsDNA Abs) reduced. A conversion of Th1/Th2 ratio (in favor of Th2), and Th17/Treg (in favor of Treg) was also detected.

In spite of many advantages of MSC and HSC transplantations, including efficacy, safety, and increased survival rate of SLE patients, some complications, including recurrence of the disease, occurrence of infections, and secondary autoimmune diseases (SAD) were observed after transplantation that should be addressed in the next studies.

系统性红斑狼疮(SLE)是一种自身免疫性疾病,是最常见的风湿性自身免疫疾病之一。它影响自体结缔组织,原因是自身耐受机制遭到破坏。在过去二十年里,干细胞疗法越来越多地被认为是帕金森病、老年痴呆症、中风、脊髓损伤、多发性硬化症、炎症性肠病、肝病、糖尿病、心脏病、骨病、肾病、呼吸系统疾病和血液异常(如贫血)等各种疾病的治疗选择。这是由于干细胞具有独特的特性,能在受损组织中分裂和分化为特化细胞。此外,干细胞还具有免疫调节特性,可影响免疫异常引起的疾病,如风湿性自身免疫性疾病。本手稿综述了干细胞疗法的两种主要类型,包括间充质干细胞(MSC)和造血干细胞(HSC)在系统性红斑狼疮动物模型或人类患者中的疗效。总而言之,间充质干细胞和造血干细胞疗法改善了疾病的活动性,以及肾脏、肺、肝脏和骨骼的严重程度(临床表现得到改善)。此外,免疫学参数也发生了变化(免疫学参数改善)。自身抗体水平降低,包括抗核抗体(ANA)和抗双链脱氧核糖核酸抗体(dsDNA Abs)。尽管间充质干细胞和造血干细胞移植有很多优点,包括疗效好、安全和提高系统性红斑狼疮患者的存活率,但移植后也出现了一些并发症,包括疾病复发、感染和继发性自身免疫性疾病(SAD),这些问题都应在下一步研究中加以解决。
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引用次数: 0
Changes upon the gluten-free diet of HLA-DQ2 and TRAFD1 gene expression in peripheral blood of celiac disease patients 无麸质饮食对乳糜泻患者外周血中 HLA-DQ2 和 TRAFD1 基因表达的影响
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2024-04-09 DOI: 10.1016/j.jtauto.2024.100240
Mariavittoria Laezza , Laura Pisapia , Benedetta Toro , Vincenzo Mercadante , Antonio Rispo , Carmen Gianfrani , Giovanna Del Pozzo

Background

Celiac disease (CD) is a chronic immuno-mediated enteropathy caused by dietary gluten in genetically susceptible individuals carrying HLA (Human Leukocytes Antigen) genes that encode for DQ2.5 and DQ8 molecules. TRAFD1 (TRAF-type zinc finger domain 1) is a gene recently found associated with CD and defined as a master regulator of IFNγ signalling and of MHC class I antigen processing/presentation. There is no specific drug therapy and the only effective treatment is the gluten-free diet (GFD). The great majority of celiac patients when compliant with GFD have a complete remission of symptoms and recovery of gut mucosa architecture and function. Until now, very few studies have investigated molecular differences occurring in CD patients upon the GFD therapy.

Methods

We looked at the expression of both HLA DQ2.5 and TRAFD1 risk genes in adult patients with acute CD at the time of and in treated patients on GFD. Specifically, we measured by qPCR the HLA-DQ2.5 and TRAFD1 mRNAs on peripheral blood mononuclear cells (PBMC) from the two groups of patients.

Results

When we compared the HLA-DQ mRNA expression, we didn't find significant variation between the two groups of patients, thus indicating that GFD patients have the same capability to present gliadin antigens to cognate T cells as patients with active disease. Conversely, TRAFD1 was more expressed in PBMC from treated CD subjects. Notably, TRAFD1 transcripts significantly increased in the patients analyzed longitudinally during the GFD, indicating a role in the downregulation of gluten-induced inflammatory pathways.

Conclusion

Our study demonstrated that HLA-DQ2.5 and TRAFD1 molecules are two important mediators of anti-gluten immune response and inflammatory process.

背景乳糜泻(CD)是一种慢性免疫介导的肠病,由饮食中的麸质引起,易感基因携带编码 DQ2.5 和 DQ8 分子的 HLA(人类白细胞抗原)基因。TRAFD1(TRAF 型锌指结构域 1)是最近发现的一种与 CD 相关的基因,被定义为 IFNγ 信号和 MHC I 类抗原处理/呈递的主调节器。目前尚无特效药物治疗,唯一有效的治疗方法是无麸质饮食(GFD)。绝大多数乳糜泻患者在接受无麸质饮食后,症状会完全缓解,肠道粘膜结构和功能也会恢复。到目前为止,很少有研究调查 CD 患者在接受 GFD 治疗后的分子差异。方法我们观察了急性 CD 成人患者在接受 GFD 治疗时和接受治疗后 HLA DQ2.5 和 TRAFD1 风险基因的表达情况。结果当我们比较 HLA-DQ mRNA 的表达时,我们没有发现两组患者之间有明显的差异,这表明 GFD 患者与活动性疾病患者一样有能力向同源 T 细胞展示麦胶蛋白抗原。相反,TRAFD1 在接受治疗的 CD 患者的 PBMC 中表达较多。值得注意的是,在纵向分析的 GFD 患者中,TRAFD1 转录物显著增加,表明其在下调麸质诱导的炎症通路中发挥作用。
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引用次数: 0
Autoantibodes to GP210 are a metric for UDCA responses in primary biliary cholangitis GP210 自身抗体是衡量原发性胆汁性胆管炎 UDCA 反应的一个指标
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2024-03-20 DOI: 10.1016/j.jtauto.2024.100239
Chan Wang , Zhuye Qin , Mingming Zhang , Yaping Dai , Luyao Zhang , Wenyan Tian , Yuhua Gong , Sufang Chen , Can Yang , Ping Xu , Xingjuan Shi , Weifeng Zhao , Suraj Timilsina , M. Eric Gershwin , Weichang Chen , Fang Qiu , Xiangdong Liu

Objectives

Antibodies to gp210 and sp100 are specific and unique anti-nuclear autoantibodies (ANAs) associated with primary biliary cholangitis (PBC). Importantly the presence of anti-gp210 and anti-sp100 responses is indicative of poor clinical outcomes. However, the utility of measuring titers of these antibodies remains unclear.

Materials and methods

Using the in-house purified gp210 (HSA108-C18) and sp100 (amino acid position 296–386), we quantitatively measured serum autoantibodies to gp210 and sp100 using chemiluminescence immunoassay (CLIA) in a very large cohort of 390 patients with PBC, including 259 cases with no prior ursodesoxycholic acid (UDCA) treatment and 131 cases with UDCA treatment. We also analyzed serial changes in anti-gp210 and anti-sp100 levels in 245 sequential samples from 88 patients.

Results

In our cross-sectional analysis, we detected anti-gp210 immunoglobulin G (IgG) and anti-sp100 IgG autoantibodies in 129 out of 390 (33.1%) and 80 out of 390 (20.5%) PBC patients, respectively. Multivariate analysis revealed that serum IgG (st.β = 0.35, P = 0.003) and gamma-glutamyltransferase (GGT) (st.β = 0.23, P = 0.042) levels at baseline were independently associated with anti-gp210 concentrations. In serial testing, we observed significant fluctuations in anti-gp210 antibody levels. These fluctuations reflected responsiveness to UDCA therapy, particularly in anti-gp210-positive patients with initially lower concentrations in the stages of disease.

Conclusions

Our study reflects that quantitative changes of anti-gp210 antibody are indicative of UDCA responses. There is a great need for newer metrics in PBC and we suggest that a more detailed and longer study of these unique ANAs is warranted.

目的gp210和sp100抗体是与原发性胆汁性胆管炎(PBC)相关的特异性和独特的抗核自身抗体(ANA)。重要的是,出现抗 gp210 和抗 sp100 反应表明临床疗效不佳。材料和方法我们使用内部纯化的 gp210(HSA108-C18)和 sp100(氨基酸位置 296-386),在 390 例 PBC 患者(包括 259 例之前未接受熊去氧胆酸(UDCA)治疗的患者和 131 例接受过 UDCA 治疗的患者)中使用化学发光免疫分析法(CLIA)定量测定了血清中的 gp210 和 sp100 自身抗体。结果在横断面分析中,我们分别在 390 例 PBC 患者中的 129 例(33.1%)和 80 例(20.5%)中检测到了抗 gp210 免疫球蛋白 G (IgG) 和抗 sp100 IgG 自身抗体。多变量分析显示,基线时的血清 IgG(st.β = 0.35,P = 0.003)和γ-谷氨酰转移酶(GGT)(st.β = 0.23,P = 0.042)水平与抗 gp210 浓度独立相关。在连续测试中,我们观察到抗 gp210 抗体水平有明显波动。这些波动反映了对 UDCA 治疗的反应性,尤其是在抗 gp210 阳性患者中,在疾病的不同阶段,抗 gp210 抗体的浓度最初较低。我们建议对这些独特的 ANA 进行更详细、更长期的研究。
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引用次数: 0
Treatment of non-systemic Sjögren's syndrome: Potential prevention of systematization with immunosuppressant agent/biotherapy 非系统性斯约格伦综合征的治疗:使用免疫抑制剂/生物疗法预防系统化的可能性
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2024-03-03 DOI: 10.1016/j.jtauto.2024.100238
Aude Belbézier , Thi Thu Thuy Nguyen , Mélanie Arnaud , Bruna Ducotterd , Marie Vangout , Alban Deroux , Catherine Mansard , Françoise Sarrot-Reynauld , Laurence Bouillet

Background

Sjögren's syndrome (SS) is a systemic autoimmune pathology manifested mainly by a dry syndrome, intense asthenia and arthromyalgia. Systemic manifestations may also occur. Since 2019, immunosuppressant agents (IS) or biotherapies are recommended only for patients with systemic involvement. However, before 2019, in some cases, paucisymptomatic patients had been treated with IS/biotherapies, often off-label. Objective: We propose to evaluate the benefit and safety of using IS/biotherapy in patients with SS without systemic involvement. Methods: We retrospectively collected the clinical records of all patients with SS diagnosed according to ACR/EULAR diagnostic criteria followed up between January 1980 and October 2023 at Grenoble University Hospital (France). Results: Eighty-three patients were included: 64 with an initially non-systemic form. Of these patients with an initially non-systemic form, 24 were treated with IS/biotherapy. None of them developed secondary systematization, whereas 11 out of 40 patients in the untreated group did (p < 0.05). On the other hand, IS/biotherapy did not appear to improve dry syndrome. There were no serious adverse events. Conclusion: Early introduction of an IS/biotherapy treatment appears to provide a benefit for the patient without side effects.

背景舍格伦综合征(SS)是一种全身性自身免疫性病变,主要表现为干燥综合征、剧烈气喘和关节肌痛。也可能出现全身表现。自2019年起,只有全身受累的患者才建议使用免疫抑制剂(IS)或生物疗法。然而,在 2019 年之前,在一些病例中,无症状的患者曾接受过免疫抑制剂/生物疗法治疗,而且往往是非标治疗。我们的目标我们建议对无全身受累的 SS 患者使用 IS/ 生物疗法的益处和安全性进行评估。方法我们回顾性地收集了格勒诺布尔大学医院(法国)1980 年 1 月至 2023 年 10 月期间根据 ACR/EULAR 诊断标准确诊的所有 SS 患者的临床记录。结果:共纳入 83 名患者:64例最初为非系统性。在这些最初为非系统型的患者中,有24人接受了IS/生物疗法治疗。他们中没有人出现继发性系统化,而未治疗组的 40 名患者中有 11 人出现了继发性系统化(p < 0.05)。另一方面,IS/生物疗法似乎没有改善干燥综合征。没有出现严重的不良反应。结论早期采用IS/生物疗法治疗似乎能为患者带来益处,且无副作用。
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引用次数: 0
Autoimmunity in centenarians. A paradox 百岁老人的自身免疫。一个悖论
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2024-03-02 DOI: 10.1016/j.jtauto.2024.100237
Juan-Manuel Anaya , Ivan David Lozada-Martinez , Isaura Torres , Yehuda Shoenfeld

Autoimmune diseases (ADs) are one of the groups of chronic illnesses that impose a significant burden of disease and health costs worldwide. Age is a crucial risk factor for the onset of ADs. Theoretically, it is inferred that with organic and immune system aging, the loss of immune tolerance and specificity of immune activity becomes more intense, the probability of autoimmunity is increasing. However, there is a group of individuals whose prevalence of ADs is very low or non-existent, despite the biological aging. This paradox in autoimmunity raises questions. Centenarians, individuals who are over 100 years old, are possibly the most successful model of biological aging in humans. Most of these individuals exhibit a favorable health phenotype. To date, primary data evidence and potential hypotheses explaining this phenomenon are lacking globally, even though this paradox could provide valuable, original, and relevant information regarding the understanding of risk or protective factors, biological drivers, and biomarkers related to autoimmunity. Herein we discuss some hypothesis that may explain the absence of ADs in centenarians, including inflammaging, immunosenescence and immune resilience, immune system hyperstimulation, proteodynamics, and genetics.

自身免疫性疾病(ADs)是慢性病中的一种,给全世界带来了沉重的疾病负担和医疗费用。年龄是自身免疫性疾病发病的关键风险因素。从理论上推断,随着机体和免疫系统的衰老,免疫耐受性和免疫活动特异性的丧失会越来越强烈,自身免疫的概率也会越来越高。然而,有这样一群人,尽管他们的生理已经衰老,但自身免疫性疾病的发病率却很低,甚至根本不发病。自身免疫的这一悖论引发了人们的疑问。百岁老人(100 岁以上的老人)可能是人类生物衰老最成功的典范。这些人中的大多数都表现出良好的健康表型。迄今为止,尽管这一悖论可为了解自身免疫相关的风险或保护因素、生物驱动因素和生物标志物提供有价值的原始相关信息,但全球仍缺乏解释这一现象的原始数据证据和潜在假说。在此,我们将讨论一些可能解释百岁老人不患注意力缺失症的假说,包括炎症衰老、免疫衰老和免疫恢复力、免疫系统过度刺激、蛋白动力学和遗传学。
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引用次数: 0
The effects of omega-3 fatty acids supplementation on hemoglobin, hematocrit, and platelet levels of patients with ESRD condition undergoing dialysis 补充欧米伽-3 脂肪酸对接受透析的 ESRD 患者的血红蛋白、血细胞比容和血小板水平的影响
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2024-02-23 DOI: 10.1016/j.jtauto.2024.100233
Zahra Mahmoudi , Zahra Roumi , Seyed Ali Askarpour , Zahra Mousavi , Hanieh Shafaei , Neda Valisoltani , Mahsa Shapouri , Seyed Reza Mirshafaei , Pouya Mirzaee , Khadijeh Abbasi Mobarakeh , Elahe Taghavi Sufiani , Zeinab Motiee Bijarpasi , Zeynab Motiei , Masoud Khosravi , Saeid Doaei , Maryam Gholamalizadeh

Background

Concomitant inflammation may boost the cardiovascular complications in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD). Omega-3 fatty acids may have certain health benefits in HD patients. The aim of this study was to investigate the effects of omega-3 fatty acids supplementation on hematocrit (HCT), hemoglobin (HB) level and platelet (PLT) counts of HD patients.

Methods

A randomized controlled trial was conducted on HD patients at a private dialysis center in Rasht, Iran. Three omega-3 fatty acid supplement capsules (3 g/d) were administered daily for two months to patients in the intervention group (n = 55). The control group (n = 60) were given three placebo capsules containing medium chain triglyceride (MCT) oil, similar to the supplemental dose of the intervention group at the same period. Three parameters of HCT, HB and PLT were measured at baseline and after the intervention.

Results

The PLT count decreased in the intervention group compared to the control group (173.38 ± 74.76 vs. 227.68 ± 86.58 103/mm3, F = 4.83, P = 0.03). No significant change was found on the levels of HCT and HB parameters between the two groups after the intervention.

Conclusion

Omega-3 supplementation in HD patients may decrease the risk of forming blood clots in the blood vessels. Further studies are warranted.

背景接受血液透析(HD)的终末期肾病(ESRD)患者合并炎症可能会增加心血管并发症。奥米加-3 脂肪酸可能对血液透析患者的健康有一定的益处。本研究旨在调查补充欧米伽-3 脂肪酸对血液透析患者的血细胞比容 (HCT)、血红蛋白 (HB) 水平和血小板 (PLT) 计数的影响。干预组(55 人)每天服用三粒欧米伽-3 脂肪酸补充胶囊(3 克/天),为期两个月。对照组(n = 60)服用三粒含有中链甘油三酯(MCT)油的安慰剂胶囊,剂量与干预组同期的补充剂量相似。结果与对照组相比,干预组的 PLT 计数下降(173.38 ± 74.76 vs. 227.68 ± 86.58 103/mm3,F = 4.83,P = 0.03)。结论HD患者补充omega-3可降低血管内形成血栓的风险。有必要进行进一步研究。
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引用次数: 0
Presentation and progression of MPO-ANCA interstitial lung disease MPO-ANCA 间质性肺病的表现和进展
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2024-02-23 DOI: 10.1016/j.jtauto.2024.100235
Lorenzo Salvati , Boaz Palterer , Elena Lazzeri , Emanuele Vivarelli , Marina Amendola , Marco Allinovi , Leonardo Caroti , Alessio Mazzoni , Laura Lasagni , Giacomo Emmi , Edoardo Cavigli , Marco Del Carria , Linda Di Pietro , Mariangela Scavone , Daniele Cammelli , Federico Lavorini , Sara Tomassetti , Elisabetta Rosi , Paola Parronchi

The association between MPO-ANCA-associated vasculitis (AAV) and interstitial lung disease (ILD) has been well established. Pulmonary fibrosis may coexist with, follow, or even precede the diagnosis of AAV, and its presence adversely affects the prognosis. The optimal approach to investigating ANCA in patients with ILD remains a subject of ongoing debate. Here we aim to describe presentation and progression of MPO-ANCA ILD. We conducted a retrospective evaluation of a cohort of individuals diagnosed with MPO-ANCA ILD, with or without accompanying renal impairment, at the Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy, between June 2016 and June 2022. Clinical records, imaging studies, pathologic examinations, and laboratory test results were collected. Among the 14 patients identified with MPO-ANCA ILD, we observed a significant association between MPO-ANCA titers assessed at the time of ILD diagnosis and renal involvement. Renal impairment in these cases often manifested as subclinical or slowly progressive kidney damage. Interestingly, complement C3 deposits were consistently found in all renal biopsy specimens, thereby suggesting the potential for novel therapeutic targets in managing renal complications associated with MPO-ANCA ILD. The presentation of MPO-ANCA vasculitis as ILD can be the first and only clinical manifestation. MPO-ANCA levels at ILD diagnosis could warn on the progression to renal involvement in patients with MPO-ANCA ILD, hence caution is needed because renal disease can be subclinical or smoldering.

MPO-ANCA相关性血管炎(AAV)与间质性肺病(ILD)之间的联系已经得到证实。肺纤维化可能与 AAV 同时存在,也可能发生在 AAV 诊断之后甚至之前,而肺纤维化的存在会对预后产生不利影响。对 ILD 患者进行 ANCA 检查的最佳方法仍是一个争论不休的话题。在此,我们旨在描述 MPO-ANCA ILD 的表现和进展。我们对2016年6月至2022年6月期间在意大利佛罗伦萨卡雷吉大学医院免疫学和细胞治疗室确诊为MPO-ANCA ILD(伴有或不伴有肾功能损害)的一组患者进行了回顾性评估。研究人员收集了临床病历、影像学检查、病理学检查和实验室检验结果。在 14 例 MPO-ANCA ILD 患者中,我们观察到 ILD 诊断时评估的 MPO-ANCA 滴度与肾脏受累之间存在显著关联。这些病例的肾功能损害通常表现为亚临床或缓慢进展的肾损害。有趣的是,在所有肾活检标本中都发现了补体C3沉积,这表明在控制与MPO-ANCA ILD相关的肾脏并发症方面,有可能找到新的治疗靶点。MPO-ANCA血管炎表现为ILD可能是首次也是唯一的临床表现。ILD诊断时的MPO-ANCA水平可对MPO-ANCA ILD患者肾脏受累的进展情况发出警告,因此需要谨慎,因为肾脏疾病可能是亚临床或隐匿性的。
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引用次数: 0
Sarcoidosis and lymphoma mortality risk: An observational study from the Spanish National Registry 肉样瘤病与淋巴瘤死亡风险:西班牙国家登记处的一项观察研究
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2024-02-19 DOI: 10.1016/j.jtauto.2024.100236
Víctor Moreno-Torres , María Martínez-Urbistondo , Pedro Durán-del Campo , Pablo Tutor , Begoña Rodríguez , Raquel Castejón , Susana Mellor-Pita

Introduction

Patients with sarcoidosis have a lower survival rate than the general population, in part due to cardiovascular disease, infections and neoplasms. Our objective was to evaluate the impact of haematological neoplasms (HN) and lymphomas on sarcoidosis patient mortality in a nation-wide analysis conducted in Spain, a country with a population of 47 million.

Methods

Retrospective and observational comparison of the HN related deaths in sarcoidosis patients and the general Spanish population reported in the Spanish Hospital Discharge Database. To determine the impact of sarcoidosis on the risk of dying from each HN lineage, a binary logistic regression considering age, female sex, tobacco and alcohol consumption, was performed.

Results

In the period 2016 and 2019, 139,531 in-hospital deaths from neoplasms were certified in Spain (77 in patients with sarcoidosis). Patients with sarcoidosis died at younger age than the general Spanish population (72.9 vs 77.6, p<0.001). Sarcoidosis patients presented a higher mortality risk from HN (20.8% vs 8.9%, p=0.001, OR=2.64, 95% CI 1.52-4.59), attributable to the higher proportion of deaths from non-Hodgkin lymphoma (NHL), (9.2% vs 2.9%, p=0.006, OR= 3.33, 95% CI 1.53-7.25) from both B cell (6.6% vs 2.5%, p=0.044, OR= 2.62, 95% 1.06-6.5) and T/NK cell lineages (2.6% vs 0.3%, p=0.024, OR= 7.88, 95% CI 1.92-32.29) as well as HN with uncertain behavior and myeloproliferative disorders (2.6% vs 0.3%, p=0.018, OR= 11.88, 95% CI 2.88-49.02). The mean age of sarcoidosis patients who died from HN (63.6 vs 71.9, p=0.032) and non-Hodgkin lymphoma (56.9 vs 71, p=0.009) was lower than that of the general population

Conclusion

Patients with sarcoidosis present a higher risk of premature death from HN, including NHL from B, T/NK cell lineage and myeloproliferative disorders in comparison with the general Spanish population. In addition to developing strategies that might help to attenuate their occurrence and impact, such as decreasing the immunosuppressive burden, specific early-detection programs for these conditions should be investigated and considered carefully.

导言肉样瘤病患者的存活率低于普通人群,部分原因在于心血管疾病、感染和肿瘤。我们的目的是在西班牙(一个拥有 4700 万人口的国家)进行的一项全国性分析中,评估血液肿瘤(HN)和淋巴瘤对肉样瘤病患者死亡率的影响。方法对西班牙医院出院数据库中报告的肉样瘤病患者和西班牙普通人群中与 HN 相关的死亡病例进行回顾性观察比较。为了确定肉样瘤病对每种 HN 死亡风险的影响,研究人员考虑了年龄、女性性别、吸烟和饮酒情况,进行了二元逻辑回归。肉样瘤病患者的死亡年龄低于西班牙普通人群(72.9 岁 vs 77.6 岁,p<0.001)。肉样瘤病患者死于 HN 的风险较高(20.8% 对 8.9%,p=0.001,OR=2.64,95% CI 1.52-4.59),这是因为死于非霍奇金淋巴瘤(NHL)的比例较高(9.2% 对 2.9%,p=0.006,OR=3.33,95% CI 1.53-7.25)。25)以及行为不确定的 HN 和骨髓增生性疾病(2.6% vs 0.3%,p=0.018,OR= 11.88,95% CI 2.88-49.02)。结论:与西班牙普通人群相比,肉样瘤病患者过早死于HN(包括B、T/NK细胞系的NHL和骨髓增生性疾病)的风险更高。除了制定有助于减少其发生和影响的策略(如减轻免疫抑制负担)外,还应仔细研究和考虑针对这些疾病的特定早期检测方案。
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引用次数: 0
Association of CCR6 functional polymorphisms with Primary Biliary Cholangitis CCR6 功能多态性与原发性胆汁性胆管炎的关系
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2024-02-15 DOI: 10.1016/j.jtauto.2024.100234
Mingming Zhang , Zhuye Qin , Yexi Huang , Wenyan Tian , You Li , Chan Wang , Weifeng Zhao , Yaping Dai , Xingjuan Shi , M. Eric Gershwin , Xiong Ma , Meilin Wang , Xiangdong Liu , Weichang Chen , Fang Qiu

The biliary epithelial cells release CC chemokine receptor 6 (CCR6) ligand 20 (CCL20), leading to recruitment of CCR6+ T cells and subsequent infiltration into the biliary epithelium in primary biliary cholangitis patients. Previous genome-wide multi-national meta-analysis, including our Han Chinese cohort, showed significant association of CCR6 and CCL20 single nucleotide polymorphisms (SNP) with PBC. We report here that significantly associated SNPs, identified in the CCR6 locus based on our Han Chinese genome-wide association study, can be separated into “protective” and “risk” groups, but only “risk” SNPs were confirmed using a separate Han Chinese PBC cohort. Only weak association of CCL20 SNPs was observed in Han Chinese PBC cohorts. Fine-mapping and logistical analysis identified a previously defined functional variant that, leads to increased CCR6 expression, which contributed to increased genetic susceptibility to PBC in Han Chinese cohort.

原发性胆汁性胆管炎患者的胆道上皮细胞会释放CC趋化因子受体6(CCR6)配体20(CCL20),导致CCR6+T细胞招募并随后浸润胆道上皮细胞。先前的全基因组多国荟萃分析(包括我们的汉族队列)显示,CCR6 和 CCL20 单核苷酸多态性(SNP)与原发性胆汁性胆管炎有显著相关性。我们在此报告,根据我们的中国汉族全基因组关联研究,在 CCR6 位点上发现的明显相关 SNP 可分为 "保护 "组和 "风险 "组,但只有 "风险 "SNP 通过单独的中国汉族 PBC 队列得到证实。在汉族 PBC 队列中仅观察到 CCL20 SNPs 的弱关联。精细图谱绘制和逻辑分析确定了一个先前定义的功能变异,该变异导致 CCR6 表达增加,从而增加了汉族队列中 PBC 的遗传易感性。
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引用次数: 0
Evaluating the inhibition of IL-17A and TNFα in a cartilage explant model cultured with Th17-derived cytokines 在使用 Th17 衍生细胞因子培养的软骨外植体模型中评估 IL-17A 和 TNFα 的抑制作用
IF 3.9 Q2 IMMUNOLOGY Pub Date : 2024-01-07 DOI: 10.1016/j.jtauto.2024.100231
Solveig Skovlund Groen , Anne-Christine Bay-Jensen , Christian S. Thudium , Morten H. Dziegiel , Marie Skougaard , Simon Francis Thomsen , Signe Holm Nielsen
<div><h3>Introduction</h3><p>T-helper 17 (Th17) cells produce IL-17A playing a critical role in activating the pathogenic chain leading to joint tissue inflammation and destruction. Elevated levels of Th17 cells and IL-17A have been detected in skin lesions, blood, and synovial fluid from patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Moreover, IL-17A inhibitors suppress disease activity in psoriasis, PsA and AS, supporting the evidence of IL-17A contributing to the disease pathogenesis. Although, IL-17A inhibitors are widely approved, it remains unclear how the inhibitory effect of IL-17A alters the extracellular matrix (ECM) of the joint in a Th17-conditioned inflammatory milieu. Therefore, the aim of this study was to establish a cartilage model cultured with conditioned medium from Th17 cells and inhibitors to explore the effect of IL-17A inhibition on joint tissue remodeling.</p></div><div><h3>Methods</h3><p>Naïve CD4<sup>+</sup> T cells from healthy human buffy coat were differentiated into Th17 cells, followed by Th17 cell activation to secrete Th17-related cytokines and molecules into media. The activated Th17 cells were isolated from the conditioned media (CM) and analyzed using flow cytometry to verify Th17 cell differentiation. The CM were assessed with ELISA to quantify the concentrations of cytokines secreted into the media by the Th17 cells. Healthy bovine cartilage explants were cultured with the Th17-CM and treated with IL-17A and TNFα inhibitors for 21 days. In harvested supernatant from the cartilage cultures, MMP- and ADAMTS-mediated biomarker fragments of type II collagen, aggrecan, and fibronectin were measured by ELISA to investigate the ECM remodeling within the cartilage tissue.</p></div><div><h3>Results</h3><p>Th17-CM stimulated a catabolic response in the cartilage. Markers of type II collagen and aggrecan degradation were upregulated, while anabolic marker of type II collagen formation remained on similar levels as the untreated explants. The addition of IL-17A inhibitor to Th17-CM decreased the elevated type II collagen and aggrecan degradation, however, degenerative levels were still elevated compared to untreated group. The addition of TNFα inhibitor completely reduced both type II collagen and aggrecan degradation compared to untreated explants. Moreover, the TNFα inhibitor treatment did not alter the type II collagen formation compared to untreated group.</p></div><div><h3>Conclusion</h3><p>This study suggests that inhibition of IL-17A in Th17-conditioned cartilage tissue only partially reduced the MMP-mediated type II collagen degradation and ADAMTS-mediated aggrecan degradation, while the TNFα inhibitor treatment fully reduced both MMP- and ADAMTS-mediated ECM degradation. This exploratory study where ECM biomarkers are combined with Th17-conditioned <em>ex vivo</em> model may hold great potential as output for describing joint disease mechanisms and predicting structural effects of trea
导言T-17(Th17)辅助细胞产生的 IL-17A 在激活导致关节组织炎症和破坏的致病链中发挥着关键作用。在银屑病关节炎(PsA)和强直性脊柱炎(AS)患者的皮损、血液和滑液中检测到 Th17 细胞和 IL-17A 水平升高。此外,IL-17A 抑制剂可抑制银屑病、银屑病关节炎和强直性脊柱炎的疾病活动,支持 IL-17A 在疾病发病机制中发挥作用的证据。尽管IL-17A抑制剂已被广泛批准,但目前仍不清楚IL-17A的抑制作用如何改变Th17条件下炎症环境中关节的细胞外基质(ECM)。因此,本研究旨在建立一个用 Th17 细胞和抑制剂的条件培养基培养的软骨模型,以探讨 IL-17A 抑制对关节组织重塑的影响。方法将健康人水包衣中的幼稚 CD4+ T 细胞分化成 Th17 细胞,然后激活 Th17 细胞,使其向培养基中分泌 Th17 相关细胞因子和分子。从条件培养基(CM)中分离出活化的 Th17 细胞,并使用流式细胞术进行分析,以验证 Th17 细胞的分化。用酶联免疫吸附法(ELISA)对条件培养基进行评估,以量化 Th17 细胞分泌到培养基中的细胞因子浓度。用 Th17-CM 培养健康牛软骨外植体,并用 IL-17A 和 TNFα 抑制剂处理 21 天。在软骨培养物收获的上清液中,通过 ELISA 测量 MMP 和 ADAMTS 介导的 II 型胶原、凝集素和纤连蛋白的生物标志物片段,以研究软骨组织内的 ECM 重塑情况。II 型胶原和凝集素降解的标志物上调,而 II 型胶原形成的合成代谢标志物与未处理的外植体保持相似水平。在 Th17-CM 中添加 IL-17A 抑制剂可降低升高的 II 型胶原和凝集素降解,但与未处理组相比,退化水平仍然升高。与未经处理的外植体相比,TNFα抑制剂可完全减少II型胶原和骨凝胶的降解。此外,与未处理组相比,TNFα 抑制剂处理并没有改变 II 型胶原的形成。结论本研究表明,在 Th17 调理的软骨组织中抑制 IL-17A 只部分减少了 MMP 介导的 II 型胶原降解和 ADAMTS 介导的骨凝集素降解,而 TNFα 抑制剂处理则完全减少了 MMP 和 ADAMTS 介导的 ECM 降解。这项探索性研究将 ECM 生物标志物与 Th17 调节的体外模型相结合,在描述关节疾病机制和预测治疗对关节组织结构的影响方面具有很大的潜力。
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Journal of Translational Autoimmunity
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