CD40−CD40L is essential for immune system modulation because it coordinates both adaptive and inflammatory responses.
Systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, thrombocytopenic purpura, and rheumatoid arthritis are among the autoimmune illnesses in which it is especially prominent. Thus, the CD40−CD40L axis is a significant therapeutic target, despite the fact that its inhibition was first constrained by thromboembolic adverse effects.
New therapeutic approaches, such as nanotechnological methods and new-generation monoclonal antibodies, have been developed as a result of recent research with the goal of enhancing therapy efficacy and safety. This study opens up new avenues for the treatment of autoimmune illnesses by examining the pathophysiological consequences of CD40−CD40L and reviewing new treatments that target this pathway.
{"title":"The role of soluble CD40L in autoimmune diseases","authors":"Meryem Mabrouk , Hicham Wahnou , Yahye Merhi , Haissam Abou-Saleh , Fadila Guessous , Younes Zaid","doi":"10.1016/j.jtauto.2025.100288","DOIUrl":"10.1016/j.jtauto.2025.100288","url":null,"abstract":"<div><div>CD40<sup>−</sup>CD40L is essential for immune system modulation because it coordinates both adaptive and inflammatory responses.</div><div>Systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, thrombocytopenic purpura, and rheumatoid arthritis are among the autoimmune illnesses in which it is especially prominent. Thus, the CD40<sup>−</sup>CD40L axis is a significant therapeutic target, despite the fact that its inhibition was first constrained by thromboembolic adverse effects.</div><div>New therapeutic approaches, such as nanotechnological methods and new-generation monoclonal antibodies, have been developed as a result of recent research with the goal of enhancing therapy efficacy and safety. This study opens up new avenues for the treatment of autoimmune illnesses by examining the pathophysiological consequences of CD40<sup>−</sup>CD40L and reviewing new treatments that target this pathway.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100288"},"PeriodicalIF":4.7,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851985","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}
Pub Date : 2025-04-15DOI: 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":"2025-04-15","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}
Pub Date : 2025-03-22DOI: 10.1016/j.jtauto.2025.100284
Xin Shen , Tingting Feng , Shangbin Li , Xingxin Wang , Wenhui Zhang , Shouyan Wang , Xiaohan Zhang , Jiguo Yang , Yuanxiang Liu
Background
Branched-chain amino acids (BCAAs), including isoleucine (Ile), leucine (Leu), and valine (Val), are substrates for synthesising nitrogenous compounds and signalling molecules involved in regulating immunity. To date, data on the role of BCAAs in autoimmune thyroiditis (AIT) are lacking; therefore, this study aimed to determine the causality using two-sample Mendelian randomisation (MR) and explored the role of BCAAs in the cGAS-STING-NLRP3 pathway in vitro.
Methods
The causal relationship between BCAAs and the pathogenesis of AIT were identified using a two-sample MR study. The anti-inflammatory effects of BCAAs and their role in the cGAS-STING-NLRP3 pathway were investigated in lipopolysaccharide (LPS)- induced thyroid follicular cells (TFCs).
Results
Our findings indicate that BCAAs are a pathogenic factor for AIT (IVW OR = 4.960; 95 % CI = (1.54,15.940); P = 0.007). Leu significantly exacerbated the inflammatory response of thyroid cells, as evidenced by the up-regulation of tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and down-regulation of TGF-β1; simultaneously aggravated cellular injury and oxidative stress; significantly increased the expression of Sestrin2/p-mTOR and cGAS/STING/NLRP3 in AIT cells. Furthermore, the expression of IL-18 and IL-1β was significantly increased. Conversely, Leu deprivation induced cell injury, decreased oxidative stress, and inhibited Sestrin2/p-mTOR and cGAS/STING/NLRP3 pathways.
Conclusion
Our findings suggest a potential causal effect of genetically predicted Leu on AIT; Leu significantly exacerbated the inflammatory response and cellular damage in AIT cells. The mechanism by which Leu induces inflammation involves activating the promoted Sestrin2/mTOR and cGAS-STING-NLRP3 signalling pathways. Our study proposes a novel mechanism for the contributions of Leu in AIT and potential therapeutic strategies involving Leu deprivation in treating AIT.
支链氨基酸（BCAAs），包括异亮氨酸（Ile）、亮氨酸（Leu）和缬氨酸（Val），是合成含氮化合物和参与调节免疫的信号分子的底物。迄今为止，缺乏关于支链氨基酸在自身免疫性甲状腺炎（AIT）中的作用的数据；因此，本研究旨在通过双样本孟德尔随机化（MR）来确定两者之间的因果关系，并探讨BCAAs在体外cGAS-STING-NLRP3通路中的作用。方法采用双样本磁共振分析方法，探讨支链氨基酸与AIT发病机制之间的因果关系。在脂多糖（LPS）诱导的甲状腺滤泡细胞（tfc）中，研究了BCAAs的抗炎作用及其在cGAS-STING-NLRP3通路中的作用。结果BCAAs是AIT的致病因素(IVW OR = 4.960；95% ci = (1.54,15.940)；p = 0.007)。亮氨酸显著加重甲状腺细胞的炎症反应，表现为肿瘤坏死因子-α (TNF-α)、白细胞介素-6上调，TGF-β1下调；同时加重细胞损伤和氧化应激；显著增加AIT细胞中Sestrin2/p-mTOR和cGAS/STING/NLRP3的表达。IL-18和IL-1β的表达显著升高。相反，Leu剥夺诱导细胞损伤，降低氧化应激，抑制Sestrin2/p-mTOR和cGAS/STING/NLRP3通路。结论基因预测的Leu对AIT有潜在的因果影响；Leu显著加重了AIT细胞的炎症反应和细胞损伤。Leu诱导炎症的机制涉及激活被促进的Sestrin2/mTOR和cGAS-STING-NLRP3信号通路。我们的研究提出了一种新的低亮氨酸在AIT中的作用机制，以及低亮氨酸剥夺治疗AIT的潜在治疗策略。
{"title":"Leucine enhances the cGAS-STING-NLRP3 pathway in autoimmune thyroiditis","authors":"Xin Shen , Tingting Feng , Shangbin Li , Xingxin Wang , Wenhui Zhang , Shouyan Wang , Xiaohan Zhang , Jiguo Yang , Yuanxiang Liu","doi":"10.1016/j.jtauto.2025.100284","DOIUrl":"10.1016/j.jtauto.2025.100284","url":null,"abstract":"<div><h3>Background</h3><div>Branched-chain amino acids (BCAAs), including isoleucine (Ile), leucine (Leu), and valine (Val), are substrates for synthesising nitrogenous compounds and signalling molecules involved in regulating immunity. To date, data on the role of BCAAs in autoimmune thyroiditis (AIT) are lacking; therefore, this study aimed to determine the causality using two-sample Mendelian randomisation (MR) and explored the role of BCAAs in the cGAS-STING-NLRP3 pathway <em>in vitro</em>.</div></div><div><h3>Methods</h3><div>The causal relationship between BCAAs and the pathogenesis of AIT were identified using a two-sample MR study. The anti-inflammatory effects of BCAAs and their role in the cGAS-STING-NLRP3 pathway were investigated in lipopolysaccharide (LPS)- induced thyroid follicular cells (TFCs).</div></div><div><h3>Results</h3><div>Our findings indicate that BCAAs are a pathogenic factor for AIT (IVW OR = 4.960; 95 % CI = (1.54,15.940); <em>P</em> = 0.007). Leu significantly exacerbated the inflammatory response of thyroid cells, as evidenced by the up-regulation of tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and down-regulation of TGF-β1; simultaneously aggravated cellular injury and oxidative stress; significantly increased the expression of Sestrin2/p-mTOR and cGAS/STING/NLRP3 in AIT cells. Furthermore, the expression of IL-18 and IL-1β was significantly increased. Conversely, Leu deprivation induced cell injury, decreased oxidative stress, and inhibited Sestrin2/p-mTOR and cGAS/STING/NLRP3 pathways.</div></div><div><h3>Conclusion</h3><div>Our findings suggest a potential causal effect of genetically predicted Leu on AIT; Leu significantly exacerbated the inflammatory response and cellular damage in AIT cells. The mechanism by which Leu induces inflammation involves activating the promoted Sestrin2/mTOR and cGAS-STING-NLRP3 signalling pathways. Our study proposes a novel mechanism for the contributions of Leu in AIT and potential therapeutic strategies involving Leu deprivation in treating AIT.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100284"},"PeriodicalIF":4.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706316","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}
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.
{"title":"A placebo-controlled Phase 2 trial of E6011, anti-human fractalkine monoclonal antibody, in primary biliary cholangitis","authors":"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","doi":"10.1016/j.jtauto.2025.100283","DOIUrl":"10.1016/j.jtauto.2025.100283","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100283"},"PeriodicalIF":4.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697669","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 : 2025-03-20DOI: 10.1016/j.jtauto.2025.100286
Fei Yan , Jing Tao , Jie Liu , Yongliang Chen , Zongju Huang
Background
Psoriasis is a chronic, immune-mediated inflammatory skin disorder with a strong genetic component. Although numerous GWAS have identified risk loci, many associated variants lie in non-coding regions, complicating functional interpretation.
Objective
This study aimed to identify novel psoriasis susceptibility genes by integrating large-scale GWAS and eQTL data using a cross-tissue TWAS approach.
Methods
We integrated psoriasis GWAS summary statistics from the FinnGen database with GTEx V8 eQTL data. A cross-tissue TWAS was performed using UTMOST, followed by validation with single-tissue TWAS via FUSION. Conditional and joint analyses were conducted to delineate independent genetic signals, and gene-based analysis was performed using MAGMA. Causal relationships were evaluated using Mendelian randomization (MR) and Bayesian colocalization analyses. Key SNPs were functionally characterized using CADD, GERP++, and RegulomeDB for pathogenicity prediction and regulatory potential assessment. Finally, functional network analysis was conducted using GeneMANIA.
Results
The cross-tissue TWAS identified 259 genes significantly associated with psoriasis (p < 0.05), with 12 remaining significant after FDR correction. Single-tissue TWAS validation revealed 655 significant genes, with an overlap of three protein-coding candidates: POLI, NFKB1, and ZFYVE28. Cross-validation with MAGMA refined the candidate set to NFKB1 and ZFYVE28. MR and colocalization analyses supported a causal relationship for NFKB1 in Skeletal Muscle, Transverse Colon, and Cultured Fibroblasts, and for ZFYVE28 in Subcutaneous Adipose Tissue and Esophageal Mucosa tissues. Functional annotation identified key SNPs including rs4235405, rs3774960, and rs1598856 for NFKB1, and rs1203786 for ZFYVE28, with varying degrees of pathogenicity and regulatory potential. GeneMANIA network analysis further implicated NFKB1 in NF-κB signaling and ZFYVE28 in vesicle-mediated transport.
Conclusion
Our integrative multi-omics approach identifies NFKB1 and ZFYVE28 as novel psoriasis susceptibility genes, providing potential biomarkers and therapeutic targets for this complex disease.
{"title":"Cross-tissue transcriptome-wide association study reveals novel psoriasis susceptibility genes","authors":"Fei Yan , Jing Tao , Jie Liu , Yongliang Chen , Zongju Huang","doi":"10.1016/j.jtauto.2025.100286","DOIUrl":"10.1016/j.jtauto.2025.100286","url":null,"abstract":"<div><h3>Background</h3><div>Psoriasis is a chronic, immune-mediated inflammatory skin disorder with a strong genetic component. Although numerous GWAS have identified risk loci, many associated variants lie in non-coding regions, complicating functional interpretation.</div></div><div><h3>Objective</h3><div>This study aimed to identify novel psoriasis susceptibility genes by integrating large-scale GWAS and eQTL data using a cross-tissue TWAS approach.</div></div><div><h3>Methods</h3><div>We integrated psoriasis GWAS summary statistics from the FinnGen database with GTEx V8 eQTL data. A cross-tissue TWAS was performed using UTMOST, followed by validation with single-tissue TWAS via FUSION. Conditional and joint analyses were conducted to delineate independent genetic signals, and gene-based analysis was performed using MAGMA. Causal relationships were evaluated using Mendelian randomization (MR) and Bayesian colocalization analyses. Key SNPs were functionally characterized using CADD, GERP++, and RegulomeDB for pathogenicity prediction and regulatory potential assessment. Finally, functional network analysis was conducted using GeneMANIA.</div></div><div><h3>Results</h3><div>The cross-tissue TWAS identified 259 genes significantly associated with psoriasis (p < 0.05), with 12 remaining significant after FDR correction. Single-tissue TWAS validation revealed 655 significant genes, with an overlap of three protein-coding candidates: POLI, NFKB1, and ZFYVE28. Cross-validation with MAGMA refined the candidate set to NFKB1 and ZFYVE28. MR and colocalization analyses supported a causal relationship for NFKB1 in Skeletal Muscle, Transverse Colon, and Cultured Fibroblasts, and for ZFYVE28 in Subcutaneous Adipose Tissue and Esophageal Mucosa tissues. Functional annotation identified key SNPs including rs4235405, rs3774960, and rs1598856 for NFKB1, and rs1203786 for ZFYVE28, with varying degrees of pathogenicity and regulatory potential. GeneMANIA network analysis further implicated NFKB1 in NF-κB signaling and ZFYVE28 in vesicle-mediated transport.</div></div><div><h3>Conclusion</h3><div>Our integrative multi-omics approach identifies NFKB1 and ZFYVE28 as novel psoriasis susceptibility genes, providing potential biomarkers and therapeutic targets for this complex disease.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100286"},"PeriodicalIF":4.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143681246","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 : 2025-03-19DOI: 10.1016/j.jtauto.2025.100285
Yu Lai , Zishao Zhong , Runze Li , Tuliang Liang , Xizi He , Yuan Liu , Hao Yu , Chuanhai Zhang , Yao Xiao , Liang Liu , Hudan Pan
Background
Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disease. While the chemokine signaling pathway plays a pivotal role in RA pathogenesis, the specific cellular interactions remain unclear.
Methods
A three-stage analytical framework was implemented. First, to uncover crucial signaling pathways in RA, we conducted an analysis of bulk RNA-seq data (GSE89408) sourced from the Gene Expression Omnibus (GEO) database. Second, utilizing single-cell transcriptome data from GEO (GSE200815 and GSE152805) and EMBL's European Bioinformatics Institute (E-MTAB-8322), we delved into key cell pairs and their ligand-receptor interactions within the chemokine signaling pathway. Third, spatial transcriptome data (SDY2213) from the IMMPORT database were employed to validate the colocalization of these pivotal cell pairs.
Results
Our enrichment analysis of bulk RNA-seq data underscored the chemokine signaling pathway's centrality in RA's pathogenesis. By integrating thirteen single-cell RNA sequencing datasets, we documented a notable elevation in the proportion of most lymphocyte types within RA synovium. The chemokine signaling pathway emerged as one of the primary pathways enriched in genes differentially expressed between RA and osteoarthritis in lymphocytes and CD8+ T cells. Cell-cell interaction analysis pinpointed the interaction between CD8+ T cells and endothelial cells (ECs) as a distinctive feature of the chemokine signaling pathway. Spatial transcriptome analysis further substantiated the co-localization of CD8+ T cells and ECs.
Conclusions
This study highlight CD8+ T cell- EC interactions via chemokine signaling as critical drivers of RA progression, potentially promoting leukocyte transendothelial migration and synovial immune infiltration.
背景类风湿性关节炎（RA）是一种常见的慢性自身免疫性疾病。虽然趋化因子信号通路在RA发病中起关键作用，但具体的细胞相互作用尚不清楚。方法采用三阶段分析框架。首先，为了揭示RA的关键信号通路，我们分析了来自Gene Expression Omnibus （GEO）数据库的大量RNA-seq数据（GSE89408）。其次，利用GEO （GSE200815和GSE152805）和EMBL的欧洲生物信息学研究所（E-MTAB-8322）的单细胞转录组数据，我们深入研究了趋化因子信号通路中的关键细胞对及其配体-受体相互作用。第三，利用import数据库中的空间转录组数据（SDY2213）验证这些关键细胞对的共定位。结果我们对大量RNA-seq数据的富集分析强调了趋化因子信号通路在RA发病机制中的中心地位。通过整合13个单细胞RNA测序数据集，我们记录了RA滑膜内大多数淋巴细胞类型的比例显著升高。趋化因子信号通路是RA和骨关节炎在淋巴细胞和CD8+ T细胞中差异表达基因富集的主要途径之一。细胞-细胞相互作用分析指出CD8+ T细胞和内皮细胞（ECs）之间的相互作用是趋化因子信号通路的一个独特特征。空间转录组分析进一步证实了CD8+ T细胞和ECs的共定位。结论本研究强调CD8+ T细胞- EC通过趋化因子信号相互作用是RA进展的关键驱动因素，可能促进白细胞跨内皮迁移和滑膜免疫浸润。
{"title":"Unveiling the crucial role of CD8+ T cell and endothelial cell interaction in rheumatoid arthritis through the integrated analysis of spatial transcriptomics and bulk/single-cell RNA-seq","authors":"Yu Lai , Zishao Zhong , Runze Li , Tuliang Liang , Xizi He , Yuan Liu , Hao Yu , Chuanhai Zhang , Yao Xiao , Liang Liu , Hudan Pan","doi":"10.1016/j.jtauto.2025.100285","DOIUrl":"10.1016/j.jtauto.2025.100285","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disease. While the chemokine signaling pathway plays a pivotal role in RA pathogenesis, the specific cellular interactions remain unclear.</div></div><div><h3>Methods</h3><div>A three-stage analytical framework was implemented. First, to uncover crucial signaling pathways in RA, we conducted an analysis of bulk RNA-seq data (GSE89408) sourced from the Gene Expression Omnibus (GEO) database. Second, utilizing single-cell transcriptome data from GEO (GSE200815 and GSE152805) and EMBL's European Bioinformatics Institute (E-MTAB-8322), we delved into key cell pairs and their ligand-receptor interactions within the chemokine signaling pathway. Third, spatial transcriptome data (SDY2213) from the IMMPORT database were employed to validate the colocalization of these pivotal cell pairs.</div></div><div><h3>Results</h3><div>Our enrichment analysis of bulk RNA-seq data underscored the chemokine signaling pathway's centrality in RA's pathogenesis. By integrating thirteen single-cell RNA sequencing datasets, we documented a notable elevation in the proportion of most lymphocyte types within RA synovium. The chemokine signaling pathway emerged as one of the primary pathways enriched in genes differentially expressed between RA and osteoarthritis in lymphocytes and CD8<sup>+</sup> T cells. Cell-cell interaction analysis pinpointed the interaction between CD8<sup>+</sup> T cells and endothelial cells (ECs) as a distinctive feature of the chemokine signaling pathway. Spatial transcriptome analysis further substantiated the co-localization of CD8<sup>+</sup> T cells and ECs.</div></div><div><h3>Conclusions</h3><div>This study highlight CD8<sup>+</sup> T cell- EC interactions via chemokine signaling as critical drivers of RA progression, potentially promoting leukocyte transendothelial migration and synovial immune infiltration.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100285"},"PeriodicalIF":4.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143681245","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 : 2025-03-07DOI: 10.1016/j.jtauto.2025.100282
Arno Belpaire , Annelies Demeyer , Elise Van Caelenberg , Nanja van Geel , Reinhart Speeckaert
Despite significant progress in the treatment of alopecia areata (AA), many aspects of its immune-based pathogenesis remain unexplored. IFN-γ, primarily produced by CD8+ T cells and NK cells, is considered central to AA pathogenesis. However, the complex immune signaling network contributes to therapeutic resistance and frequent disease flares after treatment discontinuation. The aryl hydrocarbon receptor (AhR) pathway, upregulated by IFN-γ, modulates Th17 responses, but its inhibitory effects on IFN-γ remain unclear. Although IL-17 levels are elevated in AA, clinical trials indicate that IL-17A inhibitors are ineffective. AhR expression is known to induce immune checkpoints (ICPs) such as PD-1, suggesting a potential role as a negative feedback mechanism. This study investigated AhR expression in lymphocytes from AA patients and its association with clinical and laboratory markers of disease activity. AhR expression was significantly reduced in CD4, CD8, Th1, and Th17 lymphocytes in AA patients compared to healthy controls (p < 0.005), and it correlated inversely with SALTII scores (p < 0.05). ROC analysis showed that AhR levels in CD8 cells could differentiate mild AA from healthy controls with a sensitivity of 82.35 % and specificity of 86.84 %, suggesting potential diagnostic utility. Lower AhR levels were associated with increased IFN-γ+ lymphocytes and decreased IL-17+ immune cells. Interestingly, immune profiles differed between atopic and non-atopic patients: in severe AA, higher AhR expression was linked to increased sPD-1 concentrations, whereas in limited AA, AhR failed to upregulate any investigated ICP. These findings highlight the significant downregulation of the AhR pathway in AA and suggest its potential as a therapeutic target. Future research should explore the development of AhR agonists or antagonists to modulate immune responses in AA.
{"title":"The AhR pathway is dysregulated in alopecia areata","authors":"Arno Belpaire , Annelies Demeyer , Elise Van Caelenberg , Nanja van Geel , Reinhart Speeckaert","doi":"10.1016/j.jtauto.2025.100282","DOIUrl":"10.1016/j.jtauto.2025.100282","url":null,"abstract":"<div><div>Despite significant progress in the treatment of alopecia areata (AA), many aspects of its immune-based pathogenesis remain unexplored. IFN-γ, primarily produced by CD8<sup>+</sup> T cells and NK cells, is considered central to AA pathogenesis. However, the complex immune signaling network contributes to therapeutic resistance and frequent disease flares after treatment discontinuation. The aryl hydrocarbon receptor (AhR) pathway, upregulated by IFN-γ, modulates Th17 responses, but its inhibitory effects on IFN-γ remain unclear. Although IL-17 levels are elevated in AA, clinical trials indicate that IL-17A inhibitors are ineffective. AhR expression is known to induce immune checkpoints (ICPs) such as PD-1, suggesting a potential role as a negative feedback mechanism. This study investigated AhR expression in lymphocytes from AA patients and its association with clinical and laboratory markers of disease activity. AhR expression was significantly reduced in CD4, CD8, Th1, and Th17 lymphocytes in AA patients compared to healthy controls (<em>p</em> < 0.005), and it correlated inversely with SALTII scores (<em>p</em> < 0.05). ROC analysis showed that AhR levels in CD8 cells could differentiate mild AA from healthy controls with a sensitivity of 82.35 % and specificity of 86.84 %, suggesting potential diagnostic utility. Lower AhR levels were associated with increased IFN-γ+ lymphocytes and decreased IL-17+ immune cells. Interestingly, immune profiles differed between atopic and non-atopic patients: in severe AA, higher AhR expression was linked to increased sPD-1 concentrations, whereas in limited AA, AhR failed to upregulate any investigated ICP. These findings highlight the significant downregulation of the AhR pathway in AA and suggest its potential as a therapeutic target. Future research should explore the development of AhR agonists or antagonists to modulate immune responses in AA.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100282"},"PeriodicalIF":4.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143601375","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}
The COVID-19 pandemic has raised concerns about potential links between SARS-CoV-2 infection and autoimmune diseases. This study investigated changes in the incidence rate (IR) of autoimmune diseases among children following the pandemic's onset.
Methods
A retrospective cross-sectional study analyzed data from Clalit Health Services, Israel's largest healthcare provider, examining the IR of different autoimmune diseases in children aged 0–18. The study compared pre-pandemic (2019) with pandemic/post-pandemic periods (2020–2023), encompassing a cohort of over 1.5 million children.
Results
Significant IR increases were observed across multiple autoimmune diseases. Rheumatic diseases (Juvenile Idiopathic Arthritis, Systemic Lupus Erythematosus, Henoch Schoenlein Purpura (HSP)) showed consistent increases, with HSP demonstrating the most pronounced trend. Endocrine disorders exhibited diverse patterns, with autoimmune thyroid diseases and Type 1 diabetes showing overall increases, while diabetic ketoacidosis exhibited an initial spike followed by a decline. Gastrointestinal diseases displayed heterogeneous patterns; Celiac disease and Ulcerative colitis showed general increases, Crohn's disease showed a downward trend, and autoimmune hepatitis exhibited an initial significant decrease followed by a significant increase. Dermatological conditions, including Psoriasis and Vitiligo, demonstrated consistent elevations throughout 2020–2023. Immune Thrombocytopenia Purpura showed initial decreases followed by significant increases in 2022–2023.
Conclusions
This comprehensive analysis reveals significant changes in pediatric autoimmune disease incidence following the COVID-19 pandemic, suggesting potential associations between SARS-CoV-2 infection and autoimmune dysregulation. The diverse patterns observed across different conditions highlight the complex interplay between viral infection and autoimmunity, emphasizing the need for continued surveillance and investigation of long-term immunological consequences of COVID-19 in pediatric populations.
COVID-19大流行引发了人们对SARS-CoV-2感染与自身免疫性疾病之间潜在联系的担忧。本研究调查了大流行爆发后儿童自身免疫性疾病发病率（IR）的变化。方法一项回顾性横断面研究分析了以色列最大的医疗保健提供商Clalit Health Services的数据，检查了0-18岁儿童不同自身免疫性疾病的IR。该研究将大流行前（2019年）与大流行/大流行后（2020-2023年）进行了比较，涉及150多万名儿童。结果在多种自身免疫性疾病中观察到显著的IR升高。风湿病（幼年特发性关节炎、系统性红斑狼疮、过敏性紫癜（HSP））持续增加，其中HSP的趋势最为明显。内分泌失调表现出不同的模式，自身免疫性甲状腺疾病和1型糖尿病总体增加，而糖尿病酮症酸中毒表现出最初的高峰，然后下降。胃肠道疾病表现出异质性；乳糜泻和溃疡性结肠炎总体呈上升趋势，克罗恩病呈下降趋势，自身免疫性肝炎呈初始显著下降后显著上升趋势。皮肤病，包括牛皮癣和白癜风，在2020-2023年期间持续升高。免疫性血小板减少性紫癜在2022-2023年表现出最初的下降，随后显著上升。结论这项综合分析揭示了COVID-19大流行后儿童自身免疫性疾病发病率的显著变化，提示SARS-CoV-2感染与自身免疫性失调之间存在潜在关联。在不同情况下观察到的不同模式突出了病毒感染与自身免疫之间复杂的相互作用，强调需要继续监测和调查COVID-19在儿科人群中的长期免疫后果。
{"title":"Pediatric autoimmune diseases in the light of COVID-19 pandemic, A retrospective observational big data study","authors":"Rim Kasem Ali Sliman , Hilla Cohen , Shereen Shehadeh , Reut Batcir , Yigal Elenberg Alter , Keren Cohen , Ilana Koren , Inbal Halabi , Hussein Sliman , Mohamad Hamad Saied","doi":"10.1016/j.jtauto.2025.100281","DOIUrl":"10.1016/j.jtauto.2025.100281","url":null,"abstract":"<div><h3>Background</h3><div>The COVID-19 pandemic has raised concerns about potential links between SARS-CoV-2 infection and autoimmune diseases. This study investigated changes in the incidence rate (IR) of autoimmune diseases among children following the pandemic's onset.</div></div><div><h3>Methods</h3><div>A retrospective cross-sectional study analyzed data from Clalit Health Services, Israel's largest healthcare provider, examining the IR of different autoimmune diseases in children aged 0–18. The study compared pre-pandemic (2019) with pandemic/post-pandemic periods (2020–2023), encompassing a cohort of over 1.5 million children.</div></div><div><h3>Results</h3><div>Significant IR increases were observed across multiple autoimmune diseases. Rheumatic diseases (Juvenile Idiopathic Arthritis, Systemic Lupus Erythematosus, Henoch Schoenlein Purpura (HSP)) showed consistent increases, with HSP demonstrating the most pronounced trend. Endocrine disorders exhibited diverse patterns, with autoimmune thyroid diseases and Type 1 diabetes showing overall increases, while diabetic ketoacidosis exhibited an initial spike followed by a decline. Gastrointestinal diseases displayed heterogeneous patterns; Celiac disease and Ulcerative colitis showed general increases, Crohn's disease showed a downward trend, and autoimmune hepatitis exhibited an initial significant decrease followed by a significant increase. Dermatological conditions, including Psoriasis and Vitiligo, demonstrated consistent elevations throughout 2020–2023. Immune Thrombocytopenia Purpura showed initial decreases followed by significant increases in 2022–2023.</div></div><div><h3>Conclusions</h3><div>This comprehensive analysis reveals significant changes in pediatric autoimmune disease incidence following the COVID-19 pandemic, suggesting potential associations between SARS-CoV-2 infection and autoimmune dysregulation. The diverse patterns observed across different conditions highlight the complex interplay between viral infection and autoimmunity, emphasizing the need for continued surveillance and investigation of long-term immunological consequences of COVID-19 in pediatric populations.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100281"},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143611570","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}
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.
{"title":"NETosis: A key player in autoimmunity, COVID-19, and long COVID","authors":"Diana M. Monsalve , Yeny Acosta-Ampudia , Nicolás Guerrero Acosta , Mariana Celis-Andrade , Ali Şahin , Ahsen Morva Yilmaz , Yehuda Shoenfeld , Carolina Ramírez-Santana","doi":"10.1016/j.jtauto.2025.100280","DOIUrl":"10.1016/j.jtauto.2025.100280","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100280"},"PeriodicalIF":4.7,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464117","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 : 2025-02-07DOI: 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。
{"title":"Understanding the role of immune-mediated inflammatory disease related cytokines interleukin 17 and 23 in pregnancy: A systematic review","authors":"Aniek Plug , Liana Barenbrug , Bart G.J. Moerings , Elke M.G. de Jong , Renate G. van der Molen","doi":"10.1016/j.jtauto.2025.100279","DOIUrl":"10.1016/j.jtauto.2025.100279","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>We systemically searched PubMed, EMBASE, and Web of Science (March 2024), to assess the role of IL-17 and IL-23 in pregnancy-related <em>in vitro</em> assays, animal or human studies.</div></div><div><h3>Results</h3><div>Eighty articles (8 <em>in vitro</em>, 11 animal and 61 human studies) were included. Seventy-one studies reported on IL-17 and 16 studies on IL-23. <em>In vitro</em> 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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100279"},"PeriodicalIF":4.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403512","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}
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