Journal of Translational Autoimmunity最新文献

{"title":"A comparative study of different assays for autoantibodies detection in patients with autoimmune gastritis","authors":"Małgorzata Osmola ,&nbsp;Caroline Hémont ,&nbsp;Marcin Romańczyk ,&nbsp;Amaury Druet ,&nbsp;Nicolas Chapelle ,&nbsp;Tamara Matysiak-Budnik ,&nbsp;Marco Vincenzo Lenti ,&nbsp;Jérôme C. Martin","doi":"10.1016/j.jtauto.2025.100294","DOIUrl":"10.1016/j.jtauto.2025.100294","url":null,"abstract":"<div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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 %.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100294"},"PeriodicalIF":4.7,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144167145","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}

{"title":"Characteristics of polyclonal anti-interferon-gamma autoantibodies and novel diagnostic strategies: A prospective cohort study of new biomarkers","authors":"Xidong Wang ,&nbsp;Feng Ye ,&nbsp;Hongling Liu ,&nbsp;Shaoqiang Li ,&nbsp;Jinglu Yang ,&nbsp;Xue Yu ,&nbsp;Yilei Hui ,&nbsp;Yongming Li ,&nbsp;Yangqing Zhan ,&nbsp;Yan Wang ,&nbsp;Jing Liu ,&nbsp;Zhengtu Li","doi":"10.1016/j.jtauto.2025.100292","DOIUrl":"10.1016/j.jtauto.2025.100292","url":null,"abstract":"<div><h3>Background</h3><div><em>Anti</em>-γ interferon autoantibody (AIGA) syndrome is a widespread and grossly underestimated immunodeficiency disorder characterized by high mortality rates and a lack of standardized diagnostic methods. A highly accurate AIGA biomarker that meets the requirements of absolute quantification is urgently needed to enable the early diagnosis and treatment monitoring of the disease. In our study, we aimed to identify the primary components of AIGAs, determine their function, and develop a novel diagnostic method.</div></div><div><h3>Methods</h3><div>Immune repertoire sequencing and a retrospective antibody subtype index analysis were performed for typical patients. Affinity chromatography was used to isolate and purify IgGs from AIGAs in the plasma of AIGA(+) patients. The clinical application value of chromatography for testing AIGAs was evaluated in a prospective clinical cohort.</div></div><div><h3>Results</h3><div>A total of 114 eligible subjects were enrolled. Immune repertoire sequencing revealed that 74 % of the AIGA(+) patients had IgG clone types, with the somatic hypermutation (SHM) analysis being the most informative. We isolated AIGAs from the blood and interpreted their affinity and major components completely. Based on the results of this prospective cohort study, AIGAs, an absolute quantitative biomarker, were significantly better than the ELISA method (Delong test, P = 0.0018).</div></div><div><h3>Conclusions</h3><div>Patients with AIGA syndrome have abnormally elevated IgG levels, with IgG3 subtypes dominating. The disorder is characterized by the rapid acquisition of polyclonal AIGAs. The obtained AIGAs had a good neutralization capacity and potential as absolute quantitative biomarkers.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100292"},"PeriodicalIF":4.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071497","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}

{"title":"Autoantibodies as prognostic markers in rheumatoid arthritis","authors":"Carl Turesson ,&nbsp;Johan Rönnelid ,&nbsp;Alf Kastbom","doi":"10.1016/j.jtauto.2025.100291","DOIUrl":"10.1016/j.jtauto.2025.100291","url":null,"abstract":"<div><h3>Background and purpose</h3><div>Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressively destructive polyarthritis. Key autoimmune features include the presence of autoantibodies. The purpose of this review is to discuss the diagnostic and prognostic properties of rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA), based on current use in Sweden. Furthermore, we discuss their relation to disease outcomes and their importance for management of patients with RA.</div></div><div><h3>Principal findings</h3><div>Based on current cut-offs, ACPA has a higher specificity for RA than RF, and testing for ACPA alone is recommended when investigating patients with clinically suspect RA. The diagnostic utility of RF may improve with adjusted reference range/upper limit of normal.</div><div>RF and ACPA both predict rapid radiographic progression, severe extra-articular manifestations and mortality, whereas other outcomes, such as osteoporosis, pain and disability are not as clearly related to seropositivity. RF/ACPA positive patients respond better to some targeted therapies, in particular rituximab, compared to seronegative RA patients. Recent studies indicate that treatment of ACPA-positive arthralgia with abatacept may delay and perhaps sometimes even prevent development of arthritis. Available evidence does not support an added value of repeated RF or ACPA testing.</div></div><div><h3>Conclusions</h3><div>Testing for ACPA in patients with arthralgia or suspected early RA, and for ACPA and RF at RA diagnosis, provides useful diagnostic and prognostic information, which has implications for follow-up and treatment. Repeated testing for ACPA and RF is not recommended. Potential future developments include treatment of ACPA-positive individuals for prevention of arthritis.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100291"},"PeriodicalIF":4.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143907781","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}

{"title":"Immune characterization of lupus nephritis patients undergoing dialysis","authors":"Quentin Simon ,&nbsp;François Gaillard ,&nbsp;John Tchen ,&nbsp;Delphine Bachelet ,&nbsp;Karim Sacré ,&nbsp;Katell Peoc'h ,&nbsp;Noémie Jourde-Chiche ,&nbsp;Eric Daugas ,&nbsp;Nicolas Charles","doi":"10.1016/j.jtauto.2025.100290","DOIUrl":"10.1016/j.jtauto.2025.100290","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) activity decreases in some patients with end-stage kidney disease (ESKD). The impact of ESKD on the immune cell profile of SLE patients and lupus activity remains unclear. In this study, we aimed at characterizing immunologically inactive and active SLE patients undergoing dialysis therapy. Based on multi-parametric flow cytometry assays, an extensive immunophenotyping was performed on blood samples from 47 SLE patients undergoing hemodialysis, 10 non-dialyzed SLE patients with active lupus nephritis (aLN), 6 non-dialyzed patients with a history of LN currently in remission (rLN), and 20 healthy volunteers (HV) as controls (<span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> Identifier: NCT03921398). The hemodialysis group was composed of 16 SLE patients with inactive disease (iHD), 22 with sustained low disease activity with a non-renal SLEDAI ≤4 (aHD≤4), and 9 highly active SLE patients (aHD&gt;4). A factorial discriminant analysis was performed to validate the association between immune cell signatures and lupus activity. By compiling 12 cellular variables, we describe immune profiles related to highly active SLE patients or associated with both inactive and low-disease activity groups. As non-dialyzed active SLE patients, active patients undergoing hemodialysis showed a specific combination of increased numbers of circulating CD19^hi CD27^– “atypical naive” B cells, plasmablasts, CD16⁺ inflammatory monocytes and a basopenia. This study brings a comprehensive overview of immune cell signatures observed in SLE patients undergoing dialysis. We propose a simple immunophenotypic approach for the assessment of lupus activity that may provide help to data-driven personalized medicine in hemodialyzed SLE patients.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100290"},"PeriodicalIF":4.7,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904191","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}

{"title":"The changes in global burden of autoimmune diseases two years after the COVID-19 pandemic: a trend analysis based on the Global Burden of Disease Study 2021","authors":"Danting Zhang ,&nbsp;Wanyu Hua ,&nbsp;Fangfang Sun ,&nbsp;Chao Wen ,&nbsp;Lai Yee Cheong ,&nbsp;Ruiyan Xie ,&nbsp;Koon Ho Chan ,&nbsp;Shirley C.W. Chan ,&nbsp;Xue Li ,&nbsp;Shuang Ye ,&nbsp;Desmond Y.H. Yap","doi":"10.1016/j.jtauto.2025.100289","DOIUrl":"10.1016/j.jtauto.2025.100289","url":null,"abstract":"<div><h3>Background</h3><div>Data on the epidemiological changes in the global burden of autoimmune diseases (ADs) after the Coronavirus disease 2019 (COVID-19) pandemic is lacking. This study investigated the impact of the COVID-19 pandemic on the global burden of ADs, including psoriasis (PsO), inflammatory bowel disease (IBD), type 1 diabetes (T1DM), rheumatoid arthritis (RA), and multiple sclerosis (MS).</div></div><div><h3>Methods</h3><div>Age-standardized rates (ASR), including incidence (ASIR), prevalence (ASPR), disability-adjusted life years (DALYs), and death (ASDR), were extracted from the Global Burden of Disease Study 2021 from 1990 to 2021. The changes in number and ASR of ADs burden were assessed by absolute and relative increases comparing 2021 to 2019. Joinpoint regression analysis was used to determine whether the year 2019 marked the substantial changes in trends of ASR across global, 21 geographical regions, and 204 countries. The correlations between COVID-19 incidence, vaccination and the relative increased ASIR/ASPR of ADs were also evaluated.</div></div><div><h3>Results</h3><div>Joinpoint regression analysis identified 2019 as a pivotal year, marking a global increase in the burden of PsO. The global ASR of PsO in 2021 showed an increased incidence, prevalence, and DALYs of 0.78, 5, and 0.33 DALYs per 100,000, respectively, compared to 2019 (194.1 × 10³ cases, 1651.3 × 10³ cases, and 131.4 × 10³ DALYs, respectively). Notable absolute increases in PsO incidence rates in 2021 were observed in regions with a high socio-demographic index, particularly among individuals aged 50 to 54 and among males. Furthermore, 2019 marked a joinpoint with increased ASIR or ASPR of ADs in various regions, notably PsO in High-income North America, Southern Latin America, and South Asia, as well as IBD in Southern and Eastern Sub-Saharan Africa, Central Europe, and East Asia. Regional data from the USA, England, and Japan indicated a positive correlation between COVID-19 incidence and relative increases in the burden of PsO in 2020 (Spearman R 0.35, 0.24, and 0.36, respectively, for incidence; R 0.35, 0.2, and 0.36, respectively, for prevalence; all p &lt; 0.05). Additionally, 2021 state-level vaccination rates in the USA were negatively correlated with the relative increases in the ASIR of PsO and RA (R: 0.27 and −0.54, respectively; p &lt; 0.001 for all), as well as the ASPR of PsO, RA, and MS (R: 0.45, −0.49, and −0.41, respectively; p &lt; 0.01 for all) in 2021.</div></div><div><h3>Conclusions</h3><div>The year 2019 marked a pivotal point for increased global burden of PsO and regional burdens of other ADs. These observations have important implications for subsequent healthcare planning and resource allocation.</div></div>","PeriodicalId":36425,"journal":{"name":"Journal of Translational Autoimmunity","volume":"10 ","pages":"Article 100289"},"PeriodicalIF":4.7,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877444","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}

{"title":"The role of soluble CD40L in autoimmune diseases","authors":"Meryem Mabrouk ,&nbsp;Hicham Wahnou ,&nbsp;Yahye Merhi ,&nbsp;Haissam Abou-Saleh ,&nbsp;Fadila Guessous ,&nbsp;Younes Zaid","doi":"10.1016/j.jtauto.2025.100288","DOIUrl":"10.1016/j.jtauto.2025.100288","url":null,"abstract":"<div><div>CD40⁻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⁻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⁻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}

{"title":"Identification of autoantibodies targeting citrullinated CLEC12A in rheumatoid arthritis patients","authors":"Lillian Barra ,&nbsp;Sheri Saunders ,&nbsp;Mathias Mangion ,&nbsp;Guillaume Paré ,&nbsp;Halim Maaroufi ,&nbsp;Alain Garnier ,&nbsp;Ewa Cairns ,&nbsp;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}

{"title":"Leucine enhances the cGAS-STING-NLRP3 pathway in autoimmune thyroiditis","authors":"Xin Shen ,&nbsp;Tingting Feng ,&nbsp;Shangbin Li ,&nbsp;Xingxin Wang ,&nbsp;Wenhui Zhang ,&nbsp;Shouyan Wang ,&nbsp;Xiaohan Zhang ,&nbsp;Jiguo Yang ,&nbsp;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}

{"title":"A placebo-controlled Phase 2 trial of E6011, anti-human fractalkine monoclonal antibody, in primary biliary cholangitis","authors":"Atsushi Tanaka ,&nbsp;Masanori Abe ,&nbsp;Tadashi Namisaki ,&nbsp;Shinji Shimoda ,&nbsp;Mikio Zeniya ,&nbsp;Akio Ido ,&nbsp;Hitoshi Yoshiji ,&nbsp;Hiromasa Ohira ,&nbsp;Kenichi Harada ,&nbsp;Yuko Kakuda ,&nbsp;Atsushi Umeda ,&nbsp;Yuki Kamiya ,&nbsp;Yukari Higashine ,&nbsp;Seiichiro Hojo ,&nbsp;Toshio Imai ,&nbsp;Tetsu Kawano ,&nbsp;Yasuni Nakanuma ,&nbsp;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}

{"title":"Cross-tissue transcriptome-wide association study reveals novel psoriasis susceptibility genes","authors":"Fei Yan ,&nbsp;Jing Tao ,&nbsp;Jie Liu ,&nbsp;Yongliang Chen ,&nbsp;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 &lt; 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}