Clinical and experimental immunology最新文献

{"title":"CD40 blockade hampers IgG class-switch while enhancing Granzyme B production by transitional B cells.","authors":"Felix Werner, Jens Wittner, Christian H K Lehmann, Mandy Wahlbuhl, Ida Allabauer, Adrian Hoffmann, Alexander Schnell, Tobias Krickau, Holger Hackstein, Barbara Dietel-Schor, James S Rush, Catherine H Regnier, Hans-Martin Jäck, Joachim Woelfle, Wolfgang Schuh, André Hoerning","doi":"10.1093/cei/uxaf044","DOIUrl":"https://doi.org/10.1093/cei/uxaf044","url":null,"abstract":"<p><p>CD40-CD40L interaction is crucial for the interplay between B and T cells and determines B cell fate. Here, we investigated the effects of CD40-CD40L inhibition on B cell subsets and cytokine production using the non-depleting monoclonal anti-CD40 antibody CFZ534. CFZ534 had no impact on B cell viability but inhibited TLR9-agonistic (CpG-ODN) CD40L- as well as CD40L-mediated proliferation. The plasmablast subset was reduced after stimulation with CpG-ODN+CD40L but this effect was completely restored by CFZ534-mediated CD40 blockade. IgG as well as IgM-secreting cells were significantly reduced in the presence of CFZ534 upon CD40L stimulation. CpG-ODN, but not CD40L, induced Granzyme B production in B cells after CD40-blockade and CpG-ODN/CD40L stimulation. Moreover, we found that IL-10 and Granzyme B were produced by separate B cell subsets. Hence, CD40-blockade mediated by CFZ534 increased Granzyme B production and decreased IL-10 production in CD24hiCD38hi B cells with a transitional phenotype and led to a significant decrease in the expression of the pro-inflammatory cytokines IL-6, IL-12p35 and IL-23p19 and TNFα in a B and CD4+ TH-cell co-culture system. Based on these pre-clinical results CD40 blockade by the Fc-silent, non-depleting monoclonal antibody CFZ534 exerts an anti-inflammatory effect on B cells including hampering the IgG class switch without affecting their viability. Graphical Abstract.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel missense variant in TNFAIP3 associated with autoimmunity reveals the contribution of STAT1/ mTOR pathways.","authors":"Judith Potjewijd, Hans J P M Koenen, Caspar I van der Made, Esther van Rijssen, Xuehui He, Renee Ysermans, Liset Ungethum, Ruud Theunissen, Leon J Schurgers, Jan Damoiseaux, Pieter van Paassen, Ruben L Smeets","doi":"10.1093/cei/uxaf048","DOIUrl":"https://doi.org/10.1093/cei/uxaf048","url":null,"abstract":"<p><strong>Introduction: </strong>Heterozygous loss-of-function mutations in the TNFAIP3 gene lead to A20 haploinsufficiency (HA20). A20 protein is a negative feedback regulator of NF-κB signaling. Traditionally, HA20 is associated with Behçet's disease-like symptoms, however, recent findings suggest it may also manifest with a broader array of autoimmune diseases. This study introduces a novel TNFAIP3 variant within a Dutch family, predominantly exhibiting polyautoimmunity rather than autoinflammatory characteristics.</p><p><strong>Methods: </strong>We evaluated two patients from a Dutch family with autoimmune symptoms. Whole-exome sequencing (WES) identified genetic variants. Immunoblotting on peripheral blood mononuclear cells (PBMCs) from the patients and an overexpression model using transfected HEK293T cells assessed A20 expression. Phosphoflow cytometry analyzed phosphorylation of key signaling molecules in the NF-κB, STAT and mTOR pathways. Cytokine levels in cell culture supernatants evaluated inflammatory responses.</p><p><strong>Results: </strong>A novel heterozygous c.608T>G (p.Leu203Arg) variant in TNFAIP3 was identified, affecting the OTU domain. Overexpression of this missense A20 variant in HEK293T enhanced NF-κB signaling, reflected by increased TRAF6 expression and IκBα phosphorylation. Functional assays revealed reduced A20 expression in patient PBMCs, increased NF-κB, STAT1 and mTOR pathway phosphorylation, and elevated pro-inflammatory cytokine production. These molecular alterations suggest disrupted immune regulation contributing to the autoimmune phenotype.</p><p><strong>Conclusion: </strong>The discovery of a novel TNFAIP3 variant contributing to HA20 expands the clinical spectrum to include predominant autoimmune manifestations. In addition to NF-κB and STAT1 activation, we discovered mTOR pathway activation, shedding new light on A20's function and progression toward autoimmunity. Furthermore, the involvement of mTOR pathway also provides new therapeutic possibilities.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of a new truncated CD74 isoform in increased IL-17 secretion from stromal-immune cell interactions.","authors":"Mélissa Noack, Marlène Bailly, Laura Durix, Jean-Jacques Pin, Pierre Miossec","doi":"10.1093/cei/uxaf047","DOIUrl":"https://doi.org/10.1093/cei/uxaf047","url":null,"abstract":"<p><strong>Introduction: </strong>Stromal-immune cell interactions promote pro-inflammatory cytokine secretion such as IL-17. IL-17 is involved in several chronic inflammatory diseases, affecting joints and skin. Podoplanin has been already identified as partially involved in high IL-17 secretion resulting from these cell interactions.</p><p><strong>Methods: </strong>The aim of this study was to identify new molecules, using co-cultures of activated peripheral blood mononuclear cells and synoviocytes (5:1 ratio). Cell interactions were critical to induce a high IL-17 production. The blockade of podoplanin inhibited this production, approximately 40%, confirming the contribution of other molecules. A battery of mouse monoclonal anti-human RA synoviocyte antibodies were tested in co-cultures and several were selected for their inhibitory effect on IL-17.</p><p><strong>Results: </strong>Cloning by expression allowed identifying the target of the selected 8350 antibody, a truncated isoform of CD74. CD74 blockade in co-cultures by 8350 antibody and a commercial antibody inhibited IL-17 production by 40%, but 8350 antibody had a limited effect on IL-10 inhibition. Furthermore, cell interactions increased CD74 expression, at mRNA and protein levels.</p><p><strong>Conclusion: </strong>This study identified truncated CD74 isoform as a novel molecule directly involved in high IL-17 secretion resulting from cell interactions. Inhibition of this truncated CD74 could represent a new therapeutic option for diseases with IL-17 involvement.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HLA-DR expressing lymph node fibroblasts maintain FoxP3+ regulatory T cells and are reduced in rheumatoid arthritis.","authors":"Aoife M O'Byrne, Cristoforo Grasso, Charlotte M de Winde, Aleksandra M Mikula, Catarina Gago da Graça, Johanna F Semmelink, Ester B M Remmerswaal, Janne W Bolt, Marleen G H van de Sande, Reina E Mebius, Lisa G M van Baarsen","doi":"10.1093/cei/uxaf042","DOIUrl":"https://doi.org/10.1093/cei/uxaf042","url":null,"abstract":"<p><strong>Introduction: </strong>Murine studies have demonstrated that lymph node fibroblasts can present self-antigens via major histocompatibility complex class II molecules, inducing functional regulatory T cells and contributing to peripheral tolerance.</p><p><strong>Methods: </strong>To investigate this phenomenon in humans, we developed an in vitro system co-culturing human lymph node fibroblasts with autologous CD4+ T cells.</p><p><strong>Results: </strong>Our results reveal that lymph node fibroblasts upregulate human leukocyte antigen-DR (HLA-DR) upon contact with CD4+ T cells and maintain FoxP3+ regulatory T cells. This maintenance is lost upon blockade of HLA-DR or interleukin-2, and regulatory T cells are lost in the absence of lymph node fibroblasts. Furthermore, we demonstrate that lymph node fibroblasts directly isolated from rheumatoid arthritis patients exhibit a significant reduction in the frequency of HLA-DR+ cells compared to those from individuals at risk of developing the disease.</p><p><strong>Conclusion: </strong>These findings highlight a crucial role for HLA-DR-expressing lymph node fibroblasts in maintaining peripheral tolerance within lymph nodes, a function that may be impaired in autoimmunity. Our study provides novel insights into the intricate cellular interactions within human lymph nodes and their potential implications in autoimmune disorders, opening new avenues for understanding and potentially treating these conditions.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The differential immunological impact of photon vs proton radiation therapy in high grade lymphopenia in patients with gastrointestinal tumors.","authors":"James M Heather, Daniel W Kim, Sean M Sepulveda, Emily E van Seventer, Madeleine G Fish, Ryan Corcoran, Theodore S Hong, Mark Cobbold","doi":"10.1093/cei/uxaf040","DOIUrl":"https://doi.org/10.1093/cei/uxaf040","url":null,"abstract":"<p><strong>Background: </strong>Radiation therapy has long been a cornerstone of cancer treatment. More recently, immune checkpoint blockade has also been applied across a variety of cancers, often leading to remarkable response rates. However, photon-based radiotherapy - which accounts for the vast majority - is also known to frequently induce profound lymphopenia, which might limit the efficacy of immune system-based combinations. Proton beam therapy is known to produce a less drastic lymphopenia, which raises the possibility of greater synergy with immunotherapy. In this study we aimed to explore the exact nature of the differential impact of the two radiation modalities upon the immune system.</p><p><strong>Methods: </strong>We used multiparametric flow cytometry and deep sequencing of rearranged TCRb loci to investigate a cohort of 20 patients with gastrointestinal tumors who received either therapy and developed lymphopenia.</p><p><strong>Results: </strong>Proton-treated patients remained relatively stable throughout treatment by most metrics considered, whereas those who received photons saw a profound depletion in naïve T cells, increase in effector/memory populations, and loss of TCR diversity. The repertoires of photon-treated patients underwent oligoclonal expansion after their lymphocyte count nadirs, particularly of CD8+ Temra cells, driving this reduction in diversity. Across the entire cohort, this reduction in post-nadir diversity inversely correlated with the overall survival time of those patients who died.</p><p><strong>Conclusion: </strong>This raises the possibility that increased adoption of proton-based or other lymphocyte sparing radiotherapy regimes may lead to better survival in cancer patients.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engaging PD-1 rescues regulatory T cell function and inhibits inflammatory T cells in rheumatoid arthritis.","authors":"Kaustav Chowdhury, Uma Kumar, Jaydeep Chaudhuri, Prabin Kumar, Soumabha Das, Maumita Kanjilal, Parasar Ghosh, Ravi Kiran Basyal, Uma Kanga, Santu Bandyopadhaya, Dipendra Kumar Mitra","doi":"10.1093/cei/uxaf035","DOIUrl":"https://doi.org/10.1093/cei/uxaf035","url":null,"abstract":"<p><strong>Background: </strong>Despite their synovial enrichment Regulatory T cells (Treg) fail to alleviate the joint inflammation in rheumatoid arthritis (RA). This indicates their functional impairment in the synovial milieu of RA patients.</p><p><strong>Results: </strong>Here, we demonstrate that deficit in PD-1 pathway incapacitates the synovial Treg cells and engaging PD-1 restores their suppressive function (IL-10, TGF-β secretion) which in turn suppressed the synovial inflammatory T cells (IFN-γ+, IL-17+ TNF-α+). We also showed deficit in programmed death ligand-1 (PD-L1) expression on RA synovial macrophages contributes to impaired Treg cell function.</p><p><strong>Conclusion: </strong>Rejuvenating synovial Treg cell function via PD-1 engagement may be a potential strategy to ameliorate the synovial inflammation in RA patients.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic Granulomatous disease: Lessons in Cell Biology From Monogenic Immunodeficiency.","authors":"Paige M Mortimer, Shuli Svetitsky, David C Thomas","doi":"10.1093/cei/uxaf031","DOIUrl":"https://doi.org/10.1093/cei/uxaf031","url":null,"abstract":"<p><p>Reactive oxygen species (ROS) are produced in immune cells by the phagocyte NADPH oxidase (NOX2) system that carries out coordinated transfer of electrons to molecular oxygen. The importance of the system in host defence and immunoregulation is underlined by chronic granulomatous disease (CGD), a severe monogenic immunodeficiency caused by mutations in genes encoding individual components of NOX2. CGD also leads to inflammatory manifestations due to the regulatory role of ROS in multiple signalling processes. We describe the system in detail, from its discovery to our current understanding of the oxidase. We also describe CGD and illustrate how recent insights into this disease shed light on physiology.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of IgA and IgG in Mycobacterium tuberculosis infection: A cross-sectional study in Ethiopia.","authors":"Rubiyat E Islam, Meaza Zewdie, Daniel Mussa, Yonas Abebe, Tom H M Ottenhoff, Kees L M C Franken, Fekadu Abebe, Liya Wassie","doi":"10.1093/cei/uxaf001","DOIUrl":"https://doi.org/10.1093/cei/uxaf001","url":null,"abstract":"<p><strong>Introduction: </strong>Despite the high global prevalence of Mycobacterium tuberculosis (Mtb) infection in humans, most infected individuals achieve a stable immunological equilibrium, without showing clinical signs and symptoms of tuberculosis (TB). Although the role of antibodies in TB is assumed to be relatively small compared to cell-mediated immunity, their role in TB has been documented in a few recent studies.</p><p><strong>Methods: </strong>In this cross-sectional study, we quantitated antibody responses to Mtb antigens, lipoarabinomannan (LAM), and heparin-binding hemagglutinin adhesin (HBHA) by determining antigen-specific immunoglobulin A(IgA) and G(IgG) secretion levels using enzyme-linked immunosorbent assay (ELISA) in serum and saliva of pulmonary TB patients (PTB), their household contacts (HHC), and community controls (CC) (determined by QuantiFERON TB Gold assay QFT- test result).</p><p><strong>Results: </strong>The HBHA-specific IgA levels were significantly higher in both saliva and serum in HHC groups compared to PTB patients (P=0.013, P=0.023). Exposed contacts, who were QFT-negative had higher serum HBHA-specific IgA responses compared to PTB patients (P=0.04). QFT-negative HHC and QFT-positive CC showed higher HBHA and LAM-specific IgG responses (P=0.006, P=0.002, P=0.0009, P=0.006, respectively) than PTB patients. Generally, LAM and HBHA-specific IgA levels were significantly higher in saliva compared to serum (P<0.0001) in all study groups.</p><p><strong>Conclusion: </strong>Overall, the observed higher levels of IgA and IgG in controls, and exposed but QFT-negative contacts suggest a correlation with, and perhaps a role for these antibodies in preventing the development of active TB. The findings highlighted the potential involvement of saliva IgA in the immune response to Mtb, underscoring the relevance of mucosal immunity in TB infection.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of Concern: Therapeutic effect of farnesylthiosalicylic acid on adjuvant-induced arthritis through suppressed release of inflammatory cytokines.","authors":"","doi":"10.1093/cei/uxae111","DOIUrl":"10.1093/cei/uxae111","url":null,"abstract":"","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic analysis reveals dysregulation of peripheral blood neutrophils in patients with Multiple Sclerosis.","authors":"Katie J Smith, Zachary Lim, Sonja Vermeren, Veronique E Miron, Sarah Dimeloe, Donald J Davidson, Anna Williams, Emily Gwyer Findlay","doi":"10.1093/cei/uxae115","DOIUrl":"10.1093/cei/uxae115","url":null,"abstract":"<p><p>Multiple Sclerosis (MS) is a complex auto-inflammatory disease affecting the brain and spinal cord, which results in axonal de-myelination and symptoms including fatigue, pain, and difficulties with vision and mobility. The involvement of the immune system in the pathology of MS is well established, particularly the adaptive T cell response, and there has been a particular focus on the IL-17-producing subset of Th17 cells and their role in driving disease. However, the importance of innate immune cells has not been so well characterized. Here we focussed on neutrophils, which are innate immune cells and rapid responders to inflammation, and which have recently been linked to other chronic autoimmune conditions. Multiple strands of evidence in patients with MS and in mice with the experimental autoimmune encephalomyelitis MS model suggest neutrophils may play a role in driving MS inflammation. Here, we performed proteomic analysis on neutrophils from patients with MS and healthy donors, revealing striking differences. In particular, granule proteins were significantly more abundant in the MS neutrophils compared to the healthy controls, with a particular overabundance of proteins in primary and secondary granules. In addition, members of the MAVS signalling pathway were differently regulated compared to healthy donor cells. Finally, we find that MS neutrophils do not suppress T cell activation equivalently to healthy neutrophils, and in particular are unable to suppress expression of CD161 on the T cells, indicative of a suppression of Th17 differentiation. We propose that neutrophil dysregulation in MS may contribute to dysfunctional T cell responses.</p>","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12124191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}