Stefano A P Colombo, Sara Gago, Mathilde Chamula, Robert Lord, Andrew S MacDonald, Chris Kosmidis
{"title":"Dendritic cell dysfunction, including impaired IL-12 production, is associated with chronic pulmonary aspergillosis.","authors":"Stefano A P Colombo, Sara Gago, Mathilde Chamula, Robert Lord, Andrew S MacDonald, Chris Kosmidis","doi":"10.1093/cei/uxaf038","DOIUrl":"10.1093/cei/uxaf038","url":null,"abstract":"<p><strong>Background: </strong>Growing evidence links immune dysfunction, notably impaired IFNγ production, to chronic pulmonary aspergillosis (CPA), but understanding of the immune phenotype in CPA patients remains limited.</p><p><strong>Methods: </strong>To investigate this, we recruited 25 CPA patients and 25 controls with bronchiectasis, isolating immune cells from peripheral blood for detailed flow cytometric phenotyping at resting state and after ex vivo stimulation with the TLR2/Dectin-1 agonist Zymosan.</p><p><strong>Results: </strong>CPA patients exhibited pronounced neutrophilia and a reduced frequency of conventional dendritic cell (DC) subsets at baseline compared to bronchiectasis controls. Post-stimulation, DC and monocyte subsets in CPA patients showed significantly lower expression of activation markers. Notably, cDC1s displayed reduced IL-12p40, TNFα, and CD86 expression. CPA patients with a history of tuberculosis (TB) had significantly higher frequencies of activated cDC1s. Machine learning analysis validated these immunological parameters as predictive of CPA status.</p><p><strong>Conclusion: </strong>Our findings suggest that immune dysfunction in CPA involves DC and monocyte impairments, potentially contributing to IFNγ deficiency through reduced IL-12 production and co-stimulatory capacity in cDC1s. These results also hint at the presence of innate immune memory in CPA patients with prior TB. Our study advances understanding of the immune dysfunction underlying CPA.</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/PMC12231563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274296","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}
Diana C Yanez, Jasmine Rowell, Maximillian Woodall, Stuart Adams, Lauran O'Neill, Konstantinos Mengrelis, Ching-In Lau, Susan Ross, Sarah Benkenstein, Kate Plant, Claire M Smith, Benny Chain, Mark J Peters, Tessa Crompton
{"title":"Distinctive T-cell receptor repertoire in paediatric inflammatory multisystem syndrome temporally associated with coronavirus disease 2019/multisystem inflammatory syndrome in children patients: possible thymus involvement.","authors":"Diana C Yanez, Jasmine Rowell, Maximillian Woodall, Stuart Adams, Lauran O'Neill, Konstantinos Mengrelis, Ching-In Lau, Susan Ross, Sarah Benkenstein, Kate Plant, Claire M Smith, Benny Chain, Mark J Peters, Tessa Crompton","doi":"10.1093/cei/uxaf027","DOIUrl":"10.1093/cei/uxaf027","url":null,"abstract":"<p><p>During the coronavirus disease 2019 (COVID-19) pandemic a rare new paediatric inflammatory condition (paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS)/MIS-C) was identified which correlated with previous or recent SARS-CoV-2 infection. PIMS-TS led to severe multiorgan inflammation, suggestive of disruption of central tolerance and thymus function. Here we investigated the possible role of the thymus in paediatric PIMS-TS. We confirmed that human thymus explants can be infected with SARS-CoV-2 in vitro. Comparison of T-cell populations in blood from PIMS-TS patients and age-matched healthy control children showed that although the overall proportions of CD4 and CD8 T-cell populations were decreased in PIMS-TS patients, the proportion of naïve cells in the CD4 population was higher in the PIMS-TS group. In PIMS-TS patients, the number of TREC in Peripheral blood mononuclear cells (PBMC) correlated strongly with the proportion of naïve CD4 and CD8 T cells, whereas this correlation was not present in healthy children. Sequencing rearranged TCRβ and TCRɑ transcripts from FACS-sorted CD4+CD8-CD3+ and CD4-CD8+CD3+ from blood from PIMS-TS, healthy children, and additionally paediatric severe COVID-19 patients showed that while all three groups showed similar diversity and distribution, the repertoire of the PIMS-TS and COVID-19 groups had distinctive patterns of TCR gene segment usage and VJ combinatorial usage compared to healthy controls (TRBV11-2 × TRBJ2-7, TRBV11-2 × TRBJ1-1, TRBV11-2 × TRBJ2-5, TRBV11-2 × TRBJ2-1; TRBV29-1 × TRBJ2-7, TRBV29-1 × TRBJ1-1 enriched in PIMS-TS; TRBV7-9 × TRBJ1-2, TRAV9-2 × TRAJ30, and TRAV26-1 × TRAJ39 enriched in COVID-19). The non-productive TCR rearrangements in the PIMS-TS group were also enriched for TRBV11-2, and showed bias towards distal (5'TRAV to 3'TRAJ) TCRɑ gene segment usage, suggesting involvement of the thymus in PIMS-TS.</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/PMC12202041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975540","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}
Cansu Özdemiral, Ismail Yaz, Saliha Esenboga, Nadira Nabiyeva Cevik, Hacer Neslihan Bildik, Mehmet Kilic, Ilhan Tezcan, Deniz Cagdas
{"title":"Human FCHO1 deficiency: review of the literature and additional two cases.","authors":"Cansu Özdemiral, Ismail Yaz, Saliha Esenboga, Nadira Nabiyeva Cevik, Hacer Neslihan Bildik, Mehmet Kilic, Ilhan Tezcan, Deniz Cagdas","doi":"10.1093/cei/uxae097","DOIUrl":"10.1093/cei/uxae097","url":null,"abstract":"<p><p>F-BAR domain only protein 1 (FCHO1) contributes as a critical component to an essential cellular process, clathrin-mediated endocytosis. Clathrin-mediated endocytosis involves cellular membrane invagination followed by cargo protein recruitment and adaptor protein assembly to form endocytic vesicles and maintains several cellular functions, such as signaling, differentiation, nutrition, absorption, and secretion. We aimed to determine the clinical/immunological findings of FCHO1 deficiency to generate an appropriate medical approach. We present clinical/immunological/genetic findings of two FCHO1 deficiency patients together with recently reported 17 patients. We found two different variants in the patients, one previously defined and one novel homozygous mutation [c.306C > A (p.Tyr102Ter)]. Recurrent sinopulmonary infections occurred in all patients, with viral (63.1%) and fungal (52.6%) infections frequently reported. Lymphopenia and CD4 + T cell lymphopenia are present in 77.7% (14/18) and 100% of patients, respectively. CD8+ T cell number is low in half. Hypogammaglobulinemia and low IgM are present in 83.3% (15/18) and 61.1% (11/18) of patients, respectively. Neurological disorders (Guillian-Barre Syndrome, Moya-Moya disease, encephalitis, and cranial infarction) are common [n = 6 (31.5%)]. Malignancy is present in four (21%) patients, three suffered from diffuse large B cell lymphoma, and one developed Hodgkin lymphoma. Additional clinical and laboratory results from more patients helped to define the characteristics of FCHO1 deficiency. The early application of molecular genetic analysis in CID patients is crucial. Since all transplanted patients were alive, allogeneic hematopoietic stem cell transplantation emerged as a potential curative therapy.</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/PMC11773606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575493","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":"A study of changes in hematologic parameters in patients with migraine.","authors":"Jiaonan Wu, Lulan Fu, Ziru Deng, Hanli Li, Linyan Zhong, Rupan Gao, Wei Gui","doi":"10.1093/cei/uxae113","DOIUrl":"10.1093/cei/uxae113","url":null,"abstract":"<p><strong>Introduction: </strong>To evaluate the characteristics of hematological parameters and peripheral inflammatory markers (PIMs) in migraine, including chronic migraine (CM) and episodic migraine (EM), and to explore their underlying mechanisms.</p><p><strong>Method: </strong>A total of 88 subjects were enrolled, 58 with migraine (28 with CM and 30 with EM) and 30 healthy controls. All subjects were matched for age, gender, and body mass index, and peripheral blood was collected. Hematological parameters and PIMs were compared between migraineurs and healthy controls. The patients underwent hematological laboratory testing and calculated the PIMs. PIMs included neutrophil/lymphocyte ratio, lymphocyte/monocyte ratio (LMR), neutrophil/monocyte ratio, platelet/lymphocyte ratio, and platelet/monocyte ratio (PMR) ratio.</p><p><strong>Result: </strong>Monocyte counts in migraine patients were significantly lower compared with healthy controls, while LMR and PMR were significantly higher. Statistically significant differences were observed in monocyte counts, LMR, and PMR among the three groups of CM, EM, and HC patients. Post hoc Bonferroni t-test showed that monocyte counts were significantly lower in the EM group compared with the HC group, while LMR and PMR were significantly higher. Comparison between the EM and CM groups showed that LMR was significantly higher in the EM group. Differences in monocyte counts, LMR, and PMR between the CM and HC groups were not statistically significant. Receiver operating characteristic curve analysis indicated that the area under the curve (AUC) for the diagnosing migraine using the combination of Mon, LMR, and PMR was 0.707, and the AUC for the diagnosis of EM was 0.758. The AUC value of PMR for diagnosing CM was 0.669, while the AUC for the combination of LMR and platelet/lymphocyte ratio in distinguishing CM and EM was 0.705.</p><p><strong>Conclusion: </strong>Our findings indicate that migraine and its subtypes exhibit abnormalities in monocyte counts and PIMs, which possess diagnostic predictive value for differentiating migraine and its subtypes. This suggests that systemic inflammation may play a role in the pathogenesis of migraine.</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/PMC11773810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806239","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":"How do large-scale population studies inform vaccine evaluations in England?","authors":"Freja C M Kirsebom, Victoria Hall, Julia Stowe","doi":"10.1093/cei/uxaf006","DOIUrl":"10.1093/cei/uxaf006","url":null,"abstract":"<p><p>Large-scale population studies are important to monitor and evaluate aspects of a vaccination programme including vaccine coverage, real-world effectiveness, and post-licensure vaccine safety. These types of epidemiological studies often come under the remit of public health agencies, such as the UK Health Security Agency (UKHSA) in England, which are required to undertake surveillance of vaccine-preventable diseases, including via seroepidemiological studies and data linkage studies using national-level electronic healthcare data. An individual-level national vaccine register with an accurate denominator can be the key to gaining insights into vaccine coverage, effectiveness, and safety. During the coronavirus disease 2019 pandemic, England's first vaccine register was developed. This enabled timely estimates of real-world vaccine effectiveness in the whole population of England, as well as enabling epidemiological investigations of rare potential risks from vaccines in specific populations. Population-based research studies, including prospective cohort studies, are complementary to surveillance and combined, enable more comprehensive assessments. As there was an unprecedented investment into research studies and infrastructure during the pandemic, the scale of these studies meant they were able to contribute to vaccine programme evaluations in a way that had not been possible for previous vaccine programmes. In this review, we summarise the different large-scale surveillance and research studies that have been used to evaluate and inform vaccine policy from the time of the first data linkage studies undertaken in England in the 1990s to the present-day post-COVID-19 pandemic.</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/PMC11933692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254978","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}
Muhammad Sohaib Khan, Bismah Azeem, Ashir Kanwal, Ifra Eeman Ahmed, Anum Zehra, Aqsa Kabir, Waleed Ahmed, Hania Nasir, Momina Khan, Aatika Manzoor, Muhammad Hasanain, Wania Moeen, Muzamil Khan, Gulrayz Ahmed
{"title":"Unveiling WHIM syndrome: Mavorixafor's emerging role in immune restoration and therapy.","authors":"Muhammad Sohaib Khan, Bismah Azeem, Ashir Kanwal, Ifra Eeman Ahmed, Anum Zehra, Aqsa Kabir, Waleed Ahmed, Hania Nasir, Momina Khan, Aatika Manzoor, Muhammad Hasanain, Wania Moeen, Muzamil Khan, Gulrayz Ahmed","doi":"10.1093/cei/uxaf014","DOIUrl":"10.1093/cei/uxaf014","url":null,"abstract":"<p><p>WHIM syndrome is a rare autosomal dominant immunodeficiency disorder and is an abbreviation formed from the initial letters of its main clinical presentations: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. It stems mainly from mutations where there is a gain of function in the chemokine receptor CXCR4, which is extensively located on leukocytes and significantly affects the balance of the immune system. Many therapeutic strategies have been widely explored for several years for this immunodeficiency disorder. Mavorixafor, a CXCR4 antagonist, is a recently approved drug by the Food and Drug Administration (FDA) that is being studied for its longer half-life and oral drug route against WHIM syndrome. This review aims to investigate briefly the underlying mechanisms and pathogenesis of WHIM syndrome, and the current effective treatment approaches, for example CXCR4 antagonists or Hematopoietic Stem Cell Transplantation (HSCT), against it. The review also aims to thoroughly assess the efficacy and safety of Mavorixafor in managing WHIM syndrome, exploring its pharmacokinetics, pharmacodynamics, dosing regimens, and safety. Finally, we also investigate important additional therapeutic uses of Mavorixafor.</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/PMC12001236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596428","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}
Qiyan Su, Yingyue Feng, Jin Guo, Xi Cui, Jiarui Zhu, Jumei Yang, Sigong Zhang
{"title":"Pirfenidone alleviates interstitial lung disease in mice by inhibiting neutrophil extracellular trap formation and NLRP3 inflammasome activation.","authors":"Qiyan Su, Yingyue Feng, Jin Guo, Xi Cui, Jiarui Zhu, Jumei Yang, Sigong Zhang","doi":"10.1093/cei/uxaf019","DOIUrl":"10.1093/cei/uxaf019","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic inflammatory myopathy (IIM) is a progressive autoimmune disease characterized by interstitial lung disease (ILD) with limited therapeutics available. Pirfenidone (PFD), a medication utilized for the treatment of idiopathic pulmonary fibrosis, exhibits notable antioxidant, anti-inflammatory, and inhibition of collagen synthesis. This study aims to clarify its efficacy and mechanism in treating IIM-ILD.</p><p><strong>Methods: </strong>A murine myositis-associated interstitial lung disease (MAILD) model was used to assess the therapeutic effect of PFD. The serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). Pirfenidone was utilized to disrupt neutrophil extracellular traps (NETs) formation in vitro, and its inhibitory effect on NETs was assessed through immunohistochemistry of citrullinated histone H3 and myeloperoxidase in the lung tissue and the serum cfDNA level in mice. Immunohistochemical and western blot were utilized to examine alterations in epithelial-mesenchymal transition (EMT) and NOD-like receptor protein 3 (NLRP3) inflammasome markers.</p><p><strong>Results: </strong>Pirfenidone treatment inhibited pulmonary inflammation and fibrosis in the MAILD model. Pirfenidone intervention reduced NETs formation in vitro. Pirfenidone treatment significantly reduces NETs infiltration in the lung tissue and the level of cfDNA in the serum of mice. Additionally, PFD downregulated EMT and NLRP3-related proteins in vivo. Pirfenidone treatment also notably reduced serum levels of IL-1β, IL-6, and TNF-α. After NETs stimulation, A549 cells exhibited EMT and activation of NLRP3 inflammasome. Pirfenidone attenuated EMT in A549 cells and suppressed the activation of NLRP3 inflammasome.</p><p><strong>Conclusion: </strong>Pirfenidone alleviates ILD in a murine MAILD model by inhibiting NETs formation and NLRP3 inflammasome activation, suggesting that PFD might be a potential therapeutic agent for IIM-ILD.</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/PMC12038160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673436","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}
James M Heather, Daniel W Kim, Sean M Sepulveda, Emily E van Seventer, Madeleine G Fish, Ryan Corcoran, Theodore S Hong, Mark Cobbold
{"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":"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, an increase in effector/memory populations, and a loss of TCR diversity. The repertoires of photon-treated patients underwent an 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 is 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":3.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342742/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
{"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":"10.1093/cei/uxaf048","url":null,"abstract":"<p><p>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. Here, we describe a novel TNFAIP3 variant in a Dutch family, predominantly presenting with polyautoimmunity rather than autoinflammatory manifestations. We evaluated two patients from a Dutch family with autoimmune symptoms. Whole-exome sequencing (WES) identified a heterozygous c.608T>G (p.Leu203Arg) missense variant in TNFAIP3, located within the OTU domain. Functional analyses included immunoblotting of peripheral blood mononuclear cells (PBMCs) and an overexpression model using transfected HEK293T cells. A20 protein expression was evaluated, while phosphoflow cytometry assessed phosphorylation of key signaling molecules in the NF-κB, STAT and mTOR pathways. Inflammatory cytokine production was measured in cell culture supernatants. Overexpression of this missense A20 variant in HEK293T enhanced NF-κB signaling, reflected by increased TRAF6 expression and IκBα phosphorylation. Patient-derived PBMCs demonstrated reduced A20 expression, increased phosphorylation within the NF-κB, STAT1, and mTOR pathways, and elevated production of pro-inflammatory cytokines. These molecular alterations suggest disrupted immune regulation contributing to the observed autoimmune phenotype. The identification of this 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":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12457938/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matteo Marconi, Gloria Riitano, Alessandra Daphne Fisher, Carlotta Cocchetti, Maria Teresa Pagano, Antonella Capozzi, Agostina Longo, Sara D'Arienzo, Linda Vignozzi, Maurizio Sorice, Elena Ortona, Marina Pierdominici
{"title":"Gender-affirming hormone therapy and autoimmunity: new insights from a 3-year follow-up study.","authors":"Matteo Marconi, Gloria Riitano, Alessandra Daphne Fisher, Carlotta Cocchetti, Maria Teresa Pagano, Antonella Capozzi, Agostina Longo, Sara D'Arienzo, Linda Vignozzi, Maurizio Sorice, Elena Ortona, Marina Pierdominici","doi":"10.1093/cei/uxad122","DOIUrl":"10.1093/cei/uxad122","url":null,"abstract":"","PeriodicalId":10268,"journal":{"name":"Clinical and experimental immunology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92153021","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}