Pub Date : 2024-05-31DOI: 10.1016/j.clim.2024.110267
Pedro Martínez-Fleta , María Celeste Marcos , Daniel Jimenez-Carretero , José María Galván-Román , Rosa María Girón-Moreno , Ana Adela Calero-García , Ana Arcos-García , Enrique Martín-Gayo , Hortensia de la Fuente , Laura Esparcia-Pinedo , Javier Aspa , Julio Ancochea , Arantzazu Alfranca , Francisco Sánchez-Madrid
Long-COVID (LC) is characterised by persistent symptoms for at least 3 months after acute infection. A dysregulation of the immune system and a persistent hyperinflammatory state may cause LC. LC patients present differences in activation and exhaustion states of innate and adaptive compartments. Different T CD4+ cell subsets can be identified by differential expression of chemokine receptors (CCR). However, changes in T cells with expression of CCRs such as CCR6 and CXCR3 and their relationship with CD8+ T cells remains unexplored in LC. Here, we performed unsupervised analysis and found CCR6+ CD4+ subpopulations enriched in COVID-19 convalescent individuals upon activation with SARS-CoV-2 peptides. SARS-CoV-2 specific CCR6+ CD4+ are decreased in LC patients, whereas CXCR3+ CCR6- and CCR4+ CCR6- CD4+ T cells are increased. LC patients showed lower IFN-γ-secreting CD8+ T cells after stimulation with SARS-CoV-2 Spike protein. This work underscores the role of CCR6 in the pathophysiology of LC.
{"title":"Imbalance of SARS-CoV-2-specific CCR6+ and CXCR3+ CD4+ T cells and IFN-γ + CD8+ T cells in patients with Long-COVID","authors":"Pedro Martínez-Fleta , María Celeste Marcos , Daniel Jimenez-Carretero , José María Galván-Román , Rosa María Girón-Moreno , Ana Adela Calero-García , Ana Arcos-García , Enrique Martín-Gayo , Hortensia de la Fuente , Laura Esparcia-Pinedo , Javier Aspa , Julio Ancochea , Arantzazu Alfranca , Francisco Sánchez-Madrid","doi":"10.1016/j.clim.2024.110267","DOIUrl":"10.1016/j.clim.2024.110267","url":null,"abstract":"<div><p>Long-COVID (LC) is characterised by persistent symptoms for at least 3 months after acute infection. A dysregulation of the immune system and a persistent hyperinflammatory state may cause LC. LC patients present differences in activation and exhaustion states of innate and adaptive compartments. Different T CD4<sup>+</sup> cell subsets can be identified by differential expression of chemokine receptors (CCR). However, changes in T cells with expression of CCRs such as CCR6 and CXCR3 and their relationship with CD8<sup>+</sup> T cells remains unexplored in LC. Here, we performed unsupervised analysis and found CCR6<sup>+</sup> CD4<sup>+</sup> subpopulations enriched in COVID-19 convalescent individuals upon activation with SARS-CoV-2 peptides. SARS-CoV-2 specific CCR6<sup>+</sup> CD4<sup>+</sup> are decreased in LC patients, whereas CXCR3<sup>+</sup> CCR6<sup>-</sup> and CCR4<sup>+</sup> CCR6<sup>-</sup> CD4<sup>+</sup> T cells are increased. LC patients showed lower IFN-γ-secreting CD8<sup>+</sup> T cells after stimulation with SARS-CoV-2 Spike protein. This work underscores the role of CCR6 in the pathophysiology of LC.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199517","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}
Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease that primarily affects the joints and surrounding soft tissues, characterized by chronic inflammation and proliferation of the synovium. Various immune cells are involved in the pathophysiology of RA. The complex interplay of factors such as chronic inflammation, genetic susceptibility, dysregulation of serum antibody levels, among others, contribute to the complexity of the disease mechanism, disease activity, and treatment of RA. Recently, the cytokine storm leading to increased disease activity in RA has gained significant attention. Interleukin-33 (IL-33), a member of the IL-1 family, plays a crucial role in inflammation and immune regulation. ST2 (suppression of tumorigenicity 2 receptor), the receptor for IL-33, is widely expressed on the surface of various immune cells. When IL-33 binds to its receptor ST2, it activates downstream signaling pathways to exert immunoregulatory effects. In RA, IL-33 regulates the progression of the disease by modulating immune cells such as circulating monocytes, tissue-resident macrophages, synovial fibroblasts, mast cells, dendritic cells, neutrophils, T cells, B cells, endothelial cells, and others. We have summarized and analyzed these findings to elucidate the pathways through which IL-33 regulates RA. Furthermore, IL-33 has been detected in the synovium, serum, and synovial fluid of RA patients. Due to inconsistent research results, we conducted a meta-analysis on the association between serum IL-33, synovial fluid IL-33, and the risk of developing RA in patients. The pooled SMD was 1.29 (95% CI: 1.15–1.44), indicating that IL-33 promotes the onset and pathophysiological progression of RA. Therefore, IL-33 may serve as a biomarker for predicting the risk of developing RA and treatment outcomes. As existing drugs for RA still cannot address drug resistance in some patients, new therapeutic approaches are needed to alleviate the significant burden on RA patients and healthcare systems. In light of this, we analyzed the potential of targeting the IL-33/ST2-related signaling pathway to modulate immune cells associated with RA and alleviate inflammation. We also reviewed IL-33 and RA susceptibility-related single nucleotide polymorphisms, suggesting potential involvement of IL-33 and macrophage-related drug-resistant genes in RA resistance therapy. Our review elucidates the role of IL-33 in the pathophysiology of RA, offering new insights for the treatment of RA.
类风湿性关节炎(RA)是一种全身性慢性自身免疫性疾病,主要影响关节和周围软组织,以滑膜的慢性炎症和增生为特征。各种免疫细胞参与了 RA 的病理生理学过程。慢性炎症、遗传易感性、血清抗体水平失调等因素的复杂相互作用,导致了 RA 的发病机制、疾病活动和治疗的复杂性。最近,导致 RA 疾病活动性增加的细胞因子风暴引起了广泛关注。白细胞介素-33(IL-33)是 IL-1 家族的成员之一,在炎症和免疫调节中发挥着至关重要的作用。IL-33的受体ST2(抑制肿瘤生成2受体)广泛表达于各种免疫细胞表面。当 IL-33 与其受体 ST2 结合时,会激活下游信号通路,从而发挥免疫调节作用。在 RA 中,IL-33 通过调节循环单核细胞、组织驻留巨噬细胞、滑膜成纤维细胞、肥大细胞、树突状细胞、中性粒细胞、T 细胞、B 细胞、内皮细胞等免疫细胞来调节疾病的进展。我们对这些发现进行了总结和分析,以阐明IL-33调节RA的途径。此外,在 RA 患者的滑膜、血清和滑液中也检测到了 IL-33。由于研究结果不一致,我们对血清IL-33、滑膜液IL-33与患者罹患RA风险之间的关系进行了荟萃分析。汇总的SMD为1.29(95% CI:1.15-1.44),表明IL-33会促进RA的发病和病理生理进展。因此,IL-33 可作为预测 RA 发病风险和治疗效果的生物标志物。由于现有的 RA 药物仍无法解决部分患者的耐药性问题,因此需要新的治疗方法来减轻 RA 患者和医疗系统的沉重负担。有鉴于此,我们分析了靶向 IL-33/ST2 相关信号通路以调节与 RA 相关的免疫细胞并缓解炎症的潜力。我们还回顾了IL-33和RA易感性相关的单核苷酸多态性,表明IL-33和巨噬细胞相关耐药基因可能参与RA耐药治疗。我们的综述阐明了IL-33在RA病理生理学中的作用,为RA的治疗提供了新的见解。
{"title":"The immunomodulatory of interleukin-33 in rheumatoid arthritis: A systematic review","authors":"Renli Liu, Fangfang Wang, Xing Luo, Fengfan Yang, Jie Gao, Haomiao Shen, Zhaohui Zheng","doi":"10.1016/j.clim.2024.110264","DOIUrl":"10.1016/j.clim.2024.110264","url":null,"abstract":"<div><p>Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease that primarily affects the joints and surrounding soft tissues, characterized by chronic inflammation and proliferation of the synovium. Various immune cells are involved in the pathophysiology of RA. The complex interplay of factors such as chronic inflammation, genetic susceptibility, dysregulation of serum antibody levels, among others, contribute to the complexity of the disease mechanism, disease activity, and treatment of RA. Recently, the cytokine storm leading to increased disease activity in RA has gained significant attention. Interleukin-33 (IL-33), a member of the IL-1 family, plays a crucial role in inflammation and immune regulation. ST2 (suppression of tumorigenicity 2 receptor), the receptor for IL-33, is widely expressed on the surface of various immune cells. When IL-33 binds to its receptor ST2, it activates downstream signaling pathways to exert immunoregulatory effects. In RA, IL-33 regulates the progression of the disease by modulating immune cells such as circulating monocytes, tissue-resident macrophages, synovial fibroblasts, mast cells, dendritic cells, neutrophils, T cells, B cells, endothelial cells, and others. We have summarized and analyzed these findings to elucidate the pathways through which IL-33 regulates RA. Furthermore, IL-33 has been detected in the synovium, serum, and synovial fluid of RA patients. Due to inconsistent research results, we conducted a meta-analysis on the association between serum IL-33, synovial fluid IL-33, and the risk of developing RA in patients. The pooled SMD was 1.29 (95% CI: 1.15–1.44), indicating that IL-33 promotes the onset and pathophysiological progression of RA. Therefore, IL-33 may serve as a biomarker for predicting the risk of developing RA and treatment outcomes. As existing drugs for RA still cannot address drug resistance in some patients, new therapeutic approaches are needed to alleviate the significant burden on RA patients and healthcare systems. In light of this, we analyzed the potential of targeting the IL-33/ST2-related signaling pathway to modulate immune cells associated with RA and alleviate inflammation. We also reviewed IL-33 and RA susceptibility-related single nucleotide polymorphisms, suggesting potential involvement of IL-33 and macrophage-related drug-resistant genes in RA resistance therapy. Our review elucidates the role of IL-33 in the pathophysiology of RA, offering new insights for the treatment of RA.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199519","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}
Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population.
Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.
{"title":"Allergic bronchopulmonary aspergillosis in a lung transplant recipient treated with mepolizumab","authors":"Foteini Ioakeim , Christophe Abellan , Alessio Casutt , Benoit Lechartier , Leslie Noirez , Catherine Beigelman-Aubry , John-David Aubert , Zisis Balmpouzis , Angela Koutsokera","doi":"10.1016/j.clim.2024.110265","DOIUrl":"10.1016/j.clim.2024.110265","url":null,"abstract":"<div><p>Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to <em>Aspergillus</em> spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population.</p><p>Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157536","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}
Pub Date : 2024-05-23DOI: 10.1016/j.clim.2024.110263
Salem Al-Tamemi , Abdulhakim Al-Rawas , Murtadha Al-Khabori , Khalil Al-Farsi , Mohammed Al-Huneini , Amr Abdalla , Salam Al-Kindi , David Dennison
Background
Hematopoietic stem cell transplantation (HSCT) is a curative treatment for certain inborn errors of immunity.
Methods
A 17-year retrospective cohort study was conducted on 40 immunodeficient patients who underwent HSCT.
Results
The median age at transplant was 11.0 months (4.6–61.0). Donors were primarily matched sibling donors (60%). 90% and 85% of patients received conditioning and graft-versus-host disease (GVHD) prophylaxis, respectively. The mean donor chimerism at the last follow-up was 88.6% ± 17.9% (40–100). Median serum immunoglobulin (Ig) G level, CD4+ T-cell count, and CD19+ B-cell count were 11.7 g/L (9.2–13.6), 0.9 × 109/L 0.6–1.2), and 0.5 × 109/L (0.2–0.7), respectively. 29 patients (72.5%) received intravenous immunoglobulins (IVIG) therapy, with a median duration of 10.0 months (4.0–14.0). The median post-transplant follow-up was 6.5 years (IQR:1.4–11.5). The 10-year overall probability of survival is 84.3%.
Conclusion
Monitoring IRC is important in ensuring adequate disease-free survival.
{"title":"Immune reconstitution and survival, following hematopoietic stem cell transplantation in Omani patients with inborn errors of immunity","authors":"Salem Al-Tamemi , Abdulhakim Al-Rawas , Murtadha Al-Khabori , Khalil Al-Farsi , Mohammed Al-Huneini , Amr Abdalla , Salam Al-Kindi , David Dennison","doi":"10.1016/j.clim.2024.110263","DOIUrl":"10.1016/j.clim.2024.110263","url":null,"abstract":"<div><h3>Background</h3><p>Hematopoietic stem cell transplantation (HSCT) is a curative treatment for certain inborn errors of immunity.</p></div><div><h3>Methods</h3><p>A 17-year retrospective cohort study was conducted on 40 immunodeficient patients who underwent HSCT.</p></div><div><h3>Results</h3><p>The median age at transplant was 11.0 months (4.6–61.0). Donors were primarily matched sibling donors (60%). 90% and 85% of patients received conditioning and graft-versus-host disease (GVHD) prophylaxis, respectively. The mean donor chimerism at the last follow-up was 88.6% ± 17.9% (40–100). Median serum immunoglobulin (Ig) G level, CD4+ T-cell count, and CD19+ B-cell count were 11.7 g/L (9.2–13.6), 0.9 × 10<sup>9</sup>/L 0.6–1.2), and 0.5 × 10<sup>9</sup>/L (0.2–0.7), respectively. 29 patients (72.5%) received intravenous immunoglobulins (IVIG) therapy, with a median duration of 10.0 months (4.0–14.0). The median post-transplant follow-up was 6.5 years (IQR:1.4–11.5). The 10-year overall probability of survival is 84.3%.</p></div><div><h3>Conclusion</h3><p>Monitoring IRC is important in ensuring adequate disease-free survival.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141141525","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}
Pub Date : 2024-05-23DOI: 10.1016/j.clim.2024.110262
Sahla El Mahdaoui , Marie Mathilde Hansen , Malene Bredahl Hansen , Victoria Hyslop Hvalkof , Helle Bach Søndergaard , Mie Reith Mahler , Jeppe Romme Christensen , Finn Sellebjerg , Marina Rode von Essen
Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25− Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25− Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1+ Tfh cells and CD25− Tfh cells, and the frequency of CSF CD25− Tfh cells. The study suggests that CD25− Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.
{"title":"Effects of anti-CD20 therapy on circulating and intrathecal follicular helper T cell subsets in multiple sclerosis","authors":"Sahla El Mahdaoui , Marie Mathilde Hansen , Malene Bredahl Hansen , Victoria Hyslop Hvalkof , Helle Bach Søndergaard , Mie Reith Mahler , Jeppe Romme Christensen , Finn Sellebjerg , Marina Rode von Essen","doi":"10.1016/j.clim.2024.110262","DOIUrl":"10.1016/j.clim.2024.110262","url":null,"abstract":"<div><p>Follicular helper T (Tfh) cells and their interplay with B cells likely contribute to the pathogenesis of relapsing-remitting multiple sclerosis (RRMS). Tfh cells are enriched in cerebrospinal fluid (CSF) in RRMS, but effects of anti-CD20 therapy are unknown. We investigated Tfh cells in controls, untreated and anti-CD20-treated patients with RRMS using flow cytometry. CSF Tfh cells were increased in untreated patients. Compared to paired blood samples, CD25<sup>−</sup> Tfh cells were enriched in CSF in RRMS, but not in controls. Contrast-enhancing brain MRI lesions and IgG index correlated with CSF CD25<sup>−</sup> Tfh cell frequency in untreated patients with RRMS. Anti-CD20 therapy reduced the numbers of circulating PD1<sup>+</sup> Tfh cells and CD25<sup>−</sup> Tfh cells, and the frequency of CSF CD25<sup>−</sup> Tfh cells. The study suggests that CD25<sup>−</sup> Tfh cells are recruited to the CSF in RRMS, associated with focal inflammation, and are reduced by anti-CD20 therapy.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003711/pdfft?md5=067c9241e5b14c9188b12b45b28eafd8&pid=1-s2.0-S1521661624003711-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092672","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}
Pub Date : 2024-05-22DOI: 10.1016/j.clim.2024.110261
Ubaid Ullah Kalim , Rahul Biradar , Sini Junttila , Mohd Moin Khan , Subhash Tripathi , Meraj Hasan Khan , Johannes Smolander , Kartiek Kanduri , Tapio Envall , Asta Laiho , Alexander Marson , Omid Rasool , Laura L. Elo , Riitta Lahesmaa
Gene regulatory elements, such as enhancers, greatly influence cell identity by tuning the transcriptional activity of specific cell types. Dynamics of enhancer landscape during early human Th17 cell differentiation remains incompletely understood. Leveraging ATAC-seq-based profiling of chromatin accessibility and comprehensive analysis of key histone marks, we identified a repertoire of enhancers that potentially exert control over the fate specification of Th17 cells. We found 23 SNPs associated with autoimmune diseases within Th17-enhancers that precisely overlapped with the binding sites of transcription factors actively engaged in T-cell functions. Among the Th17-specific enhancers, we identified an enhancer in the intron of RORA and demonstrated that this enhancer positively regulates RORA transcription. Moreover, CRISPR-Cas9-mediated deletion of a transcription factor binding site-rich region within the identified RORA enhancer confirmed its role in regulating RORA transcription. These findings provide insights into the potential mechanism by which the RORA enhancer orchestrates Th17 differentiation.
{"title":"A proximal enhancer regulates RORA expression during early human Th17 cell differentiation","authors":"Ubaid Ullah Kalim , Rahul Biradar , Sini Junttila , Mohd Moin Khan , Subhash Tripathi , Meraj Hasan Khan , Johannes Smolander , Kartiek Kanduri , Tapio Envall , Asta Laiho , Alexander Marson , Omid Rasool , Laura L. Elo , Riitta Lahesmaa","doi":"10.1016/j.clim.2024.110261","DOIUrl":"10.1016/j.clim.2024.110261","url":null,"abstract":"<div><p>Gene regulatory elements, such as enhancers, greatly influence cell identity by tuning the transcriptional activity of specific cell types. Dynamics of enhancer landscape during early human Th17 cell differentiation remains incompletely understood. Leveraging ATAC-seq-based profiling of chromatin accessibility and comprehensive analysis of key histone marks, we identified a repertoire of enhancers that potentially exert control over the fate specification of Th17 cells. We found 23 SNPs associated with autoimmune diseases within Th17-enhancers that precisely overlapped with the binding sites of transcription factors actively engaged in T-cell functions. Among the Th17-specific enhancers, we identified an enhancer in the intron of RORA and demonstrated that this enhancer positively regulates RORA transcription. Moreover, CRISPR-Cas9-mediated deletion of a transcription factor binding site-rich region within the identified RORA enhancer confirmed its role in regulating RORA transcription. These findings provide insights into the potential mechanism by which the RORA enhancer orchestrates Th17 differentiation.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S152166162400370X/pdfft?md5=ec84d01de2fe59f7a407e8d211a2b03c&pid=1-s2.0-S152166162400370X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141092671","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}
Pub Date : 2024-05-22DOI: 10.1016/j.clim.2024.110260
Ivy L. Debreceni , Jennifer Y. Barr , Ellen M. Upton , Yi-Guang Chen , Scott M. Lieberman
Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.
{"title":"IL-27 promotes pathogenic T cells in a mouse model of Sjögren's disease","authors":"Ivy L. Debreceni , Jennifer Y. Barr , Ellen M. Upton , Yi-Guang Chen , Scott M. Lieberman","doi":"10.1016/j.clim.2024.110260","DOIUrl":"https://doi.org/10.1016/j.clim.2024.110260","url":null,"abstract":"<div><p>Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39<sup>hi</sup> exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141090966","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}
Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. Irg1-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.
成纤维细胞样滑膜细胞(FLS)在类风湿性关节炎(RA)中起着至关重要的作用。伊塔康酸(ITA)是从三羧酸(TCA)循环中提取的一种内源性代谢物,因其抗炎、抗病毒和抗菌作用而备受关注。本研究评估了 ITA 对 FLS 的影响及其治疗 RA 的潜力。ITA在体外明显减少了FLS的增殖和迁移,并通过细胞外通量分析仪测量了线粒体氧化磷酸化和糖酵解。在 TCA 循环中,ITA 会积累包括琥珀酸盐和柠檬酸盐在内的代谢物。在Ⅱ型胶原诱导的关节炎(CIA)大鼠中,关节内注射ITA可减少关节炎和骨侵蚀。在胶原抗体诱导的关节炎中,缺乏产生ITA能力的Irg1缺陷小鼠的关节炎比对照小鼠更严重。ITA通过抑制FLS的增殖和迁移改善了CIA。因此,ITA可能是一种治疗RA的新型药物。
{"title":"Itaconate reduces proliferation and migration of fibroblast-like synoviocytes and ameliorates arthritis models","authors":"Maria Tada , Yuki Kudo , Michihito Kono , Masatoshi Kanda , Shuhei Takeyama , Kodai Sakiyama , Hotaka Ishizu , Tomohiro Shimizu , Tsutomu Endo , Ryo Hisada , Yuichiro Fujieda , Masaru Kato , Olga Amengual , Norimasa Iwasaki , Tatsuya Atsumi","doi":"10.1016/j.clim.2024.110255","DOIUrl":"10.1016/j.clim.2024.110255","url":null,"abstract":"<div><p>Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. <em>Irg1</em>-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064914","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}
Pub Date : 2024-05-18DOI: 10.1016/j.clim.2024.110259
M.Y. Hardy , L.M. Henneken , A.K. Russell , Y. Okura , A. Mizoroki , Y. Ozono , S. Kobayashi , Y. Murakami , J.A. Tye-Din
The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52).
Objective
To assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides that encompass immunodominant T cell epitopes.
Methods
We employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-γ enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 μg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody).
Results
In HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87% (IQR 72–92). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens.
Conclusion
DONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.
治疗乳糜泻(Ceeliac disease,CeD)的无麸质饮食是一种限制性饮食,往往不能诱导症状和/或粘膜疾病的完全缓解。麸质过敏症发病机制的核心是麸质特异性 CD4+ T 细胞,85% 以上的麸质过敏症患者的 CD4+ T 细胞受到 HLA-DQ2.5 的限制,这使得 HLA-DQ2.5 成为抑制麸质依赖性免疫的一个有吸引力的靶点。最近,一种新型抗HLA-DQ2.5抗体(DONQ52)被开发出来,它能特异性识别HLA-DQ2.5和多个麸质表位的复合物:目的:评估DONQ52抑制CeD患者T细胞对包含免疫优势T细胞表位的最具免疫原性的麸质多肽反应的能力:方法:我们在CeD患者中采用了体内麸质挑战模型,该模型可定量读出与疾病相关的麸质特异性T细胞反应。HLA-DQ2.5+ CeD 患者食用含有小麦、大麦或黑麦的食物 3 天,并在开始挑战前(D1)和挑战后 6 天(D6)采集血液。分离外周血单核细胞,并用干扰素(IFN)-γ 酶联免疫吸附点测定法(ELISpot)评估其对包含一系列免疫优势 T 细胞表位的麸质肽的反应。评估了 DONQ52(4 或 40 μg/mL)的抑制作用,并与泛 HLA-DQ 阻断(SPVL3 抗体)进行了比较:结果:在HLA-DQ2.5+ CeD患者中,DONQ52能降低T细胞对所有麦麸肽的反应,其效果等同于或高于泛HLA-DQ抗体阻断。它能将T细胞对最具有免疫优势的小麦表位的反应降低87.3%(IQR 72.4-92.4)。值得注意的是,DONQ52 还大大降低了 T 细胞对优势大麦角蛋白和黑麦鞘氨醇衍生肽的反应。DONQ52 对非麸质抗原的 T 细胞反应没有影响:结论:DONQ52 能显著阻断 HLA-DQ2.5 限制的 T 细胞对 CeD 中免疫原性最强的麸质多肽的反应。我们的研究结果支持体外数据,即 DONQ52 对多种谷蛋白肽:HLA-DQ2.5 复合物具有选择性和广泛的交叉反应性。这项工作提供了多特异性抗体阻断可能有效抑制 CeD 中致病性麸质特异性 T 细胞反应的概念证明,并为正在进行的治疗开发提供了支持。
{"title":"A bispecific antibody targeting HLA-DQ2.5-gluten peptides potently blocks gluten-specific T cells induced by gluten ingestion in patients with celiac disease","authors":"M.Y. Hardy , L.M. Henneken , A.K. Russell , Y. Okura , A. Mizoroki , Y. Ozono , S. Kobayashi , Y. Murakami , J.A. Tye-Din","doi":"10.1016/j.clim.2024.110259","DOIUrl":"10.1016/j.clim.2024.110259","url":null,"abstract":"<div><p>The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52).</p></div><div><h3>Objective</h3><p>To assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides that encompass immunodominant T cell epitopes.</p></div><div><h3>Methods</h3><p>We employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-γ enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 μg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody).</p></div><div><h3>Results</h3><p>In HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87% (IQR 72–92). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens.</p></div><div><h3>Conclusion</h3><p>DONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.</p></div>","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1521661624003681/pdfft?md5=9fdf4526b65a872dc51c5c1e70e84367&pid=1-s2.0-S1521661624003681-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070807","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}
Pub Date : 2024-05-17DOI: 10.1016/j.clim.2024.110257
Jianfang Liao, Juan Cao
{"title":"Regarding the “Renal dysfunction in AQP4 NMOSD and MS; a potential predictor of relapse and prognosis”","authors":"Jianfang Liao, Juan Cao","doi":"10.1016/j.clim.2024.110257","DOIUrl":"10.1016/j.clim.2024.110257","url":null,"abstract":"","PeriodicalId":10392,"journal":{"name":"Clinical immunology","volume":null,"pages":null},"PeriodicalIF":8.6,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141049939","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}