Talita P Domiciano, Youngho Lee, Thacyana T Carvalho, Daiko Wakita, Daisy Martinon, Prasant K Jena, Justyna Fert-Bober, Vanessa Borges, Timothy R Crother, Shuang Chen, Debbie Moreira, Jennifer E Van Eyk, Magali Noval Rivas, Moshe Arditi, Kenichi Shimada
Kawasaki disease (KD) is the leading cause of acquired heart disease in children. While circulating neutrophils are increased and activated during acute KD, it is unclear whether neutrophils and neutrophil extracellular traps (NETs) contribute to the pathogenesis of KD. Peptidylarginine deiminase 4 (PAD4), an enzyme involved in protein citrullination and essential for NETs formation, is implicated in the pathogenesis of various diseases. Here, we used the Lactobacillus casei cell wall extract (LCWE)-induced mouse model of KD vasculitis to determine the contribution of PAD4 in KD vasculitis. We found that the pan-PADs inhibitor, Cl-amidine, significantly reduced LCWE-induced cardiovascular lesions, but neutrophil-specific Padi4 KO mice did not impact development of KD vasculitis. While in vitro treatment of macrophages, which highly express Padi4, with Cl-amidine inhibited IL-1βsecretion, macrophage-specific Padi4 KO mice did not reduce the lesions. Padi4-/- mice also developed KD vasculitis, AFM30a, a PAD2 inhibitor, significantly reduced KD vasculitis in Padi4-/- mice, indicating a compensatory role of PAD2 in PAD4 deficiency. We also identified several citrullinated proteins in macrophages with constitutively active NLRP3 inflammasome that were inhibited by Cl-amidine treatment, suggesting that protein citrullination participates in NLRP3 inflammasome activation. These data indicate a dispensable role for PAD4-dependent NETs formation, and a redundant role of PAD2 and PAD4 in this murine KD vasculitis. The cardioprotective effects of Cl-amidine to reduce the severity of murine KD vasculitis is not limited to PAD4 inhibition and may include decreased citrullination in the inflammasome pathway.
{"title":"Redundant role of PAD2 and PAD4 in the development of cardiovascular lesions in a mouse model of Kawasaki Disease vasculitis","authors":"Talita P Domiciano, Youngho Lee, Thacyana T Carvalho, Daiko Wakita, Daisy Martinon, Prasant K Jena, Justyna Fert-Bober, Vanessa Borges, Timothy R Crother, Shuang Chen, Debbie Moreira, Jennifer E Van Eyk, Magali Noval Rivas, Moshe Arditi, Kenichi Shimada","doi":"10.1093/cei/uxae080","DOIUrl":"https://doi.org/10.1093/cei/uxae080","url":null,"abstract":"Kawasaki disease (KD) is the leading cause of acquired heart disease in children. While circulating neutrophils are increased and activated during acute KD, it is unclear whether neutrophils and neutrophil extracellular traps (NETs) contribute to the pathogenesis of KD. Peptidylarginine deiminase 4 (PAD4), an enzyme involved in protein citrullination and essential for NETs formation, is implicated in the pathogenesis of various diseases. Here, we used the Lactobacillus casei cell wall extract (LCWE)-induced mouse model of KD vasculitis to determine the contribution of PAD4 in KD vasculitis. We found that the pan-PADs inhibitor, Cl-amidine, significantly reduced LCWE-induced cardiovascular lesions, but neutrophil-specific Padi4 KO mice did not impact development of KD vasculitis. While in vitro treatment of macrophages, which highly express Padi4, with Cl-amidine inhibited IL-1βsecretion, macrophage-specific Padi4 KO mice did not reduce the lesions. Padi4-/- mice also developed KD vasculitis, AFM30a, a PAD2 inhibitor, significantly reduced KD vasculitis in Padi4-/- mice, indicating a compensatory role of PAD2 in PAD4 deficiency. We also identified several citrullinated proteins in macrophages with constitutively active NLRP3 inflammasome that were inhibited by Cl-amidine treatment, suggesting that protein citrullination participates in NLRP3 inflammasome activation. These data indicate a dispensable role for PAD4-dependent NETs formation, and a redundant role of PAD2 and PAD4 in this murine KD vasculitis. The cardioprotective effects of Cl-amidine to reduce the severity of murine KD vasculitis is not limited to PAD4 inhibition and may include decreased citrullination in the inflammasome pathway.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206110","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}
Fatemeh Karami, Hassan Namdar Ahmadabad, Marjan Shaheli
This study aimed to investigate the effects of CpG Oligodeoxynucleotide (CpG ODNs)-Coated Chitosan Nanoparticles (CNP) on the phenotype of murine macrophages and their pro-inflammatory cytokine profile in vitro. CNP-CpG ODNs loaded with FITC-scrambled siRNA were prepared using the ionotropic gelation method. Peritoneal macrophages were isolated and exposed to CNP-CpG ODNs. Treated macrophages were assessed for uptake capacity. Flow cytometry was used to evaluate the expression levels of MHC-II, CD40, and CD86 costimulatory molecules in treated macrophages. Furthermore, the secretion levels of proinflammatory cytokines (TNF-α and IL-6) and the release of nitric oxide (NO) were measured in the culture supernatant of treated macrophages using sandwich ELISA and the Griess reaction, respectively. These in vitro studies showed that CNP-CpG ODNs had no cytotoxic effect on macrophages and were efficiently taken up by them. Additionally, CNP-CpG ODNs significantly increased the production of TNF-α, IL-6, and NO in the culture supernatant compared to CNP alone. Moreover, CNP-CpG ODNs enhanced the expression of MHC-II, CD40, and CD86 costimulatory molecules on macrophages. These findings indicate that incorporating CpG ODNs into CNPs promotes macrophage maturation and a proinflammatory phenotype. Therefore, CNP-CpG ODNs may serve as an effective system for targeted gene delivery to macrophages, enhancing immune responses.
{"title":"CpG Oligodeoxynucleotide-Coated Chitosan Nanoparticles Enhance Macrophage Proinflammatory Phenotype In Vitro","authors":"Fatemeh Karami, Hassan Namdar Ahmadabad, Marjan Shaheli","doi":"10.1093/cei/uxae081","DOIUrl":"https://doi.org/10.1093/cei/uxae081","url":null,"abstract":"This study aimed to investigate the effects of CpG Oligodeoxynucleotide (CpG ODNs)-Coated Chitosan Nanoparticles (CNP) on the phenotype of murine macrophages and their pro-inflammatory cytokine profile in vitro. CNP-CpG ODNs loaded with FITC-scrambled siRNA were prepared using the ionotropic gelation method. Peritoneal macrophages were isolated and exposed to CNP-CpG ODNs. Treated macrophages were assessed for uptake capacity. Flow cytometry was used to evaluate the expression levels of MHC-II, CD40, and CD86 costimulatory molecules in treated macrophages. Furthermore, the secretion levels of proinflammatory cytokines (TNF-α and IL-6) and the release of nitric oxide (NO) were measured in the culture supernatant of treated macrophages using sandwich ELISA and the Griess reaction, respectively. These in vitro studies showed that CNP-CpG ODNs had no cytotoxic effect on macrophages and were efficiently taken up by them. Additionally, CNP-CpG ODNs significantly increased the production of TNF-α, IL-6, and NO in the culture supernatant compared to CNP alone. Moreover, CNP-CpG ODNs enhanced the expression of MHC-II, CD40, and CD86 costimulatory molecules on macrophages. These findings indicate that incorporating CpG ODNs into CNPs promotes macrophage maturation and a proinflammatory phenotype. Therefore, CNP-CpG ODNs may serve as an effective system for targeted gene delivery to macrophages, enhancing immune responses.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206225","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}
Juan Francisco Gutiérrez-Bautista, Irene Díaz-Alberola, María Tarriño, María Aguilera, Fernando Cobo, Juan Antonio Reguera, Javier Rodríguez-Granger, Joaquín Mendoza, Miguel Ángel López-Nevot, Antonio Sampedro
The COVID-19 pandemic highlighted the importance of effective vaccination strategies in controlling the spread of infectious diseases. SARS-CoV-2 vaccine has demonstrated high efficacy in preventing COVID-19 infection in the general population. However, the efficacy of this vaccine in patients with predominantly antibody deficiencies, such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA), should be closely monitored. CVID and XLA are rare genetic disorders that impair the immune system's ability to produce antibodies, which are crucial for fighting infections. Patients with these disorders have a higher risk of severe disease and mortality from COVID-19 due to their compromised immune systems. In this study, we evaluated the humoral and cellular immune responses after four doses of mRNA-1273 and one BNT162b2 bivalent vaccine in a cohort of patients with CVID and XLA. The response in this population was lower than in the control group. However, the administration of the third dose improved the number of patients with seroconversion and the intensity of the humoral response, as well as the number of patients with a positive cellular response. Finally, the administration of the fourth and fifth doses improves the antibody titer and neutralization against wild type variant, but not against the prevalent XBB1.5 variant.
{"title":"Follow-up of Immune Response in Patients with Common Variable Immunodeficiency following SARS-CoV-2 Vaccination","authors":"Juan Francisco Gutiérrez-Bautista, Irene Díaz-Alberola, María Tarriño, María Aguilera, Fernando Cobo, Juan Antonio Reguera, Javier Rodríguez-Granger, Joaquín Mendoza, Miguel Ángel López-Nevot, Antonio Sampedro","doi":"10.1093/cei/uxae039","DOIUrl":"https://doi.org/10.1093/cei/uxae039","url":null,"abstract":"The COVID-19 pandemic highlighted the importance of effective vaccination strategies in controlling the spread of infectious diseases. SARS-CoV-2 vaccine has demonstrated high efficacy in preventing COVID-19 infection in the general population. However, the efficacy of this vaccine in patients with predominantly antibody deficiencies, such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA), should be closely monitored. CVID and XLA are rare genetic disorders that impair the immune system's ability to produce antibodies, which are crucial for fighting infections. Patients with these disorders have a higher risk of severe disease and mortality from COVID-19 due to their compromised immune systems. In this study, we evaluated the humoral and cellular immune responses after four doses of mRNA-1273 and one BNT162b2 bivalent vaccine in a cohort of patients with CVID and XLA. The response in this population was lower than in the control group. However, the administration of the third dose improved the number of patients with seroconversion and the intensity of the humoral response, as well as the number of patients with a positive cellular response. Finally, the administration of the fourth and fifth doses improves the antibody titer and neutralization against wild type variant, but not against the prevalent XBB1.5 variant.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"237 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140833491","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}
Luciana Polaco Covre, Carlos Henrique Fantecelle, Ariadne Mendes Queiroz, Julia Miranda Fardin, Pedro Henrique Miranda, Sian Henson, Alessandra Marcia da Fonseca-Martins, Herbert Leonel de Matos Guedes, David Mosser, Aloisio Falqueto, Arne Akbar, Daniel Claudio Oliveira Gomes
Natural killer (NK) cells include different subsets with diverse effector capacities that are poorly understood in the context of parasitic diseases. Here, we investigated inhibitory and activating receptor expression on NK cells in patients with cutaneous leishmaniasis (CL) and explored their phenotypic and functional heterogeneity based on CD57 and NKG2C expression. The expression of CD57 identified NK cells that accumulated in CL patients and exhibited features of senescence. The CD57+ cells exhibited heightened levels of the activating receptor NKG2C and diminished expression of the inhibitory receptor NKG2A. RNA sequencing analyses based on NKG2C transcriptome have revealed two distinct profiles among CL patients associated with cytotoxic and functional genes. The CD57+NKG2C+ subset accumulated in the blood of patients and presented conspicuous features of senescence, including the expression of markers such as p16, yH2ax, and p38, as well as reduced proliferative capacity. In addition, they positively correlated with the number of days until lesion resolution. This study provides a broad understanding of the NK cell biology during Leishmania infection and reinforces the role of senescent cells in the adverse clinical outcomes of cutaneous leishmaniasis.
自然杀伤（NK）细胞包括具有不同效应能力的不同亚群，而这些亚群在寄生虫病中的作用却鲜为人知。在这里，我们研究了皮肤利什曼病（CL）患者 NK 细胞上抑制性和激活性受体的表达，并根据 CD57 和 NKG2C 的表达探讨了它们的表型和功能异质性。CD57 的表达确定了在 CL 患者中积累并表现出衰老特征的 NK 细胞。CD57+细胞的活化受体NKG2C水平升高，而抑制受体NKG2A表达减少。基于 NKG2C 转录组的 RNA 测序分析显示，CL 患者有两种不同的细胞毒性基因和功能基因。CD57+NKG2C+ 亚群在患者血液中积累，并呈现出明显的衰老特征，包括 p16、yH2ax 和 p38 等标记物的表达，以及增殖能力的降低。此外，它们还与病变消退的天数呈正相关。这项研究让人们对利什曼病感染期间的 NK 细胞生物学有了广泛的了解，并加强了衰老细胞在皮肤利什曼病不良临床结果中的作用。
{"title":"NKG2C+CD57+ natural killer with senescent features cells are induced in cutaneous leishmaniasis and accumulate in patients with lesional healing impairment","authors":"Luciana Polaco Covre, Carlos Henrique Fantecelle, Ariadne Mendes Queiroz, Julia Miranda Fardin, Pedro Henrique Miranda, Sian Henson, Alessandra Marcia da Fonseca-Martins, Herbert Leonel de Matos Guedes, David Mosser, Aloisio Falqueto, Arne Akbar, Daniel Claudio Oliveira Gomes","doi":"10.1093/cei/uxae040","DOIUrl":"https://doi.org/10.1093/cei/uxae040","url":null,"abstract":"Natural killer (NK) cells include different subsets with diverse effector capacities that are poorly understood in the context of parasitic diseases. Here, we investigated inhibitory and activating receptor expression on NK cells in patients with cutaneous leishmaniasis (CL) and explored their phenotypic and functional heterogeneity based on CD57 and NKG2C expression. The expression of CD57 identified NK cells that accumulated in CL patients and exhibited features of senescence. The CD57+ cells exhibited heightened levels of the activating receptor NKG2C and diminished expression of the inhibitory receptor NKG2A. RNA sequencing analyses based on NKG2C transcriptome have revealed two distinct profiles among CL patients associated with cytotoxic and functional genes. The CD57+NKG2C+ subset accumulated in the blood of patients and presented conspicuous features of senescence, including the expression of markers such as p16, yH2ax, and p38, as well as reduced proliferative capacity. In addition, they positively correlated with the number of days until lesion resolution. This study provides a broad understanding of the NK cell biology during Leishmania infection and reinforces the role of senescent cells in the adverse clinical outcomes of cutaneous leishmaniasis.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140833546","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}
Vasista Adiga, Hima Bindhu, Asma Ahmed, Nirutha Chetan Kumar, Himanshu Tripathi, George D’Souza, Mary Dias, Sudarshan Shivalingaiah, Srishti Rao, K N Shanti, Catherine Hawrylowicz, Pratibha Dwarkanath, Annapurna Vyakarnam
Neonate responses to pathogen-associated molecular patterns (PAMPS) differ from adults; such understanding is poor in Indian neonates, despite recognised significant infectious risk. Immune profiling analysis was undertaken of ten secreted mediators contextualised with cellular source induced by six PAMPs in umbilical cord (CB; n=21) and adult-blood (PBMC, n=14) from a tertiary care hospital in South India. Differential cytokine expression analysis (minimum log2-fold difference; adj p-value<0.05) identified bacterial PAMPs induced higher concentrations of IL-1β, IL-10, TNF-α in adults versus IL-8, GM-CSF, IFN-γ and IL-2 in CB. CB responded to poly I:C and SARS-CoV-2 lysate with a dominant IL-8 response, whereas, in PBMC, CXCL-10 dominated poly I:C, but not SARS-CoV-2, responses, highlighting potential IL-8 importance, in absence of Type I Interferons, in antiviral CB immunity. Candida albicans was the only PAMP to uniformly induce higher secretion of effectors in CB. The predominant source of IL-8/IL-6/TNF-α/IL-1β in both CB and PBMC was polyfunctional monocytes and IFN-γ /IL-2/IL-17 from innate lymphocytes. Correlation matrix analyses revealed IL-8 to be the most differentially regulated, correlating positively in CB versus negatively in PBMC with IL-6, GM-CSF, IFN-γ, IL-2, consistent with more negatively regulated cytokine modules in adults, potentially linked to higher anti-inflammatory IL-10. Cord and adult blood from India respond robustly to PAMPs with unique effector combinations. These data provide a strong foundation to monitor, explore, mechanisms that regulate such immunity during the life course, an area of significant global health importance given infection-related infant mortality incidence.
{"title":"Immune profiling reveals umbilical cord blood mononuclear cells from South India display an IL-8 dominant, CXCL-10 deficient polyfunctional monocyte response to pathogen-associated molecular patterns (PAMPs) that is distinct from adult blood cells","authors":"Vasista Adiga, Hima Bindhu, Asma Ahmed, Nirutha Chetan Kumar, Himanshu Tripathi, George D’Souza, Mary Dias, Sudarshan Shivalingaiah, Srishti Rao, K N Shanti, Catherine Hawrylowicz, Pratibha Dwarkanath, Annapurna Vyakarnam","doi":"10.1093/cei/uxae034","DOIUrl":"https://doi.org/10.1093/cei/uxae034","url":null,"abstract":"Neonate responses to pathogen-associated molecular patterns (PAMPS) differ from adults; such understanding is poor in Indian neonates, despite recognised significant infectious risk. Immune profiling analysis was undertaken of ten secreted mediators contextualised with cellular source induced by six PAMPs in umbilical cord (CB; n=21) and adult-blood (PBMC, n=14) from a tertiary care hospital in South India. Differential cytokine expression analysis (minimum log2-fold difference; adj p-value&lt;0.05) identified bacterial PAMPs induced higher concentrations of IL-1β, IL-10, TNF-α in adults versus IL-8, GM-CSF, IFN-γ and IL-2 in CB. CB responded to poly I:C and SARS-CoV-2 lysate with a dominant IL-8 response, whereas, in PBMC, CXCL-10 dominated poly I:C, but not SARS-CoV-2, responses, highlighting potential IL-8 importance, in absence of Type I Interferons, in antiviral CB immunity. Candida albicans was the only PAMP to uniformly induce higher secretion of effectors in CB. The predominant source of IL-8/IL-6/TNF-α/IL-1β in both CB and PBMC was polyfunctional monocytes and IFN-γ /IL-2/IL-17 from innate lymphocytes. Correlation matrix analyses revealed IL-8 to be the most differentially regulated, correlating positively in CB versus negatively in PBMC with IL-6, GM-CSF, IFN-γ, IL-2, consistent with more negatively regulated cytokine modules in adults, potentially linked to higher anti-inflammatory IL-10. Cord and adult blood from India respond robustly to PAMPs with unique effector combinations. These data provide a strong foundation to monitor, explore, mechanisms that regulate such immunity during the life course, an area of significant global health importance given infection-related infant mortality incidence.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140833539","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}
Kavina Shah, Maria Leandro, Mark Cragg, Florian Kollert, Franz Schuler, Christian Klein, Venkat Reddy
Summary B and T cells collaborate to drive autoimmune disease (AID). Historically, B and T cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T cell therapy and T cell engagers (TCE) that recruit T cells to induce B cell cytotoxicity have delivered promising results for anti-CD19 CAR T cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab or epcoritamab. Limited evidence suggests that anti-CD19 CAR T cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T cell collaboration toward overcoming rituximab-resistant AID.
摘要 B 细胞和 T 细胞共同作用，导致自身免疫性疾病（AID）。而大多数自身免疫性疾病（包括类风湿性关节炎、系统性红斑狼疮、多发性硬化症和器官移植）患者都受益于使用抗CD20单克隆抗体（如利妥昔单抗、奥克利珠单抗或ofatumumab）进行的靶向BCD（B-T细胞）治疗。难治性 AID 是不完全 BCD 患者面临的一个重要问题，这些患者体内存在更多的 IgD-CD27+ 交换记忆 B 细胞、CD19+CD20- B 细胞以及抗 CD20 抗体不能直接靶向的浆细胞，而大多数淋巴组织浆细胞都表达 CD19。此外，B-T 细胞合作主要存在于淋巴组织以及关节和肾脏等炎症部位，在这些部位，由于接触关键效应细胞的机会有限，BCD 的效果可能不佳。在治疗癌症方面，嵌合抗原受体（CAR）T细胞疗法和T细胞诱导剂（TCE）能招募T细胞诱导B细胞细胞毒性，在抗CD19 CAR T细胞疗法、CD19 TCE blinatumomab和CD20 TCE（如mosunetuzumab、glofitamab或epcoritamab）方面取得了令人鼓舞的成果。有限的证据表明，抗 CD19 CAR T 细胞疗法可有效治疗难治性 AID，而我们正在等待对 TCE 用于非肿瘤适应症的评估。因此，我们在此讨论新型疗法的潜在机制优势，即依靠 T 细胞作为效应细胞来破坏 B-T 细胞协作，从而克服利妥昔单抗耐药的 AID。
{"title":"Disrupting B and T cell Collaboration in Autoimmune Disease: T cell engagers versus CAR T cell therapy?","authors":"Kavina Shah, Maria Leandro, Mark Cragg, Florian Kollert, Franz Schuler, Christian Klein, Venkat Reddy","doi":"10.1093/cei/uxae031","DOIUrl":"https://doi.org/10.1093/cei/uxae031","url":null,"abstract":"Summary B and T cells collaborate to drive autoimmune disease (AID). Historically, B and T cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T cell therapy and T cell engagers (TCE) that recruit T cells to induce B cell cytotoxicity have delivered promising results for anti-CD19 CAR T cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab or epcoritamab. Limited evidence suggests that anti-CD19 CAR T cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T cell collaboration toward overcoming rituximab-resistant AID.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140625655","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}
Mohammad Ali, Stephanie Longet, Isabel Neale, Patpong Rongkard, Forhad Uddin Hassan Chowdhury, Jennifer Hill, Anthony Brown, Stephen Laidlaw, Tom Tipton, Ashraful Hoque, Nazia Hassan, Carl-Philipp Hackstein, Sandra Adele, Hossain Delowar Akther, Priyanka Abraham, Shrebash Paul, Md Matiur Rahman, Md Masum Alam, Shamima Parvin, Forhadul Hoque Mollah, Md Mozammel Hoque, Shona C Moore, Subrata K Biswas, Lance Turtle, Thushan I de Silva, Ane Ogbe, John Frater, Eleanor Barnes, Adriana Tomic, Miles W Carroll, Paul Klenerman, Barbara Kronsteiner, Fazle Rabbi Chowdhury, Susanna J Dunachie
Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.
{"title":"Obesity Differs from Diabetes Mellitus in Antibody and T Cell Responses Post COVID-19 Recovery","authors":"Mohammad Ali, Stephanie Longet, Isabel Neale, Patpong Rongkard, Forhad Uddin Hassan Chowdhury, Jennifer Hill, Anthony Brown, Stephen Laidlaw, Tom Tipton, Ashraful Hoque, Nazia Hassan, Carl-Philipp Hackstein, Sandra Adele, Hossain Delowar Akther, Priyanka Abraham, Shrebash Paul, Md Matiur Rahman, Md Masum Alam, Shamima Parvin, Forhadul Hoque Mollah, Md Mozammel Hoque, Shona C Moore, Subrata K Biswas, Lance Turtle, Thushan I de Silva, Ane Ogbe, John Frater, Eleanor Barnes, Adriana Tomic, Miles W Carroll, Paul Klenerman, Barbara Kronsteiner, Fazle Rabbi Chowdhury, Susanna J Dunachie","doi":"10.1093/cei/uxae030","DOIUrl":"https://doi.org/10.1093/cei/uxae030","url":null,"abstract":"Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140625860","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}
Lucia Martin-Gutierrez, Kirsty E Waddington, Annalisa Maggio, Leda Coelewij, Alexandra Oppong, Nina Yang, Marsilio Adriani, Petra Nytrova, Rachel Farrell, Inés Pineda-Torra, Elizabeth C Jury
Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4+ T cells are pathogenic in RRMS, and defective T cell function could be mediated in part by liver X receptors (LXRs) - nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the ‘lipid metabolism’ and ‘signalling of nuclear receptors’ pathways were dysregulated in CD4+ T cells isolated from RRMS patients compared with healthy donors. While LXRB and genes associated with cholesterol metabolism were upregulated, other T cell LXR-target genes, including genes involved in cellular lipid uptake (inducible degrader of the LDL receptor, IDOL), and the rate-limiting enzyme for glycosphingolipid biosynthesis (UDP-glucosylceramide synthase, UGCG) were downregulated in T cells from patients with RRMS compared to healthy donors. Correspondingly, plasma membrane glycosphingolipids were reduced, and cholesterol levels increased in RRMS CD4+ T cells, an effect partially recapitulated in healthy T cells by in vitro culture with T cell receptor stimulation in the presence of serum from RRMS patients. Notably, stimulation with LXR-agonist GW3965 normalised membrane cholesterol levels, and reduced proliferation and IL17 cytokine production in RRMS CD4+ T-cells. Thus, LXR-mediated lipid metabolism pathways were dysregulated in T cells from patients with RRMS and could contribute to RRMS pathogenesis. Therapies that modify lipid metabolism could help restore immune cell function.
据报道，复发性缓解型多发性硬化症（RRMS）患者的血液、脑脊液和脑组织中胆固醇、氧甾醇、鞘脂和脂肪酸浓度发生了变化，并与疾病进展和治疗反应有关。CD4+ T细胞是RRMS的致病因子，T细胞功能缺陷可能部分是由肝X受体（LXRs）介导的，肝X受体是调节脂质平衡和免疫的核受体。RNA测序和通路分析发现，与健康供体相比，从RRMS患者体内分离出的CD4+T细胞中，"脂质代谢 "和 "核受体信号 "通路中的基因出现了失调。虽然 LXRB 和胆固醇代谢相关基因上调，但与健康供体相比，RRMS 患者的 T 细胞中其他 T 细胞 LXR 靶基因，包括参与细胞脂质摄取的基因（低密度脂蛋白受体诱导降解器，IDOL）和糖磷脂生物合成的限速酶（UDP-葡萄糖酰甘油酰胺合成酶，UGCG）均下调。相应地，RRMS CD4+ T细胞的质膜糖磷脂减少，胆固醇水平升高，在有RRMS患者血清存在的情况下，通过体外培养和T细胞受体刺激，这种效应在健康T细胞中得到了部分再现。值得注意的是，用 LXR 激动剂 GW3965 刺激 RRMS CD4+ T 细胞可使膜胆固醇水平恢复正常，并减少其增殖和 IL17 细胞因子的产生。因此，在RRMS患者的T细胞中，LXR介导的脂质代谢途径失调，并可能导致RRMS的发病。改变脂质代谢的疗法有助于恢复免疫细胞的功能。
{"title":"Dysregulated Lipid Metabolism Networks Modulate T-cell Function in People with Relapsing Remitting Multiple Sclerosis","authors":"Lucia Martin-Gutierrez, Kirsty E Waddington, Annalisa Maggio, Leda Coelewij, Alexandra Oppong, Nina Yang, Marsilio Adriani, Petra Nytrova, Rachel Farrell, Inés Pineda-Torra, Elizabeth C Jury","doi":"10.1093/cei/uxae032","DOIUrl":"https://doi.org/10.1093/cei/uxae032","url":null,"abstract":"Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4+ T cells are pathogenic in RRMS, and defective T cell function could be mediated in part by liver X receptors (LXRs) - nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the ‘lipid metabolism’ and ‘signalling of nuclear receptors’ pathways were dysregulated in CD4+ T cells isolated from RRMS patients compared with healthy donors. While LXRB and genes associated with cholesterol metabolism were upregulated, other T cell LXR-target genes, including genes involved in cellular lipid uptake (inducible degrader of the LDL receptor, IDOL), and the rate-limiting enzyme for glycosphingolipid biosynthesis (UDP-glucosylceramide synthase, UGCG) were downregulated in T cells from patients with RRMS compared to healthy donors. Correspondingly, plasma membrane glycosphingolipids were reduced, and cholesterol levels increased in RRMS CD4+ T cells, an effect partially recapitulated in healthy T cells by in vitro culture with T cell receptor stimulation in the presence of serum from RRMS patients. Notably, stimulation with LXR-agonist GW3965 normalised membrane cholesterol levels, and reduced proliferation and IL17 cytokine production in RRMS CD4+ T-cells. Thus, LXR-mediated lipid metabolism pathways were dysregulated in T cells from patients with RRMS and could contribute to RRMS pathogenesis. Therapies that modify lipid metabolism could help restore immune cell function.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615818","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}
Sebastian Malmqvist, Reuben Clark, Gunnar Johannsen, Annsofi Johannsen, Elisabeth A Boström, Ronaldo Lira-Junior
Peri-implantitis and periodontitis are common oral inflammatory diseases, which seem to exhibit critical differences in some of their molecular features. Thus, we assessed the immune cell composition of peri-implantitis and periodontitis lesions and the corresponding inflammatory profile in soft tissues and crevicular fluid. Peri-implantitis, periodontitis and control patients were recruited (n=62), and soft tissue biopsies were collected during surgery. Crevicular fluid around implant or tooth was collected. The proportions of major immune cell populations in tissues were analyzed by flow cytometry, and the inflammatory profile in tissue and crevicular fluid by a multiplex immunoassay. No significant difference was seen between peri-implantitis and periodontitis lesions in the proportions of immune cells. Peri-implantitis tissues showed an increased frequency of B cells in comparison with control tissues, along with higher levels of IL-1β, TNF-α, IL-4, and BAFF in tissue and crevicular fluid. Moreover, TNF-α, IL-17A and BAFF were higher in peri-implantitis tissues, but not in periodontitis, than in control tissues. The immune cell composition did not differ significantly between peri-implantitis and periodontitis, but an enhanced inflammatory profile was seen in peri-implantitis tissue. Peri-implantitis lesions were enriched in B cells, and displayed increased levels of IL-1β, TNF-α, IL-4, and BAFF in both tissue and crevicular fluid.
种植体周围炎和牙周炎是常见的口腔炎症性疾病，它们在某些分子特征上似乎存在重大差异。因此，我们评估了种植体周围炎和牙周炎病变的免疫细胞组成以及软组织和缝隙液中相应的炎症特征。我们招募了种植体周围炎、牙周炎和对照组患者（n=62），并在手术过程中收集了软组织活检样本。收集种植体或牙齿周围的缝隙液。通过流式细胞术分析了组织中主要免疫细胞群的比例，并通过多重免疫测定分析了组织和缝隙液中的炎症特征。种植体周围炎和牙周炎病变的免疫细胞比例没有明显差异。与对照组织相比，种植体周围炎组织中的 B 细胞频率增加，组织和缝隙液中的 IL-1β、TNF-α、IL-4 和 BAFF 水平也较高。此外，与对照组织相比，种植体周围炎组织中的 TNF-α、IL-17A 和 BAFF 含量更高，牙周炎组织中则没有。种植体周围炎和牙周炎的免疫细胞组成无明显差异，但种植体周围炎组织的炎症特征增强。种植体周围炎病变部位富含 B 细胞，组织和缝隙液中的 IL-1β、TNF-α、IL-4 和 BAFF 含量均有所增加。
{"title":"Immune cell composition and inflammatory profile of human peri-implantitis and periodontitis lesions","authors":"Sebastian Malmqvist, Reuben Clark, Gunnar Johannsen, Annsofi Johannsen, Elisabeth A Boström, Ronaldo Lira-Junior","doi":"10.1093/cei/uxae033","DOIUrl":"https://doi.org/10.1093/cei/uxae033","url":null,"abstract":"Peri-implantitis and periodontitis are common oral inflammatory diseases, which seem to exhibit critical differences in some of their molecular features. Thus, we assessed the immune cell composition of peri-implantitis and periodontitis lesions and the corresponding inflammatory profile in soft tissues and crevicular fluid. Peri-implantitis, periodontitis and control patients were recruited (n=62), and soft tissue biopsies were collected during surgery. Crevicular fluid around implant or tooth was collected. The proportions of major immune cell populations in tissues were analyzed by flow cytometry, and the inflammatory profile in tissue and crevicular fluid by a multiplex immunoassay. No significant difference was seen between peri-implantitis and periodontitis lesions in the proportions of immune cells. Peri-implantitis tissues showed an increased frequency of B cells in comparison with control tissues, along with higher levels of IL-1β, TNF-α, IL-4, and BAFF in tissue and crevicular fluid. Moreover, TNF-α, IL-17A and BAFF were higher in peri-implantitis tissues, but not in periodontitis, than in control tissues. The immune cell composition did not differ significantly between peri-implantitis and periodontitis, but an enhanced inflammatory profile was seen in peri-implantitis tissue. Peri-implantitis lesions were enriched in B cells, and displayed increased levels of IL-1β, TNF-α, IL-4, and BAFF in both tissue and crevicular fluid.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588616","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}
Allergic asthma (AA) is closely associated with the polarization of T helper (Th)2 and Th17 cells. Interleukin (IL)-18 acts as an inducer of Th2 and Th17 cell responses. However, expressions of IL-18 and IL-18 receptor alpha (IL-18Rα) in blood Th2 and Th17 cells of patients with AA remain unclear. We therefore investigated their expressions in Th2 and Th17 cells using flow cytometric analysis, quantitative real-time PCR (qPCR), and murine AA model. We observed increased proportions of Th2, Th17, IL-18+, IL-18+ Th2, and IL-18+ Th17 cells in blood CD4+ T cells of patients with AA. Additionally, house dust mite seemed to upregulate further IL-18 expression in Th2 and Th17, and upregulate IL-18Rα expression in CD4+ T, Th2, and Th17 cells of AA patients. It was also found that the plasma levels of IL-4, IL-17A, and IL-18 in AA patients were elevated, and they were correlated between each other. In ovalbumin (OVA)-induced asthma mouse (AM), we observed that the percentages of blood CD4+ T, Th2, and Th17 cells were increased. Moreover, OVA-induced AM expressed higher level of IL-18Rα in blood Th2 cells, which was downregulated by IL-18. Increased IL-18Rα expression was also observed in blood Th2 cells of OVA-induced FcεRIα−/− mice. Collectively, our findings suggest the involvement of Th2 cells in AA by expressing excessive IL-18 and IL-18Rα in response to allergen, and that IL-18 and IL-18Rα expressing Th2 cells are likely to be the potential targets for AA therapy.
{"title":"Allergens induce upregulated IL-18 and IL-18Rα expression in blood Th2 and Th17 cells of patients with allergic asthma","authors":"Junling Wang, Mengmeng Zhan, Yaping Zhai, Siqin Wang, Fangqiu Gu, Zhuo Zhao, Zhaolong Zhang, Yifei Li, Xin Dong, Yijie Zhang, Bingyu Qin","doi":"10.1093/cei/uxae022","DOIUrl":"https://doi.org/10.1093/cei/uxae022","url":null,"abstract":"Allergic asthma (AA) is closely associated with the polarization of T helper (Th)2 and Th17 cells. Interleukin (IL)-18 acts as an inducer of Th2 and Th17 cell responses. However, expressions of IL-18 and IL-18 receptor alpha (IL-18Rα) in blood Th2 and Th17 cells of patients with AA remain unclear. We therefore investigated their expressions in Th2 and Th17 cells using flow cytometric analysis, quantitative real-time PCR (qPCR), and murine AA model. We observed increased proportions of Th2, Th17, IL-18+, IL-18+ Th2, and IL-18+ Th17 cells in blood CD4+ T cells of patients with AA. Additionally, house dust mite seemed to upregulate further IL-18 expression in Th2 and Th17, and upregulate IL-18Rα expression in CD4+ T, Th2, and Th17 cells of AA patients. It was also found that the plasma levels of IL-4, IL-17A, and IL-18 in AA patients were elevated, and they were correlated between each other. In ovalbumin (OVA)-induced asthma mouse (AM), we observed that the percentages of blood CD4+ T, Th2, and Th17 cells were increased. Moreover, OVA-induced AM expressed higher level of IL-18Rα in blood Th2 cells, which was downregulated by IL-18. Increased IL-18Rα expression was also observed in blood Th2 cells of OVA-induced FcεRIα−/− mice. Collectively, our findings suggest the involvement of Th2 cells in AA by expressing excessive IL-18 and IL-18Rα in response to allergen, and that IL-18 and IL-18Rα expressing Th2 cells are likely to be the potential targets for AA therapy.","PeriodicalId":10179,"journal":{"name":"Clinical & Experimental Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588581","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}
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