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Flaman MJ, Pioli KT, Pioli PD. Highlights of 2024: New insights into the molecular regulation of antibody-secreting cells and their subsets. Immunol Cell Biol 2025. [PMID: 40268331 DOI: 10.1111/imcb.70024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2025]
Abstract
Collectively, 2024 has significantly increased the wealth of knowledge regarding antibody-secreting cell heterogeneity in health and disease. This 'Highlights of 2024' article discusses key studies contributing to the understanding of how tissue residency and disease state influence the transcriptional programming of antibody-secreting cell phenotypes.
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Affiliation(s)
- Michael James Flaman
- Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - KimAnh Trang Pioli
- Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Peter Dion Pioli
- Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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2
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He L, Li X, Jiang S, Ou Y, Wang S, Shi N, Yang Z, Yuan JL, Silverman G, Niu H. The influence of the gut microbiota on B cells in autoimmune diseases. Mol Med 2025; 31:149. [PMID: 40264032 PMCID: PMC12016346 DOI: 10.1186/s10020-025-01195-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 04/01/2025] [Indexed: 04/24/2025] Open
Abstract
Mounting evidence shows that gut microbiota communities and the human immune system coexist and influence each other, and there are a number of reports of a correlation between specific changes in gut microbiota and the occurrence of autoimmune diseases. B lymphocytes play a central role in the regulation of both gut microbiota communities and in autoimmune diseases. Here, we summarize evidence of the influence of gut microbiota-B cell pathways on autoimmune diseases and how B cells regulate microorganisms, which provides mechanistic insights with relevance for identification of potential therapeutic targets and related fields.
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Affiliation(s)
- Lun He
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Xin Li
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Shan Jiang
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Yanhua Ou
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Shanshan Wang
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Na Shi
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Zhongshan Yang
- Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, China
| | - Jia-Li Yuan
- Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, China.
| | - Gregg Silverman
- Division of Rheumatology, New York University School of Medicine, New York, NY, 10016, USA.
| | - Haitao Niu
- Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education; Guangzhou Key Laboratory for Germ-free Animals and Microbiota Application, School of Medicine, Jinan University, Guangzhou, 510632, China.
- Yunnan Provincial Key Laboratory of Molecular Biology for Sinomedicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, China.
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3
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Jiang S, Zhu D, Wang Y. Tumor-infiltrating B cells in non-small cell lung cancer: current insights and future directions. Cancer Cell Int 2025; 25:68. [PMID: 40011889 DOI: 10.1186/s12935-025-03668-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 01/29/2025] [Indexed: 02/28/2025] Open
Abstract
Tumor-infiltrating immune cells have been widely recognized as playing an important role in the promotion or inhibition of tumor growth. Recently there has been increasing attention on tumor-infiltrating B cells in the tumor microenvironment. However, the role of B cells in non-small cell lung cancer remains largely unknown. Reviewing recent studies, here we describe the distribution, phenotype, and heterogeneity of B lymphocytes in the non-small cell lung cancer, present their functions and discuss the prognostic significance of the different B-cell subtypes as well as potential therapeutic strategies targeting TIL-Bs. Finally, the review highlights the need for future research to further elucidate their precise function in the tumor microenvironment.
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Affiliation(s)
- Shuyue Jiang
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Daxing Zhu
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ye Wang
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China.
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He N, Yuan D, Luo M, Xu Q, Wen Z, Wang Z, Zhao J, Liu Y. Ferroptosis contributes to immunosuppression. Front Med 2025; 19:1-22. [PMID: 39560919 DOI: 10.1007/s11684-024-1080-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 04/18/2024] [Indexed: 11/20/2024]
Abstract
As a novel form of cell death, ferroptosis is mainly regulated by the accumulation of soluble iron ions in the cytoplasm and the production of lipid peroxides and is closely associated with several diseases, including acute kidney injury, ischemic reperfusion injury, neurodegenerative diseases, and cancer. The term "immunosuppression" refers to various factors that can directly harm immune cells' structure and function and affect the synthesis, release, and biological activity of immune molecules, leading to the insufficient response of the immune system to antigen production, failure to successfully resist the invasion of foreign pathogens, and even organ damage and metabolic disorders. An immunosuppressive phase commonly occurs in the progression of many ferroptosis-related diseases, and ferroptosis can directly inhibit immune cell function. However, the relationship between ferroptosis and immunosuppression has not yet been published due to their complicated interactions in various diseases. Therefore, this review deeply discusses the contribution of ferroptosis to immunosuppression in specific cases. In addition to offering new therapeutic targets for ferroptosis-related diseases, the findings will help clarify the issues on how ferroptosis contributes to immunosuppression.
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Affiliation(s)
- Nina He
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, China
- National Medicine Functional Experimental Teaching Center, Changsha, 410008, China
| | - Dun Yuan
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Minjie Luo
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, China
- National Medicine Functional Experimental Teaching Center, Changsha, 410008, China
| | - Qing Xu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, China
- National Medicine Functional Experimental Teaching Center, Changsha, 410008, China
| | - Zhongchi Wen
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, China
- National Medicine Functional Experimental Teaching Center, Changsha, 410008, China
| | - Ziqin Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, China
- National Medicine Functional Experimental Teaching Center, Changsha, 410008, China
| | - Jie Zhao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, China.
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, China.
- National Medicine Functional Experimental Teaching Center, Changsha, 410008, China.
| | - Ying Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, China.
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, 410008, China.
- National Medicine Functional Experimental Teaching Center, Changsha, 410008, China.
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5
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Liu JC, Zeng Q, Duan YG, Yeung WSB, Li RHW, Ng EHY, Cheung KW, Zhang Q, Chiu PCN. B cells: roles in physiology and pathology of pregnancy. Front Immunol 2024; 15:1456171. [PMID: 39434884 PMCID: PMC11491347 DOI: 10.3389/fimmu.2024.1456171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 09/23/2024] [Indexed: 10/23/2024] Open
Abstract
B cells constitute a diverse and adaptable immune cell population with functions that can vary according to the environment and circumstances. The involvement of B cells in pregnancy, as well as the associated molecular pathways, has yet to be investigated. This review consolidates current knowledge on B cell activities and regulation during pregnancy, with a particular focus on the roles of various B cell subsets and the effects of B cell-derived factors on pregnancy outcomes. Moreover, the review examines the significance of B cell-associated autoantibodies, cytokines, and signaling pathways in relation to pregnancy complications such as pregnancy loss, preeclampsia, and preterm birth.
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Affiliation(s)
- Jin-Chuan Liu
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Qunxiong Zeng
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Yong-Gang Duan
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - William S. B. Yeung
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Raymond H. W. Li
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Ernest H. Y. Ng
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Ka-Wang Cheung
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Qingqing Zhang
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Philip C. N. Chiu
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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Álvarez-López AI, Álvarez-Sánchez N, Cruz-Chamorro I, Santos-Sánchez G, Ponce-España E, Bejarano I, Lardone PJ, Carrillo-Vico A. Melatonin synergistically potentiates the effect of methylprednisolone on reducing neuroinflammation in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. J Autoimmun 2024; 148:103298. [PMID: 39067314 DOI: 10.1016/j.jaut.2024.103298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 07/13/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024]
Abstract
Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of unknown etiology characterized by infiltration of encephalitogenic cells in the central nervous system (CNS) resulting in the presence of multifocal areas of demyelination leading to neurodegeneration. The infiltrated immune cells population is composed mainly of effector CD4+ and CD8+ T lymphocytes, B cells, macrophages, and dendritic cells that secrete pro-inflammatory factors that eventually damage myelin leading to axonal damage. The most common clinical form of MS is relapsing-remitting (RR), characterized by neuroinflammatory episodes followed by partial or total recovery of neurological deficits. The first-line treatment for RRMS relapses is a high dose of glucocorticoids, especially methylprednisolone, for three to five consecutive days. Several studies have reported the beneficial effects of melatonin in the context of neuroinflammation associated with MS or experimental autoimmune encephalomyelitis (EAE), the preclinical model for MS. Therefore, the objective of this study was to evaluate the effect of the combined treatment of melatonin and methylprednisolone on the neuroinflammatory response associated with the EAE development. This study shows for the first time the protective synergistic effect of co-treatment with melatonin and methylprednisolone on reducing the severity of EAE by decreasing CD4 lymphocytes, B cells, macrophages and dendritic cells in the CNS, as well as modulating the population of infiltrated T and B cells toward regulatory phenotypes to the detriment of pro-inflammatory effector functions. In addition to the potentiation of the protective role of methylprednisolone, treatment with melatonin from the clinical onset of EAE improves the natural course of the EAE and the response to a subsequent treatment with methylprednisolone in a later relapse of the disease, pointing melatonin as potential therapeutic tool in combination with methylprednisolone for the treatment of relapses in MS.
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Affiliation(s)
- Ana Isabel Álvarez-López
- Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, 41013, Spain; Departamento de Bioquímica Médica y Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Seville, 41009, Spain
| | - Nuria Álvarez-Sánchez
- Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, 41013, Spain
| | - Ivan Cruz-Chamorro
- Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, 41013, Spain; Departamento de Bioquímica Médica y Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Seville, 41009, Spain
| | - Guillermo Santos-Sánchez
- Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, 41013, Spain; Departamento de Bioquímica Médica y Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Seville, 41009, Spain
| | - Eduardo Ponce-España
- Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, 41013, Spain; Departamento de Bioquímica Médica y Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Seville, 41009, Spain
| | - Ignacio Bejarano
- Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, 41013, Spain; Departamento de Bioquímica Médica y Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Seville, 41009, Spain
| | - Patricia Judith Lardone
- Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, 41013, Spain; Departamento de Bioquímica Médica y Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Seville, 41009, Spain.
| | - Antonio Carrillo-Vico
- Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, 41013, Spain; Departamento de Bioquímica Médica y Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Seville, 41009, Spain.
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7
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Ye J, Wei B, Zhou G, Xu Y, He Y, Hu X, Chen X, Zhang G, Liu H. Multi-dimensional characterization of apoptosis in the tumor microenvironment and therapeutic relevance in melanoma. Cell Oncol (Dordr) 2024; 47:1333-1353. [PMID: 38502270 PMCID: PMC11322377 DOI: 10.1007/s13402-024-00930-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2024] [Indexed: 03/21/2024] Open
Abstract
PURPOSE Melanoma is widely utilized as a prominent model for the development of immunotherapy, thought an inadequate immune response can occur. Moreover, the development of apoptosis-related therapies and combinations with other therapeutic strategies is impeded by the limited understanding of apoptosis's role within diverse tumor immune microenvironments (TMEs). METHODS Here, we constructed an apoptosis-related tumor microenvironment signature (ATM) and employ multi-dimensional analysis to understand the roles of apoptosis in tumor microenvironment. We further assessed the clinical applications of ATM in nine independent cohorts, and anticipated the impact of ATM on cellular drug response in cultured cells. RESULTS Our ATM model exhibits robust performance in survival prediction in multiple melanoma cohorts. Different ATM groups exhibited distinct molecular signatures and biological processes. The low ATM group exhibited significant enrichment in B cell activation-related pathways. What's more, plasma cells showed the lowest ATM score, highlighting their role as pivotal contributors in the ATM model. Mechanistically, the analysis of the interplay between plasma cells and other immune cells elucidated their crucial role in orchestrating an effective anti-tumor immune response. Significantly, the ATM signature exhibited associations with therapeutic efficacy of immune checkpoint blockade and the drug sensitivity of various agents, including FDA-approved and clinically utilized drugs targeting the VEGF signaling pathway. Finally, ATM was associated with tertiary lymphoid structures (TLS), exhibiting stronger patient stratification ability compared to classical "hot tumors". CONCLUSION Our findings indicate that ATM is a prognostic factor and is associated with the immune response and drug sensitivity in melanoma.
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Affiliation(s)
- Jing Ye
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, 410008, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, 410008, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Changsha, Hunan, 410008, China
| | - Benliang Wei
- Big Data Institute, Central South University, Changsha, Hunan, 410008, China
| | - Guowei Zhou
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, 410008, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, 410008, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Changsha, Hunan, 410008, China
| | - Yantao Xu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, 410008, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, 410008, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Changsha, Hunan, 410008, China
| | - Yi He
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan, 410008, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, 410008, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, 410008, China
- Xiangya Clinical Research Center for Cancer Immunotherapy, Changsha, Hunan, 410008, China
| | - Xiheng Hu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan, 410008, China.
- Furong Laboratory, Changsha, Hunan, China.
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan, 410008, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, 410008, China.
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, 410008, China.
- Xiangya Clinical Research Center for Cancer Immunotherapy, Changsha, Hunan, 410008, China.
- Furong Laboratory, Changsha, Hunan, China.
| | - Guanxiong Zhang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan, 410008, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, 410008, China.
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, 410008, China.
- Xiangya Clinical Research Center for Cancer Immunotherapy, Changsha, Hunan, 410008, China.
| | - Hong Liu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan, 410008, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, Hunan, 410008, China.
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, Hunan, 410008, China.
- Xiangya Clinical Research Center for Cancer Immunotherapy, Changsha, Hunan, 410008, China.
- Big Data Institute, Central South University, Changsha, Hunan, 410008, China.
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8
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Wang FQ, Shao L, Dang X, Wang YF, Chen S, Liu Z, Mao Y, Jiang Y, Hou F, Guo X, Li J, Zhang L, Sang Y, Zhao X, Ma R, Zhang K, Zhang Y, Yang J, Wen X, Liu J, Wei W, Zhang C, Li W, Qin X, Lei Y, Feng H, Yang X, She CH, Zhang C, Su H, Chen X, Yang J, Lau YL, Wu Q, Ban B, Song Q, Yang W. Unraveling transcriptomic signatures and dysregulated pathways in systemic lupus erythematosus across disease states. Arthritis Res Ther 2024; 26:99. [PMID: 38741185 PMCID: PMC11089778 DOI: 10.1186/s13075-024-03327-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 04/21/2024] [Indexed: 05/16/2024] Open
Abstract
OBJECTIVES This study aims to elucidate the transcriptomic signatures and dysregulated pathways in patients with Systemic Lupus Erythematosus (SLE), with a particular focus on those persisting during disease remission. METHODS We conducted bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) from a well-defined cohort comprising 26 remission patients meeting the Low Lupus Disease Activity State (LLDAS) criteria, 76 patients experiencing disease flares, and 15 healthy controls. To elucidate immune signature changes associated with varying disease states, we performed extensive analyses, including the identification of differentially expressed genes and pathways, as well as the construction of protein-protein interaction networks. RESULTS Several transcriptomic features recovered during remission compared to the active disease state, including down-regulation of plasma and cell cycle signatures, as well as up-regulation of lymphocytes. However, specific innate immune response signatures, such as the interferon (IFN) signature, and gene modules involved in chromatin structure modification, persisted across different disease states. Drug repurposing analysis revealed certain drug classes that can target these persistent signatures, potentially preventing disease relapse. CONCLUSION Our comprehensive transcriptomic study revealed gene expression signatures for SLE in both active and remission states. The discovery of gene expression modules persisting in the remission stage may shed light on the underlying mechanisms of vulnerability to relapse in these patients, providing valuable insights for their treatment.
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Affiliation(s)
- Frank Qingyun Wang
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Li Shao
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Xiao Dang
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Yong-Fei Wang
- School of Life and Health Sciences, School of Medicine, and Warshel Institute for Computational Biology, The Chinese University of Hong Kong - Shenzhen, Shenzhen, Guangdong, China
| | - Shuxiong Chen
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Zhongyi Liu
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Yujing Mao
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Yuping Jiang
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Fei Hou
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Xianghua Guo
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Jian Li
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Lili Zhang
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Yuting Sang
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Xuan Zhao
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Ruirui Ma
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Kai Zhang
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Yanfang Zhang
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Jing Yang
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Xiwu Wen
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Jiong Liu
- Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Wei Wei
- Medical Laboratory of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Chuanpeng Zhang
- Medical Laboratory of Jining Medical University, Jining Medical University, Jining, Shandong, China
| | - Weiyang Li
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Xiao Qin
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Yao Lei
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Hong Feng
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Xingtian Yang
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Chun Hing She
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Caicai Zhang
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Huidong Su
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Xinxin Chen
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Jing Yang
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Yu Lung Lau
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
| | - Qingjun Wu
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Bo Ban
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
| | - Qin Song
- Department of Rheumatology and Lupus Research Institute, Affiliated Hospital of Jining Medical University, Jining, Shandong, China.
| | - Wanling Yang
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China.
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9
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Chen P, Chu Y, Liu R. Tumour-reactive plasma cells in antitumour immunity: current insights and future prospects. IMMUNOTHERAPY ADVANCES 2024; 4:ltae003. [PMID: 38736973 PMCID: PMC11088280 DOI: 10.1093/immadv/ltae003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 04/24/2024] [Indexed: 05/14/2024] Open
Abstract
Tumour-reactive plasma cells (TRPCs) have been reported to be positively associated with the long-term survival of patients with various cancers. However, unlike tumour-specific antigen (TSA)-induced T cells which have precise effects against tumours, plasma cells require TSA to obtain specific responses. Therefore, the search for a TSA suitable for B-cell recognition is urgent. In this review, we discuss the functions of tumour-reactive plasma cells. Further, this review also explores the concept of screening for neoantigen-reactive plasma cells, drawing inspiration from T-cell screening methods. While challenges exist, such as epitope prediction and efficient screening, the development of novel techniques may lead to the discovery of highly specific plasma cells for adoptive cell therapy. In conclusion, tumour-reactive plasma cells are emerging as powerful players in cancer immunotherapy. Their ability to produce antibodies against a variety of antigens, especially neoantigens, opens new avenues for personalised treatments. Overcoming challenges in epitope prediction and screening will be crucial in harnessing the full potential of these plasma cells for the benefit of cancer patients.
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Affiliation(s)
- Peng Chen
- Shanghai Fifth People’s Hospital and Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yiwei Chu
- Department of Immunology, School of Basic Medical Sciences, and MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai, China
| | - Ronghua Liu
- Shanghai Fifth People’s Hospital and Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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10
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Yuan C, Zhao X, Feng Y, Chen L, Lin Y, Li T, Song Q. Comparison of B cells' immune response induced by PEDV virulent and attenuated strains. Front Microbiol 2024; 15:1344344. [PMID: 38585694 PMCID: PMC10995339 DOI: 10.3389/fmicb.2024.1344344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 03/07/2024] [Indexed: 04/09/2024] Open
Abstract
Porcine epidemic diarrhea virus (PEDV) is an acute, highly contagious enterovirus that infects pigs of all ages. The B cells are important for antigen presentation, antibody production, and cytokine secretion to resist infection. However, the role of B cells in PEDV infection remains unclear. In this study, the effects of PEDV virulent (QY2016) and attenuated strains (CV777) on B cells sorted from neonatal piglets, nursery piglets, and gilts were investigated. The results showed that PEDV-QY2016 and PEDV-CV777 could significantly increase the expression of CD54 and CD27 in B cells from neonatal piglets. The percentages of CD80, MHC II, and IgM expressed on neonatal piglet B cells infected with PEDV-QY2016 were significantly lower than those expressed on the B cells infected with PEDV-CV777. Both PEDV-QY2016 and PEDV-CV777 could stimulate IFN-α and GM-CSF secretions in neonatal piglet B cells; IL-1, IFN-α, and IL-4 secretion in nursery piglet B cells; and IL-1, TGF-β secretion, and GM-CSF in gilt B cells. Furthermore, both PEDV-QY2016 and PEDV-CV777 could induce the secretion of IgA, IgM, and IgG in nursery piglet B cells but could not induce the secretion of IgA, IgM, and IgG in neonatal piglet B cells. The secretion of IgA, IgM, and IgG was significantly higher by the PEDV-CV777 strains infected B cells than those by the PEDV-QY2016 strains infected gilt B cells. In conclusion, the surface molecule expression, cytokine secretion, and antibody production of B cells induced by PEDV are closely related to the ages of pigs and the virulence of the PEDV strain.
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Affiliation(s)
- Chen Yuan
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
- Veterinary Biological Technology Innovation Center of Hebei Province, Baoding, China
| | - Xue Zhao
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
- Veterinary Biological Technology Innovation Center of Hebei Province, Baoding, China
| | - Yawen Feng
- Hebei Provincial Institute of Veterinary Drug Control, Shijiazhuang, China
| | - Ligong Chen
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
- Veterinary Biological Technology Innovation Center of Hebei Province, Baoding, China
| | - Yidan Lin
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
- Veterinary Biological Technology Innovation Center of Hebei Province, Baoding, China
| | - Tanqing Li
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
- Veterinary Biological Technology Innovation Center of Hebei Province, Baoding, China
| | - Qinye Song
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
- Veterinary Biological Technology Innovation Center of Hebei Province, Baoding, China
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11
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Chen W, Hong SH, Jenks SA, Anam FA, Tipton CM, Woodruff MC, Hom JR, Cashman KS, Faliti CE, Wang X, Kyu S, Wei C, Scharer CD, Mi T, Hicks S, Hartson L, Nguyen DC, Khosroshahi A, Lee S, Wang Y, Bugrovsky R, Ishii Y, Lee FEH, Sanz I. Distinct transcriptomes and autocrine cytokines underpin maturation and survival of antibody-secreting cells in systemic lupus erythematosus. Nat Commun 2024; 15:1899. [PMID: 38429276 PMCID: PMC10907730 DOI: 10.1038/s41467-024-46053-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 02/09/2024] [Indexed: 03/03/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple autoantibody types, some of which are produced by long-lived plasma cells (LLPC). Active SLE generates increased circulating antibody-secreting cells (ASC). Here, we examine the phenotypic, molecular, structural, and functional features of ASC in SLE. Relative to post-vaccination ASC in healthy controls, circulating blood ASC from patients with active SLE are enriched with newly generated mature CD19-CD138+ ASC, similar to bone marrow LLPC. ASC from patients with SLE displayed morphological features of premature maturation and a transcriptome epigenetically initiated in SLE B cells. ASC from patients with SLE exhibited elevated protein levels of CXCR4, CXCR3 and CD138, along with molecular programs that promote survival. Furthermore, they demonstrate autocrine production of APRIL and IL-10, which contributed to their prolonged in vitro survival. Our work provides insight into the mechanisms of generation, expansion, maturation and survival of SLE ASC.
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Affiliation(s)
- Weirong Chen
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - So-Hee Hong
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
- Department of Microbiology, Ewha Womans University, Seoul, Republic of Korea
| | - Scott A Jenks
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Fabliha A Anam
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Christopher M Tipton
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Matthew C Woodruff
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Jennifer R Hom
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Kevin S Cashman
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Caterina Elisa Faliti
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Xiaoqian Wang
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Shuya Kyu
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, School of Medicine, Emory University, Atlanta, GA, USA
| | - Chungwen Wei
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Christopher D Scharer
- Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Tian Mi
- Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Sakeenah Hicks
- Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Louise Hartson
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Doan C Nguyen
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, School of Medicine, Emory University, Atlanta, GA, USA
| | - Arezou Khosroshahi
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Saeyun Lee
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Youliang Wang
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Regina Bugrovsky
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - Yusho Ishii
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA
| | - F Eun-Hyung Lee
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, School of Medicine, Emory University, Atlanta, GA, USA.
| | - Ignacio Sanz
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, School of Medicine, Emory University, Atlanta, GA, USA.
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12
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Bryushkova EA, Mushenkova NV, Turchaninova MA, Lukyanov DK, Chudakov DM, Serebrovskaya EO. B cell clonality in cancer. Semin Immunol 2024; 72:101874. [PMID: 38508089 DOI: 10.1016/j.smim.2024.101874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 01/05/2024] [Accepted: 01/05/2024] [Indexed: 03/22/2024]
Abstract
Carcinogenesis in the process of long-term co-evolution of tumor cells and immune environment essentially becomes possible due to incorrect decisions made, remembered, and reproduced by the immune system at the level of clonal populations of antigen-specific T- and B-lymphocytes. Tumor-immunity interaction determines the nature of such errors and, consequently, delineates the possible ways of successful immunotherapeutic intervention. It is generally recognized that tumor-infiltrating B cells (TIL-B) can play both pro-tumor and anti-tumor roles. However, the exact mechanisms that determine the contribution of clonal B cell lineages with different specificities and functions remain largely unclear. This is due to the variability of cancer types, the molecular heterogeneity of tumor cells, and, to a large extent, the individual pattern of each immune response. Further progress requires detailed investigation of the functional properties and phenotypes of clonally heterogeneous B cells in relation to their antigenic specificities, which determine the functionality of both effector B lymphocytes and immunoglobulins produced in the tumor environment. Based on a real understanding of the role of clonal antigen-specific populations of B lymphocytes in the tumor microenvironment, we need to learn how to develop new methods of targeted immunotherapy, as well as adapt existing treatment options to the specific needs of different patients and patient subgroups. In this review, we will cover B cells functional diversity and their multifaceted roles in the tumor environment.
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Affiliation(s)
- E A Bryushkova
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia; Department of Molecular Biology, Lomonosov Moscow State University, Moscow, Russia
| | - N V Mushenkova
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; Unicorn Capital Partners, Moscow, Russia
| | - M A Turchaninova
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
| | - D K Lukyanov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia; Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - D M Chudakov
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia; Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia; Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
| | - E O Serebrovskaya
- Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia; Current position: Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany
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13
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Flati I, Di Vito Nolfi M, Dall’Aglio F, Vecchiotti D, Verzella D, Alesse E, Capece D, Zazzeroni F. Molecular Mechanisms Underpinning Immunometabolic Reprogramming: How the Wind Changes during Cancer Progression. Genes (Basel) 2023; 14:1953. [PMID: 37895302 PMCID: PMC10606647 DOI: 10.3390/genes14101953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Metabolism and the immunological state are intimately intertwined, as defense responses are bioenergetically expensive. Metabolic homeostasis is a key requirement for the proper function of immune cell subsets, and the perturbation of the immune-metabolic balance is a recurrent event in many human diseases, including cancer, due to nutrient fluctuation, hypoxia and additional metabolic changes occurring in the tumor microenvironment (TME). Although much remains to be understood in the field of immunometabolism, here, we report the current knowledge on both physiological and cancer-associated metabolic profiles of immune cells, and the main molecular circuits involved in their regulation, highlighting similarities and differences, and emphasizing immune metabolic liabilities that could be exploited in cancer therapy to overcome immune resistance.
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Affiliation(s)
| | | | | | | | | | | | - Daria Capece
- Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L’Aquila, Via Vetoio, Coppito 2, 67100 L’Aquila, Italy; (I.F.); (M.D.V.N.); (F.D.); (D.V.); (D.V.); (E.A.); (F.Z.)
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14
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Koutsogiannaki S, Kim S, Yuki K. Age-dependent transcriptomic profiles of leukocytes in pediatric population. Clin Immunol 2023; 255:109728. [PMID: 37562722 PMCID: PMC10543464 DOI: 10.1016/j.clim.2023.109728] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/24/2023] [Accepted: 07/30/2023] [Indexed: 08/12/2023]
Abstract
Immunity at birth is considered immature. Following birth, our immune function is considered to grow and reach maturation over time. To obtain granular information of leukocyte functions and transcriptomic profiles in pediatric cohort, we examined leukocyte profiles in infants, preschool and school children using single cell RNA sequencing of their peripheral blood mononuclear cells (PBMCs). Monocytes and natural killer (NK) cells showed immaturity in infants. Their innate and adaptive immunity was developed by preschool age. Adaptive immune cells showed different maturation patterns. CD4, CD8 naïve T cells and plasma cells continued to mature untill school age. In CD8 naïve T cells, innate immunity was upregulated in infants, in support of our knowledge that they manifests more innate cell-like phenotype soon after birth. Many signaling pathways have been differentially up- and/or down-regulated in infants, preschool and school children. Their contribution to the development of the immune system needs to be delineated.
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Affiliation(s)
- Sophia Koutsogiannaki
- Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia Division, Boston Children's Hospital, Boston, MA, 02115, United States; Department of Anaesthesia and Immunology, Harvard Medical School, Boston, MA, 02115, United States; Broad Institute of MIT and Harvard, Cambridge, MA, 02141, United States
| | - Samuel Kim
- Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia Division, Boston Children's Hospital, Boston, MA, 02115, United States
| | - Koichi Yuki
- Department of Anesthesiology, Critical Care and Pain Medicine, Cardiac Anesthesia Division, Boston Children's Hospital, Boston, MA, 02115, United States; Department of Anaesthesia and Immunology, Harvard Medical School, Boston, MA, 02115, United States; Broad Institute of MIT and Harvard, Cambridge, MA, 02141, United States.
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15
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Sae-fung A, Mutirangura A, Jitkaew S. Identification and validation of a novel ferroptosis-related gene signature for prognosis and potential therapeutic target prediction in cholangiocarcinoma. Front Immunol 2023; 13:1051273. [PMID: 36733386 PMCID: PMC9887182 DOI: 10.3389/fimmu.2022.1051273] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/30/2022] [Indexed: 01/18/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly heterogeneous and aggressive malignancy of the bile ducts with a poor prognosis and high mortality rate. Effective targeted therapy and accurate prognostic biomarkers are still lacking. Ferroptosis is a form of regulated cell death implicated in cancer progression and has emerged as a potential therapeutic target in various cancers. However, a comprehensive analysis of ferroptosis-related genes (FRGs) for predicting CCA prognosis and therapeutic targets and determining the role of ferroptosis in CCA remain to be performed. Here, we developed a prognostic FRG signature using a least absolute shrinkage and selection operator Cox regression analysis in a training cohort. We then validated it using four independent public datasets. The six-FRG signature was developed to predict CCA patient survival, stratifying them into low-risk and high-risk groups based on survival time. Significantly, the high-risk CCA patients had shorter overall survival. A receiver operating characteristic curve analysis further confirmed the prognostic FRG signature's strong predictive ability, indicating that it was an independent prognostic indicator for CCA patients. Furthermore, the high-risk group was associated with fluke infection and high clinical stages. Cancer-associated fibroblast (CAF) score and CAF markers were significantly higher in the high-risk group than the low-risk group. Moreover, our FRG signature could predict immune checkpoint markers for immunotherapy and drug sensitivity. The mRNA expression levels of the six-FRG signature was validated in 10 CCA cell lines and dividing them into low-risk and high-risk groups using the FRG signature. We further showed that high-risk CCA cell lines were more resistant to ferroptosis inducers, including erastin and RSL3, than the low-risk CCA cell lines. Our study constructed a novel FRG signature model to predict CCA prognoses which might provide prognostic biomarkers and potential therapeutic targets for CCA patients. Ferroptosis sensitivity in high-risk and low-risk CCA cell lines suggests that ferroptosis resistance is associated with high-risk group CCA. Therefore, ferroptosis could be a promising therapeutic target for precision therapy in CCA patients.
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Affiliation(s)
- Apiwit Sae-fung
- Graduate Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Apiwat Mutirangura
- Department of Anatomy, Faculty of Medicine, Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Chulalongkorn University, Bangkok, Thailand
| | - Siriporn Jitkaew
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand,Age-Related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand,*Correspondence: Siriporn Jitkaew,
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16
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Younger DS. Pediatric neuropsychiatric disorders with motor and nonmotor phenomena. HANDBOOK OF CLINICAL NEUROLOGY 2023; 196:367-387. [PMID: 37620079 DOI: 10.1016/b978-0-323-98817-9.00028-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2023]
Abstract
The concept of pediatric autoimmune neuropsychiatric disorders associated with group A beta-hemolytic streptococcus (PANDAS) has become seminal since first introduced more than two decades ago. At the time of this writing, most neurologists, pediatricians, psychiatrists, and general pediatricians will probably have heard of this association or treated an affected child with PANDAS. The concept of an acute-onset, and typically self-limited, postinfectious autoimmune neuropsychiatric disorder resembling PANDAS manifesting vocal and motor tics and obsessive-compulsive disorder has broadened to other putative microbes and related endogenous and exogenous disease triggers. These disorders with common features of hypometabolism in the medial temporal lobe and hippocampus in brain 18fluorodeoxyglucose positron emission tomography fused to magnetic resonance imaging (FDG PET-MRI), form a spectrum: with the neuropsychiatric disorder Tourette syndrome and PANDAS with its well-defined etiopathogenesis at one end, and pediatric abrupt-onset neuropsychiatric syndrome (PANS), alone or associated with specific bacterial and viral pathogens, at the other end. The designation of PANS in the absence of a specific trigger, as an exclusionary diagnosis, reflects the current problem in nosology.
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Affiliation(s)
- David S Younger
- Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States; Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States.
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17
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Le TA, Chu VT, Lino AC, Schrezenmeier E, Kressler C, Hamo D, Rajewsky K, Dörner T, Dang VD. Efficient CRISPR-Cas9-mediated mutagenesis in primary human B cells for identifying plasma cell regulators. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 30:621-632. [PMID: 36514352 PMCID: PMC9722396 DOI: 10.1016/j.omtn.2022.11.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022]
Abstract
Human B lymphocytes are attractive targets for immunotherapies in autoantibody-mediated diseases. Gene editing technologies could provide a powerful tool to determine gene regulatory networks regulating B cell differentiation into plasma cells, and identify novel therapeutic targets for prevention and treatment of autoimmune disorders. Here, we describe a new approach that uses CRISPR-Cas9 technology to target genes in primary human B cells in vitro for identifying plasma cell regulators. We found that sgRNA and Cas9 components can be efficiently delivered into primary human B cells through RD114-pseudotyped retroviral vectors. Using this system, we achieved approximately 80% of gene knockout efficiency. We disrupted expression of a triad of transcription factors, IRF4, PRDM1, and XBP1, and showed that human B cell survival and plasma cell differentiation are severely impaired. Specifically, that IRF4, PRDM1, and XBP1 were expressed at different stages during plasma cell differentiation, IRF4, PRDM1, and XBP1-targeted B cells failed to progress to the pre-plasmablast, plasma cell state, and plasma cell survival, respectively. Our method opens a new avenue to study gene functions in primary human B cells and identify novel plasma cell regulators for therapeutic applications.
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Affiliation(s)
- Tuan Anh Le
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Van Trung Chu
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Immune Regulation and Cancer, 13125 Berlin, Germany
| | - Andreia C. Lino
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Eva Schrezenmeier
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Christopher Kressler
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Dania Hamo
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Klaus Rajewsky
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Immune Regulation and Cancer, 13125 Berlin, Germany
| | - Thomas Dörner
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Corresponding author Thomas Dörner, Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
| | - Van Duc Dang
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Faculty of Biology, VNU University of Science, Vietnam National University, Hanoi, Vietnam
- Corresponding author Van Duc Dang, Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Charitéplatz 1, 10117 Berlin, Germany.
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18
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Ganesan N, Ronsmans S, Hoet P. Differential immunological effects of silica nanoparticles on peripheral blood mononuclear cells of silicosis patients and controls. Front Immunol 2022; 13:1025028. [PMID: 36311760 PMCID: PMC9606771 DOI: 10.3389/fimmu.2022.1025028] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 09/21/2022] [Indexed: 11/29/2022] Open
Abstract
Silicosis is a fibrotic disease caused by the inhalation of respirable silica particles, which are typically engulfed by alveolar macrophages and subsequently induce the release of inflammatory cytokines. Various animal experimental and human studies have focused on modeling silicosis, to assess the interactions of macrophages and other cell types with silica particles. There is still, however, limited knowledge on the differential response upon silica-exposure between silicosis patients and controls. We focused on studying the responsiveness of peripheral blood mononuclear cells (PBMCs) to silica nanoparticles (SiNPs) - Ludox and NM-200 - of silicosis patients and controls. The proliferative capacity of T- CD3+ and B- CD19+ cells, were evaluated via Carboxyfluorescein succinimidyl ester (CFSE) assay. The activation status of lymphocyte subsets and response to silica were also evaluated by comparing the extent of micro-granuloma or aggregate formation with the cytokine secretion profiles between both groups of individuals. The proliferative capacity of CD19+ cells was elevated in silicotic patients as opposed to controls. Subsets of regulatory T cells (CD4+ CD25+ and CD8+ CD25+) and immunoglobulins IgM and IgG were also significantly increased in patients. The number and the size of aggregates formed were higher with SiNPs stimulation in patients compared to controls. Multivariable analysis also elucidated the role of key cytokines like interleukin-1β (IL-1β), IL-6 and interferon-gamma (IFN-γ), which were upregulated in SiNP-stimulated PBMCs of patients compared to controls. Our ex vivo model thus has potential to provide insights into the immunological effects of silica particles in lymphocytes of silicosis patients and controls.
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Affiliation(s)
- Nirosha Ganesan
- Laboratory of Toxicology, Unit of Environment & Health, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Steven Ronsmans
- Laboratory of Toxicology, Unit of Environment & Health, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium
- Clinic for Occupational and Environmental Medicine, Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Peter Hoet
- Laboratory of Toxicology, Unit of Environment & Health, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- *Correspondence: Peter Hoet,
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19
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Stephenson S, Care MA, Doody GM, Tooze RM. APRIL Drives a Coordinated but Diverse Response as a Foundation for Plasma Cell Longevity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:926-937. [PMID: 36130130 PMCID: PMC7613700 DOI: 10.4049/jimmunol.2100623] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 06/29/2022] [Indexed: 01/04/2023]
Abstract
Ab-secreting cells survive in niche microenvironments, but cellular responses driven by particular niche signals are incompletely defined. The TNF superfamily member a proliferation-inducing ligand (APRIL) can support the maturation of transitory plasmablasts into long-lived plasma cells. In this study, we explore the biological programs established by APRIL in human plasmablasts. Under conditions allowing the maturation of ex vivo- or in vitro-generated plasmablasts, we find that APRIL drives activation of ERK, p38, and JNK, accompanied by a classical NF-κB response and activation of the AKT/FOXO1 pathway. Time-course gene expression data resolve coordinated transcriptional responses propagated via immediate early genes and NF-κB targets and converging onto modules of genes enriched for MYC targets and metabolism/cell growth-related pathways. This response is shared between APRIL and an alternate TNF superfamily member CD40L but is not a feature of alternative niche signals delivered by IFN-α or SDF1. However, APRIL and CD40L responses also diverge. CD40L drives expression of genes related to the activated B cell state whereas APRIL does not. Thus, APRIL establishes a broad foundation for plasma cell longevity with features of cellular refueling while being uncoupled from support of the B cell state.
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Affiliation(s)
- Sophie Stephenson
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom; and
| | - Matthew A Care
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom; and
- Bioinformatics Group, School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom
| | - Gina M Doody
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom; and
| | - Reuben M Tooze
- Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom; and
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20
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Bhat AA, Nisar S, Singh M, Ashraf B, Masoodi T, Prasad CP, Sharma A, Maacha S, Karedath T, Hashem S, Yasin SB, Bagga P, Reddy R, Frennaux MP, Uddin S, Dhawan P, Haris M, Macha MA. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022; 42:689-715. [PMID: 35791509 PMCID: PMC9395317 DOI: 10.1002/cac2.12295] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
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Affiliation(s)
- Ajaz A. Bhat
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Mayank Singh
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Bazella Ashraf
- Department of BiotechnologySchool of Life SciencesCentral University of KashmirGanderbalJammu & Kashmir191201India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Chandra P. Prasad
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Atul Sharma
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Selma Maacha
- Division of Translational MedicineResearch BranchSidra MedicineDoha26999Qatar
| | | | - Sheema Hashem
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Syed Besina Yasin
- Department of PathologySher‐I‐Kashmir Institute of Medical SciencesSrinagarJammu & Kashmir190011India
| | - Puneet Bagga
- Department of Diagnostic ImagingSt. Jude Children's Research HospitalMemphisTN38105USA
| | - Ravinder Reddy
- Center for Advanced Metabolic Imaging in Precision MedicineDepartment of RadiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA19104USA
| | | | - Shahab Uddin
- Translational Research InstituteHamad Medical CorporationDoha3050Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
- Laboratory Animal Research CenterQatar UniversityDoha2713Qatar
| | - Muzafar A. Macha
- Watson‐Crick Centre for Molecular MedicineIslamic University of Science and TechnologyAwantiporaJammu & Kashmir192122India
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21
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Immune Cell Infiltration Characteristics of Pigmented Villous Nodular Synovitis and Prediction of Potential Diagnostic Markers Based on Bioinformatics. BIOMED RESEARCH INTERNATIONAL 2022; 2022:8708692. [PMID: 35711523 PMCID: PMC9197622 DOI: 10.1155/2022/8708692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 05/21/2022] [Indexed: 11/21/2022]
Abstract
Background Pigmented villous nodular synovitis (PVNS) is a tumor-like proliferative disease characterized by impairment of daily activities, decreased quality of life, and a high recurrence rate. However, the specific pathological mechanisms are still ill-defined and controversial. The purpose of this study was to define potential diagnostic markers and evaluate immune cell infiltration in the pathogenesis of PVNS. Method The expression profile of GSE3698 was reanalyzed in the Gene Expression Omnibus (GEO) database. First, differentially expressed genes (DEGs) were identified using the R package “limma” and analyzed by Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Next, the DEGs were imported into the STRING database and Cytoscape to construct a protein–protein interaction (PPI) network. Then, cytoHubba and ROC curve analyses were used to determine potential diagnostic biomarkers of PVNS. Finally, we used CIBERSORT to estimate the proportions of 22 immune cell subtypes in PVNS and analyzed the correlation between diagnostic markers and infiltrating immune cells. Result We found 139 DEGs (including 93 upregulated genes and 46 downregulated genes). TYROBP, FCER1G, LAPTM5, and HLA-DPB1 were identified as potential diagnostic biomarkers of PVNS. Immune cell infiltration analysis indicated that neutrophils and M2 macrophages might be associated with the genesis and progression of PVNS. Furthermore, our correlation analysis of diagnostic markers and infiltrating immune cells found that TYROBP, FCER1G, LAPTM5, and HLA-DPB1 were positively correlated with M2 macrophage infiltration and that neutrophils, TYROBP, FCER1G, and LAPTM5 were negatively correlated with plasma cell infiltration. Conclusions We identified TYROBP, FCER1G, LAPTM5, and HLA-DPB1 as potential diagnostic markers for PVNS and concluded that immune cell infiltration plays an important role in the genesis and progression of PVNS.
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22
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B cells in autoimmune hepatitis: bystanders or central players? Semin Immunopathol 2022; 44:411-427. [PMID: 35488094 PMCID: PMC9256567 DOI: 10.1007/s00281-022-00937-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/07/2022] [Indexed: 02/07/2023]
Abstract
B cells are central for the adaptive immune system to mount successful immune responses not only as antibody producers but also as regulators of cellular immunity. These multifaceted features are also reflected in autoimmunity where autoreactive B cells can fuel disease by production of cytotoxic autoantibodies, presentation of autoantigens to autoreactive T cells, and secretion of cytokines and chemokines that either promote detrimental immune activation or impair regulatory T and B cells. The role of B cells and autoantibodies in autoimmune hepatitis (AIH) have been controversially discussed, with typical autoantibodies and hypergammaglobulinemia indicating a key role, while strong HLA class II association suggests T cells as key players. In this review, we summarize current knowledge on B cells in AIH and how different B cell subpopulations may drive AIH progression beyond autoantibodies. We also discuss recent findings of B cell-directed therapies in AIH.
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23
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Dang VD, Mohr E, Szelinski F, Le TA, Ritter J, Hinnenthal T, Stefanski AL, Schrezenmeier E, Ocvirk S, Hipfl C, Hardt S, Cheng Q, Hiepe F, Löhning M, Dörner T, Lino AC. CD39 and CD326 Are Bona Fide Markers of Murine and Human Plasma Cells and Identify a Bone Marrow Specific Plasma Cell Subpopulation in Lupus. Front Immunol 2022; 13:873217. [PMID: 35464469 PMCID: PMC9024045 DOI: 10.3389/fimmu.2022.873217] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/15/2022] [Indexed: 12/18/2022] Open
Abstract
Antibody-secreting cells (ASCs) contribute to immunity through production of antibodies and cytokines. Identification of specific markers of ASC would allow selective targeting of these cells in several disease contexts. Here, we performed an unbiased, large-scale protein screening, and identified twelve new molecules that are specifically expressed by murine ASCs. Expression of these markers, particularly CD39, CD81, CD130, and CD326, is stable and offers an improved resolution for ASC identification. We accessed their expression in germ-free conditions and in T cell deficient mice, showing that at least in part their expression is controlled by microbial- and T cell-derived signals. Further analysis of lupus mice revealed the presence of a subpopulation of LAG-3– plasma cells, co-expressing high amounts of CD39 and CD326 in the bone marrow. This population was IgM+ and correlated with IgM anti-dsDNA autoantibodies in sera. Importantly, we found that CD39, CD81, CD130, and CD326 are also expressed by human peripheral blood and bone marrow ASCs. Our data provide innovative insights into ASC biology and function in mice and human, and identify an intriguing BM specific CD39++CD326++ ASC subpopulation in autoimmunity.
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Affiliation(s)
- Van Duc Dang
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Faculty of Biology, VNU University of Science, Vietnam National University, Hanoi, Vietnam
| | - Elodie Mohr
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
| | - Franziska Szelinski
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Tuan Anh Le
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Jacob Ritter
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Timo Hinnenthal
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
| | - Ana-Luisa Stefanski
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Eva Schrezenmeier
- Berlin Institute of Health (BIH), Berlin, Germany
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Soeren Ocvirk
- Intestinal Microbiology Research Group, Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
| | - Christian Hipfl
- Centre for Musculoskeletal Surgery, Department of Orthopedics, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Sebastian Hardt
- Centre for Musculoskeletal Surgery, Department of Orthopedics, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Qingyu Cheng
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Falk Hiepe
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Max Löhning
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Dörner
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Andreia C. Lino
- Deutsches Rheuma-Forschungszentrum, A Leibniz Institute, Berlin, Germany
- Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
- *Correspondence: Andreia C. Lino,
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24
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Venglar O, Bago JR, Motais B, Hajek R, Jelinek T. Natural Killer Cells in the Malignant Niche of Multiple Myeloma. Front Immunol 2022; 12:816499. [PMID: 35087536 PMCID: PMC8787055 DOI: 10.3389/fimmu.2021.816499] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022] Open
Abstract
Natural killer (NK) cells represent a subset of CD3- CD7+ CD56+/dim lymphocytes with cytotoxic and suppressor activity against virus-infected cells and cancer cells. The overall potential of NK cells has brought them to the spotlight of targeted immunotherapy in solid and hematological malignancies, including multiple myeloma (MM). Nonetheless, NK cells are subjected to a variety of cancer defense mechanisms, leading to impaired maturation, chemotaxis, target recognition, and killing. This review aims to summarize the available and most current knowledge about cancer-related impairment of NK cell function occurring in MM.
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Affiliation(s)
- Ondrej Venglar
- Faculty of Science, University of Ostrava, Ostrava, Czechia.,Faculty of Medicine, University of Ostrava, Ostrava, Czechia.,Hematooncology Clinic, University Hospital Ostrava, Ostrava, Czechia
| | - Julio Rodriguez Bago
- Faculty of Medicine, University of Ostrava, Ostrava, Czechia.,Hematooncology Clinic, University Hospital Ostrava, Ostrava, Czechia
| | - Benjamin Motais
- Faculty of Science, University of Ostrava, Ostrava, Czechia.,Faculty of Medicine, University of Ostrava, Ostrava, Czechia
| | - Roman Hajek
- Faculty of Medicine, University of Ostrava, Ostrava, Czechia.,Hematooncology Clinic, University Hospital Ostrava, Ostrava, Czechia
| | - Tomas Jelinek
- Faculty of Medicine, University of Ostrava, Ostrava, Czechia.,Hematooncology Clinic, University Hospital Ostrava, Ostrava, Czechia
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25
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Budiningsih I, Dachlan YP, Hadi U, Middeldorp JM. Quantitative cytokine level of TNF-α, IFN-γ, IL-10, TGF-β and circulating Epstein-Barr virus DNA load in individuals with acute Malaria due to P. falciparum or P. vivax or double infection in a Malaria endemic region in Indonesia. PLoS One 2021; 16:e0261923. [PMID: 34962938 PMCID: PMC8714090 DOI: 10.1371/journal.pone.0261923] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 12/13/2021] [Indexed: 01/15/2023] Open
Abstract
Plasmodium falciparum Malaria and Epstein-Barr Virus (EBV) infection are risk factors in the development of Burkitt’s lymphoma. In Indonesia, 100% of the population is persistently infected with EBV early in life and at risk of developing EBV-linked cancers. Currently, 10.7 million people in Indonesia are living in Malaria-endemic areas. This cross-sectional study was initiated to investigate how acute Malaria dysregulates immune control over latent EBV infection. Using blood and plasma samples of 68 patients with acute Malaria and 27 healthy controls, we measured the level of parasitemia for each plasmodium type (P. falciparum, P. vivax, and mixed) by microscopy and rapid test. The level of 4 regulatory cytokines was determined by quantitative ELISA and the level of circulating EBV genome by real-time PCR targeting the single copy EBNA-1 sequence. All Plasmodium-infected cases had high-level parasitemia (>1000 parasites/ul blood) except for one case. EBV-DNA levels were significantly more elevated in P. falciparum and P. vivax infections (P<0.05) compared to controls. EBV-DNA levels were not related to age, gender, Malaria symptoms, or plasmodium type. TNF-α and IL-10 levels were increased in Malaria cases versus controls, but IFN-γ and TGF- β levels were comparable between the groups. Only TNF-α levels in P. falciparum cases showed a clear correlation with elevated EBV DNA levels (R2 = 0.8915). This is the first study addressing the relation between EBV (re)activation and cytokine responses during acute Malaria, revealing a clear correlation between pro-inflammatory cytokine TNF-α and EBV-DNA levels, specifically in P. falciparum cases, suggesting this cytokine to be key in dysregulating EBV homeostasis during acute P. falciparum Malaria.
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Affiliation(s)
- Insani Budiningsih
- Post Graduate Doctoral Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Yoes Prijatna Dachlan
- Department of Parasitology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Usman Hadi
- Department of Internal Medicine, Dr. Soetomo Hospital-School of Medicine, Universitas Airlangga, Surabaya, Indonesia
- * E-mail: (UH); (JMM)
| | - Jaap Michiel Middeldorp
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
- * E-mail: (UH); (JMM)
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26
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Dang VD, Stefanski AL, Lino AC, Dörner T. B- and Plasma Cell Subsets in Autoimmune Diseases: Translational Perspectives. J Invest Dermatol 2021; 142:811-822. [PMID: 34955289 DOI: 10.1016/j.jid.2021.05.038] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/04/2021] [Accepted: 05/14/2021] [Indexed: 12/22/2022]
Abstract
B lymphocytes play a central role in immunity owing to their unique antibody-producing capacity that provides protection against certain infections and during vaccination. In autoimmune diseases, B cells can gain pathogenic relevance through autoantibody production, antigen presentation, and proinflammatory cytokine secretion. Recent data indicate that B and plasma cells can function as regulators through the production of immunoregulatory cytokines and/or employing checkpoint molecules. In this study, we review the key findings that define subsets of B and plasma cells with pathogenic and protective functions in autoimmunity. In addition to harsh B-cell depletion, we discuss the strategies that have the potential to reinstall the balance of pathogenic and protective B cells with the potential of more specific and personalized therapies.
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Affiliation(s)
- Van Duc Dang
- German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany; Department of Rheumatology and Clinical Immunology, Charite Universitatsmedizin Berlin, Berlin, Germany; Faculty of Biology, VNU University of Science, Vietnam National University, Hanoi, Vietnam
| | - Ana-Luisa Stefanski
- German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany; Department of Rheumatology and Clinical Immunology, Charite Universitatsmedizin Berlin, Berlin, Germany
| | - Andreia C Lino
- German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany; Department of Rheumatology and Clinical Immunology, Charite Universitatsmedizin Berlin, Berlin, Germany
| | - Thomas Dörner
- German Rheumatism Research Center (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany; Department of Rheumatology and Clinical Immunology, Charite Universitatsmedizin Berlin, Berlin, Germany.
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27
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Zhou B, Li S, Ye J, Liu Y, Hu L, Tang Y, Wu Z, Zhang P. Immunopathological events surrounding IL-6 and IFN-α: A bridge for anti-lupus erythematosus drugs used to treat COVID-19. Int Immunopharmacol 2021; 101:108254. [PMID: 34710657 PMCID: PMC8527889 DOI: 10.1016/j.intimp.2021.108254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 09/26/2021] [Accepted: 10/08/2021] [Indexed: 01/11/2023]
Abstract
With the outbreak and rapid spread of COVID-19, the world health situation is unprecedentedly severe. Systemic lupus erythematosus (SLE) is a common autoimmune disease, which can cause multiple organ damage. Numerous studies have shown that immune factors have important roles in the pathogenesis of both COVID-19 and SLE. In the early stages of COVID-19 and SLE pathogenesis, IFN-α expression is frequently increased, which aggravates the virus infection and promotes SLE development. In addition, increased IL-6 levels, caused by different mechanisms, are observed in the peripheral blood of patients with severe COVID-19 and SLE, stimulating a series of immune cascades that lead to a cytokine storm, as well as causing B cell hyperfunction and production of numerous of antibodies, aggravating both COVID-19 and SLE. In this review, we explore the background immunopathological mechanisms in COVID-19 and SLE and analyze the advantages and disadvantages of commonly used SLE drugs for patients with COVID-19, to optimize treatment plans for patients with SLE who develop COVID-19.
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Affiliation(s)
- Bangyi Zhou
- Nanfang Hospital, Southern Medical University/The First School of Clinical Medicine, Southern Medical University, People’s Republic of China,Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou 510282, Guangdong, People’s Republic of China
| | - Siying Li
- School of Traditional Chinese Medicine, Southern Medical University, People’s Republic of China
| | - Jujian Ye
- Zhujiang Hospital, Southern Medical University/The Second School of Clinical Medicine, Southern Medical University, People’s Republic of China,Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou 510282, Guangdong, People’s Republic of China
| | - Yi Liu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, People’s Republic of China
| | - Longtai Hu
- School of Traditional Chinese Medicine, Southern Medical University, People’s Republic of China
| | - Yan Tang
- Zhujiang Hospital, Southern Medical University/The Second School of Clinical Medicine, Southern Medical University, People’s Republic of China
| | - Zhijian Wu
- Department of Cardiology, Boai Hospital of Zhongshan, Southern Medical University, People’s Republic of China,Corresponding authors
| | - Peidong Zhang
- Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou 510282, Guangdong, People’s Republic of China,Corresponding authors
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Körber N, Pohl L, Weinberger B, Grubeck-Loebenstein B, Wawer A, Knolle PA, Roggendorf H, Protzer U, Bauer T. Hepatitis B Vaccine Non-Responders Show Higher Frequencies of CD24 highCD38 high Regulatory B Cells and Lower Levels of IL-10 Expression Compared to Responders. Front Immunol 2021; 12:713351. [PMID: 34566969 PMCID: PMC8461011 DOI: 10.3389/fimmu.2021.713351] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 08/25/2021] [Indexed: 12/16/2022] Open
Abstract
Background The cellular mechanisms involved in the lack of protective antibody response after hepatitis B vaccination are still rather unclear. Regulatory B cells (Breg) known as modulators of B-and T-cell responses may contribute to poor vaccine responsiveness. The current study aimed to investigate the role of regulatory B cells (Breg) in hepatitis B vaccine non-responsiveness after immunization with second- or third-generation hepatitis B vaccines. Method We performed comparative phenotypic and frequency analysis of Breg subsets (CD24+CD27+ and CD24highCD38high Breg) in second-generation hepatitis B vaccine non-responders (2nd HBvac NR, n = 11) and responders (2nd HBvac R, n = 8) before (d0), on day 7 (d7), and 28 (d28) after booster vaccination. Cryopreserved peripheral blood mononuclear cells were stimulated ex vivo with a combination of CpG, PMA, and Ionomycin (CpG+P/I) and analyzed for numbers and IL-10 expression levels of Breg by flow cytometry-based analyses. Results Flow cytometry-based analyses revealed elevated frequencies of CD24+CD27+ Breg at all time points and significantly higher frequencies of CD24highCD38high Breg on d0 (p = 0.004) and 28 (p = 0.012) in 2nd HBvac NR compared to 2nd HBvac R. In parallel, we observed significantly lower levels of CpG+P/I-induced IL-10 expression levels of CD24+CD27+ and CD24highCD38high Breg (d0: p < 0.0001; d7: p = 0.0004; d28: p = 0.0003 and d0: p = 0.016; d7: p = 0.016, respectively) in 2nd HBvac NR compared to 2nd HBvac R before and after booster immunization. Frequencies of CD24+CD27+ and CD24highCD38high Breg significantly decreased after third-generation hepatitis B booster vaccination (d7: p = 0.014; d28: p = 0.032 and d7: p = 0.045, respectively), whereas IL-10 expression levels of both Breg subsets remained stable. Conclusion Here we report significantly higher frequencies of CD24highCD38high Breg in parallel with significantly lower IL-10 expression levels of CD24+CD27+ and CD24highCD38high Breg in 2nd HBvac NR compared to 2nd HBvac R. Anti-HBs seroconversion accompanied by a decrease of Breg numbers after booster immunization with a third-generation hepatitis B vaccine could indicate a positive effect of third-generation hepatitis B vaccines on Breg-mediated immunomodulation in hepatitis B vaccine non-responders.
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Affiliation(s)
- Nina Körber
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany.,German Center for Infection Research (DZIF), Munich, Germany
| | - Laureen Pohl
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
| | - Birgit Weinberger
- Institute for Biomedical Aging Research, Universität Innsbruck, Innsbruck, Austria
| | | | - Andrea Wawer
- Occupational Health Unit, School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Percy A Knolle
- German Center for Infection Research (DZIF), Munich, Germany.,Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Hedwig Roggendorf
- German Center for Infection Research (DZIF), Munich, Germany.,Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Ulrike Protzer
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany.,German Center for Infection Research (DZIF), Munich, Germany.,Institute of Virology, School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Tanja Bauer
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany.,German Center for Infection Research (DZIF), Munich, Germany
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Namba T, Ichii O, Nakamura T, Masum MA, Otani Y, Hosotani M, Elewa YHA, Kon Y. Compartmentalization of interleukin 36 subfamily according to inducible and constitutive expression in the kidneys of a murine autoimmune nephritis model. Cell Tissue Res 2021; 386:59-77. [PMID: 34287716 DOI: 10.1007/s00441-021-03495-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 06/21/2021] [Indexed: 12/22/2022]
Abstract
The interleukin (IL) 36 subfamily belongs to the IL-1 family and is comprised of agonists (IL-36α, IL-36β, IL-36γ) and antagonists (IL-36Ra, IL-38). We previously reported IL-36α overexpression in renal tubules of chronic nephritis mice. To understand the localization status and biological relationships among each member of the IL-36 subfamily in the kidneys, MRL/MpJ-Faslpr/lpr mice were investigated as autoimmune nephritis models using pathology-based techniques. MRL/MpJ-Faslpr/lpr mice exhibited disease onset from 3 months and severe nephritis at 6-7 months (early and late stages, respectively). Briefly, IL-36γ and IL-36Ra were constitutively expressed in murine kidneys, while the expression of IL-36α, IL-36β, IL-36Ra, and IL-38 was induced in MRL/MpJ-Faslpr/lpr mice. IL-36α expression was significantly increased and localized to injured tubular epithelial cells (TECs). CD44+-activated parietal epithelial cells (PECs) also exhibited higher IL-36α-positive rates, particularly in males. IL-36β and IL-38 are expressed in interstitial plasma cells. Quantitative indices for IL-36α and IL-38 positively correlated with nephritis severity. Similar to IL-36α, IL-36Ra localized to TECs and PECs at the late stage; however, MRL/MpJ-Faslpr/lpr and healthy MRL/MpJ mice possessed IL-36Ra+ smooth muscle cells in kidney arterial tunica media at both stages. IL-36γ was constitutively expressed in renal sympathetic axons regardless of strain and stage. IL-36 receptor gene was ubiquitously expressed in the kidneys and was induced proportional to disease severity. MRL/MpJ-Faslpr/lpr mice kidneys possessed significantly upregulated IL-36 downstream candidates, including NF-κB- or MAPK-pathway organizing molecules. Thus, the IL-36 subfamily contributes to homeostasis and inflammation in the kidneys, and especially, an IL-36α-dominant imbalance could strongly impact nephritis deterioration.
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Affiliation(s)
- Takashi Namba
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Osamu Ichii
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan.
- Laboratory of Agrobiomedical Science, Faculty of Agriculture, Hokkaido University, Sapporo, Hokkaido, 060-8589, Japan.
| | - Teppei Nakamura
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
- Section of Biological Safety Research, Chitose Laboratory, Japan Food Research Laboratories, Chitose, Hokkaido, 066-0052, Japan
| | - Md Abdul Masum
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
- Department of Anatomy, Histology and Physiology, Faculty of Animal Science and Veterinary Medicine, Sher-E-Bangla Agricultural University, Dhaka, 1207, Bangladesh
| | - Yuki Otani
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
| | - Marina Hosotani
- Laboratory of Veterinary Anatomy, Department of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, 069-8501, Japan
| | - Yaser Hosny Ali Elewa
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zigazig, 44519, Egypt
| | - Yasuhiro Kon
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan
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Isho B, Florescu A, Wang AA, Gommerman JL. Fantastic IgA plasma cells and where to find them. Immunol Rev 2021; 303:119-137. [PMID: 34046908 DOI: 10.1111/imr.12980] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022]
Abstract
IgA is produced in large quantities at mucosal surfaces by IgA+ plasma cells (PC), protecting the host from pathogens, and restricting commensal access to the subepithelium. It is becoming increasingly appreciated that IgA+ PC are not constrained to mucosal barrier sites. Rather, IgA+ PC may leave these sites where they provide both host defense and immunoregulatory function. In this review, we will outline how IgA+ PC are generated within the mucosae and how they subsequently migrate to their "classical" effector site, the gut lamina propria. From there we provide examples of IgA+ PC displacement from the gut to other parts of the body, referencing examples during homeostasis and inflammation. Lastly, we will speculate on mechanisms of IgA+ PC displacement to other tissues. Our aim is to provide a new perspective on how IgA+ PC are truly fantastic beasts of the immune system and identify new places to find them.
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Affiliation(s)
- Baweleta Isho
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | | | - Angela A Wang
- Department of Immunology, University of Toronto, Toronto, ON, Canada
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31
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Grasseau A, Boudigou M, Michée-Cospolite M, Delaloy C, Mignen O, Jamin C, Cornec D, Pers JO, Le Pottier L, Hillion S. The diversity of the plasmablast signature across species and experimental conditions: A meta-analysis. Immunology 2021; 164:120-134. [PMID: 34041745 DOI: 10.1111/imm.13344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 03/15/2021] [Accepted: 04/12/2021] [Indexed: 12/17/2022] Open
Abstract
Antibody-secreting cells (ASC) are divided into two principal subsets, including the long-lived plasma cell (PC) subset residing in the bone marrow and the short-lived subset, also called plasmablast (PB). PB are described as a proliferating subset circulating through the blood and ending its differentiation in tissues. Due to their inherent heterogeneity, the molecular signature of PB is not fully established. The purpose of this study was to decipher a specific PB signature in humans and mice through a comprehensive meta-analysis of different data sets exploring the PB differentiation in both species and across different experimental conditions. The present study used recent analyses using whole RNA sequencing in prdm1-GFP transgenic mice to define a reliable and accurate PB signature. Next, we performed similar analysis using current data sets obtained from human PB and PC. The PB-specific signature is composed of 155 and 113 genes in mouse and human being, respectively. Although only nine genes are shared between the human and mice PB signature, the loss of B-cell identity such as the down-regulation of PAX5, MS4A1, (CD20) CD22 and IL-4R is a conserved feature across species and across the different experimental conditions. Additionally, we observed that the IRF8 and IRF4 transcription factors have a specific dynamic range of expression in human PB. We thus demonstrated that IRF4/IRF8 intranuclear staining was useful to define PB in vivo and in vitro and able to discriminate between atypical PB populations and transient states.
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Affiliation(s)
| | | | | | - Céline Delaloy
- UMR U1236, INSERM, Etablissement Français du Sang (EFS) de Bretagne, Université de Rennes 1, Rennes, France
| | | | - Christophe Jamin
- UMR1227, LBAI, INSERM, Univ Brest, Brest, France.,UMR1227, LBAI, INSERM, CHU de Brest, Univ Brest, Brest, France
| | - Divi Cornec
- UMR1227, LBAI, INSERM, Univ Brest, Brest, France.,UMR1227, LBAI, INSERM, CHU de Brest, Univ Brest, Brest, France
| | - Jacques-Olivier Pers
- UMR1227, LBAI, INSERM, Univ Brest, Brest, France.,UMR1227, LBAI, INSERM, CHU de Brest, Univ Brest, Brest, France
| | | | - Sophie Hillion
- UMR1227, LBAI, INSERM, Univ Brest, Brest, France.,UMR1227, LBAI, INSERM, CHU de Brest, Univ Brest, Brest, France
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32
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Liu Y, Luo Y, Zhu T, Jiang M, Tian Z, Tang G, Liang X. Regulatory B Cells Dysregulated T Cell Function in an IL-35-Dependent Way in Patients With Chronic Hepatitis B. Front Immunol 2021; 12:653198. [PMID: 33912178 PMCID: PMC8072152 DOI: 10.3389/fimmu.2021.653198] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 03/23/2021] [Indexed: 11/26/2022] Open
Abstract
Interleukin (IL)-35-secreting B (IL-35+B) cells are critical regulators in autoimmune and infectious diseases and exert suppressive functions in parallel with IL-10-producing B (B10) cells. However, the role of IL-35+B cells in persistent hepatitis B virus (HBV) infection remains unclear. To elucidate the role of IL-35+B cells in the progress of chronic HBV infection, we determined the frequency of IL-35+B cells and their relationship with the classical human regulatory B cell (Breg) subsets, namely, CD19+CD24hiCD38hi and CD19+CD24hiCD27+. Then, the regulatory effect and mechanism of Bregs on effector T cells were investigated in vitro. Here, we found that compared with healthy controls, the frequency of IL-35+B cells was increased in patients with chronic HBV infection and was enriched in human classical Breg subset CD19+CD24hiCD38hi B cells. Moderate correlation was observed between the frequency of IL-35+B cells and alanine aminotransferase levels (Spearman r = 0.401), but only mild correlation was noted between the frequency of IL-35+B cells and HBV DNA level (Spearman r = 0.314). The frequency of IL-35+B cells was negatively correlated with interferon-γ (IFN-γ)-producing CD4+ and CD8+ cells but positively correlated with IL-4-producing T cells. Bregs dysregulated T cell function through an IL-35-dependent mechanism and depended on cell-to-cell contact. In conclusion, IL-35+ B cell was enriched in CD19+CD24hiCD38hi B cell subset during persistent HBV infection and Breg cells exerted dysregulation in T cell function through IL-35 dependent mechanism and depend on cell-to-cell contact.
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Affiliation(s)
- YaYun Liu
- Department of Infectious Diseases, Changhai Hospital, Navy Military Medical University, Shanghai, China
| | - Ying Luo
- Department of Clinical Experiment Center, Changhai Hospital, Navy Military Medical University, Shanghai, China
| | - Tong Zhu
- Department of Infectious Diseases, Changhai Hospital, Navy Military Medical University, Shanghai, China
| | - Meng Jiang
- Department of Infectious Diseases, Changhai Hospital, Navy Military Medical University, Shanghai, China
| | - ZhaoFeng Tian
- Department of Laboratory Diagnostics, Changhai Hospital, Navy Military Medical University, Shanghai, China
| | - GuSheng Tang
- Department of Hematology Laboratory Center, Changhai Hospital, Navy Military Medical University, Shanghai, China
| | - XueSong Liang
- Department of Infectious Diseases, Changhai Hospital, Navy Military Medical University, Shanghai, China
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33
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Lutterotti A, Hayward-Koennecke H, Sospedra M, Martin R. Antigen-Specific Immune Tolerance in Multiple Sclerosis-Promising Approaches and How to Bring Them to Patients. Front Immunol 2021; 12:640935. [PMID: 33828551 PMCID: PMC8019937 DOI: 10.3389/fimmu.2021.640935] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 02/26/2021] [Indexed: 01/28/2023] Open
Abstract
Antigen-specific tolerance induction aims at treating multiple sclerosis (MS) at the root of its pathogenesis and has the prospect of personalization. Several promising tolerization approaches using different technologies and modes of action have already advanced to clinical testing. The prerequisites for successful tolerance induction include the knowledge of target antigens, core pathomechanisms, and how to pursue a clinical development path that is distinct from conventional drug development. Key aspects including patient selection, outcome measures, demonstrating the mechanisms of action as well as the positioning in the rapidly growing spectrum of MS treatments have to be considered to bring this therapy to patients.
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Affiliation(s)
- Andreas Lutterotti
- Neuroimmunology and MS Research Section, Neurology Clinic, University Hospital Zurich & University of Zurich, Zurich, Switzerland
| | - Helen Hayward-Koennecke
- Neuroimmunology and MS Research Section, Neurology Clinic, University Hospital Zurich & University of Zurich, Zurich, Switzerland
| | - Mireia Sospedra
- Neuroimmunology and MS Research Section, Neurology Clinic, University Hospital Zurich & University of Zurich, Zurich, Switzerland
| | - Roland Martin
- Neuroimmunology and MS Research Section, Neurology Clinic, University Hospital Zurich & University of Zurich, Zurich, Switzerland
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Abstract
The opposing roles of innate and adaptive immune cells in suppressing or supporting cancer initiation, progression, metastasis and response to therapy has been long debated. The mechanisms by which different monocyte and T cell subtypes affect and modulate cancer have been extensively studied. However, the role of B cells and their subtypes have remained elusive, perhaps partially due to their heterogeneity and range of actions. B cells can produce a variety of cytokines and present tumor-derived antigens to T cells in combination with co-stimulatory or inhibitory ligands based on their phenotype. Unlike most T cells, B cells can be activated by innate immune stimuli, such as endotoxin. Furthermore, the isotype and specificity of the antibodies produced by plasma cells regulate distinct immune responses, including opsonization, antibody-mediated cellular cytotoxicity (ADCC) and complement activation. B cells are shaped by the tumor environment (TME), with the capability to regulate the TME in return. In this review, we will describe the mechanisms of B cell action, including cytokine production, antigen presentation, ADCC, opsonization, complement activation and how they affect tumor development and response to immunotherapy. We will also discuss how B cell fate within the TME is affected by tumor stroma, microbiome and metabolism.
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Affiliation(s)
- Shabnam Shalapour
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
| | - Michael Karin
- Department of Pharmacology, School of Medicine, University of California San Diego, CA 92093, USA; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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35
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Michaud D, Steward CR, Mirlekar B, Pylayeva-Gupta Y. Regulatory B cells in cancer. Immunol Rev 2021; 299:74-92. [PMID: 33368346 PMCID: PMC7965344 DOI: 10.1111/imr.12939] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/25/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
Tumorigenesis proceeds through discrete steps where acquisition of genetic lesions and changes in the surrounding microenvironment combine to drive unrestricted neoplastic proliferation and metastasis. The ability of tumor-infiltrating immune cells to promote tumor growth via the provision of signals that enable tumor cell survival and proliferation as well as contribute to immune suppression is an active area of research. Recent efforts have provided us with mechanistic insights into how B cells can positively and negatively regulate immune responses. Negative regulation of immune responses in cancer can be mediated by regulatory B cells and is often a result of increased production of cytokines that can directly and indirectly affect anti-tumor immune function and cancer cell growth. Signals that lead to the expansion of regulatory B cells and the spectrum of their functional roles are not well understood and are the subject of active research by many groups. Here, we elaborate broadly on the history of regulatory B cells in cancer and summarize recent studies that have established genetic models for the study of regulatory B cell function and their potential for therapeutic intervention in the setting of solid cancers.
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Affiliation(s)
- Daniel Michaud
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
- Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Colleen R Steward
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Bhalchandra Mirlekar
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
- Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Yuliya Pylayeva-Gupta
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
- Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
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Woodruff MC, Ramonell RP, Nguyen DC, Cashman KS, Saini AS, Haddad NS, Ley AM, Kyu S, Howell JC, Ozturk T, Lee S, Suryadevara N, Case JB, Bugrovsky R, Chen W, Estrada J, Morrison-Porter A, Derrico A, Anam FA, Sharma M, Wu HM, Le SN, Jenks SA, Tipton CM, Staitieh B, Daiss JL, Ghosn E, Diamond MS, Carnahan RH, Crowe JE, Hu WT, Lee FEH, Sanz I. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat Immunol 2020; 21:1506-1516. [PMID: 33028979 PMCID: PMC7739702 DOI: 10.1038/s41590-020-00814-z] [Citation(s) in RCA: 540] [Impact Index Per Article: 108.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/16/2020] [Indexed: 12/15/2022]
Abstract
A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling.
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Affiliation(s)
- Matthew C Woodruff
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - Richard P Ramonell
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Doan C Nguyen
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Kevin S Cashman
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
| | - Ankur Singh Saini
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
| | - Natalie S Haddad
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
- MicroB-plex, Atlanta, GA, USA
| | - Ariel M Ley
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Shuya Kyu
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | | | - Tugba Ozturk
- Department of Neurology, Emory University, Atlanta, GA, USA
| | - Saeyun Lee
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | | | - James Brett Case
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Regina Bugrovsky
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
| | - Weirong Chen
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
| | - Jacob Estrada
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
| | - Andrea Morrison-Porter
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Andrew Derrico
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Fabliha A Anam
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
| | - Monika Sharma
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
| | - Henry M Wu
- Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, GA, USA
| | - Sang N Le
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Scott A Jenks
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - Christopher M Tipton
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA
| | - Bashar Staitieh
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA
| | | | - Eliver Ghosn
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA
| | - Michael S Diamond
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA
| | - Robert H Carnahan
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - James E Crowe
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - William T Hu
- Department of Neurology, Emory University, Atlanta, GA, USA
| | - F Eun-Hyung Lee
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, USA.
| | - Ignacio Sanz
- Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA.
- Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA.
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Zhang L, Mack R, Breslin P, Zhang J. Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches. J Hematol Oncol 2020; 13:157. [PMID: 33228751 PMCID: PMC7686726 DOI: 10.1186/s13045-020-00994-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 11/09/2020] [Indexed: 02/08/2023] Open
Abstract
Aging drives the genetic and epigenetic changes that result in a decline in hematopoietic stem cell (HSC) functioning. Such changes lead to aging-related hematopoietic/immune impairments and hematopoietic disorders. Understanding how such changes are initiated and how they progress will help in the development of medications that could improve the quality life for the elderly and to treat and possibly prevent aging-related hematopoietic diseases. Here, we review the most recent advances in research into HSC aging and discuss the role of HSC-intrinsic events, as well as those that relate to the aging bone marrow niche microenvironment in the overall processes of HSC aging. In addition, we discuss the potential mechanisms by which HSC aging is regulated.
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Affiliation(s)
- Lei Zhang
- Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, 60153, USA
| | - Ryan Mack
- Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, 60153, USA
| | - Peter Breslin
- Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, 60153, USA.,Departments of Molecular/Cellular Physiology and Department of Biology, Loyola University Medical Center and Loyola University Chicago, Chicago, IL, 60660, USA
| | - Jiwang Zhang
- Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, 60153, USA. .,Department of Pathology, Loyola University Medical Center, Maywood, IL, 60153, USA.
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38
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Wang AA, Gommerman JL, Rojas OL. Plasma Cells: From Cytokine Production to Regulation in Experimental Autoimmune Encephalomyelitis. J Mol Biol 2020; 433:166655. [PMID: 32976908 DOI: 10.1016/j.jmb.2020.09.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 09/15/2020] [Accepted: 09/16/2020] [Indexed: 01/01/2023]
Abstract
B cells are a critical arm of the adaptive immune system. After encounter with antigen, B cells are activated and differentiate into plasmablasts (PBs) and plasma cells (PCs). Although their frequency is low, PB/PCs can be found in all lymphoid organs including peripheral lymph nodes and spleen. Upon immunization, depending on the location of where B cells encounter their antigen, PB/PCs subsequently home to and accumuate in the bone marrow and the intestine where they can survive as long-lived plasma cells for years, continually producing antibody. Recent evidence has shown that, in addition to producing antibodies, PB/PCs can also produce cytokines such as IL-17, IL-10, and IL-35. In addition, PB/PCs that produce IL-10 have been shown to play a regulatory role during experimental autoimmune encephalomyelitis, an animal model of neuroinflammation. The purpose of this review is to describe the phenotype and function of regulatory PB/PCs in the context of experimental autoimmune encephalomyelitis and in patients with multiple sclerosis.
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Affiliation(s)
- Angela A Wang
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | | | - Olga L Rojas
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
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39
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Woodruff M, Ramonell R, Cashman K, Nguyen D, Saini A, Haddad N, Ley A, Kyu S, Howell JC, Ozturk T, Lee S, Chen W, Estrada J, Morrison-Porter A, Derrico A, Anam F, Sharma M, Wu H, Le S, Jenks S, Tipton CM, Hu W, Lee FEH, Sanz I. Dominant extrafollicular B cell responses in severe COVID-19 disease correlate with robust viral-specific antibody production but poor clinical outcomes. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2020. [PMID: 32511635 DOI: 10.1101/2020.04.29.20083717] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
A wide clinical spectrum has become a hallmark of the SARS-CoV-2 (COVID-19) pandemic, although its immunologic underpinnings remain to be defined. We have performed deep characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation as previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody secreting cell expansion and early production of high levels of SARS-CoV-2-specific antibodies. Yet, these patients fared poorly with elevated inflammatory biomarkers, multi-organ failure, and death. Combined, the findings strongly indicate a major pathogenic role for immune activation in subsets of COVID-19 patients. Our study suggests that, as in autoimmunity, targeted immunomodulatory therapy may be beneficial in specific patient subpopulations that can be identified by careful immune profiling.
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40
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Human B cells infected by Trypanosoma cruzi undergo F-actin disruption and cell death via caspase-7 activation and cleavage of phospholipase Cγ1. Immunobiology 2020; 225:151904. [DOI: 10.1016/j.imbio.2020.151904] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/08/2020] [Accepted: 01/15/2020] [Indexed: 02/08/2023]
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41
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Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol 2020; 20:294-307. [DOI: 10.1038/s41577-019-0257-x] [Citation(s) in RCA: 201] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
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42
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Wu H, Su Z, Barnie PA. The role of B regulatory (B10) cells in inflammatory disorders and their potential as therapeutic targets. Int Immunopharmacol 2019; 78:106111. [PMID: 31881524 DOI: 10.1016/j.intimp.2019.106111] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/08/2019] [Accepted: 12/02/2019] [Indexed: 02/06/2023]
Abstract
Over the past decade, studies have identified subset of B cells, which play suppressive functions in additions to the conventional functions of B cells: antigen processing and presentation, activation of T cells and antibody productions. Because of their regulatory function, they were named as B regulatory cells (Bregs). Bregs restrict the severity of autoimmune disorders in animal disease models such as experimental autoimmune myocarditis (EAM), experimental autoimmune encephalitis (EAE), and collagen-induced arthritis (CIA) but can contribute to the development of infection and cancer. In humans, the roles of B regulatory cells in autoimmune diseases have not been clearly established because of the inconsistent findings from many researchers. This is believed to arise from the speculated fact that Bregs lack specific marker, which can be used to identify and characterize them in human diseases. The CD19+CD24hiCD38hiCD1dhiB cells have been associated with the regulatory function. Available evidences highlight the relevance of increasing IL-10-producing B cells in autoimmune diseases and the possibility of serving as new therapeutic targets in inflammatory disorders. This review empanels the functions of Bregs in autoimmune diseases in both human and animal models, and further evaluates the possibility of Bregs as therapeutic targets in inflammatory disorders. Consequently, this might help identify possible research gaps, which need to be clarified as researchers speculate the possibility of targeting some subsets of Bregs in the treatment of inflammatory disorders.
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Affiliation(s)
- Hongxia Wu
- Department of Laboratory, People's Hospital of Jiangyin, Jiangsu 214400, China
| | - Zhaoliang Su
- International Genome Center, Jiangsu University, Zhenjiang 212013, China
| | - Prince Amoah Barnie
- International Genome Center, Jiangsu University, Zhenjiang 212013, China; Department of Biomedical Sciences, School of Allied Health Sciences, University of Cape Coast, Ghana.
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43
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Abstract
Fingolimod is the first orally administered drug approved for the treatment of relapsing-remitting multiple sclerosis (MS). This drug, modulating sphingosine receptors, regulates the trafficking of lymphocytes between primary and secondary lymphoid organs, trapping naïve T cells and central memory T cells in secondary lymphoid organs, without affecting effector memory T cells and therefore without compromising immunosurveillance. Additionally, fingolimod inhibits expression of Th1 and Th17 cytokines and enhances regulatory T-cell differentiation. It also acts on the B arm of immunity through an increased ratio of naïve to memory B cells, higher percentage of plasma cells, and highly increased proportion of transitional B cells as well as additional regulatory subsets. Fingolimod treatment enhances the capacity of regulatory B cells to transmigrate across brain endothelial cells. In fact, patients treated with fingolimod have increased regulatory B-cell frequency in the cerebrospinal fluid. These findings suggest a novel role for fingolimod in MS, by both direct effects and indirect partitioning effects on lymphocytes.
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Affiliation(s)
| | - Diego Centonze
- Unit of Neurology, IRCCS Neuromed, Pozzilli, IS, Italy.
- Department of Systems Medicine, Tor Vergata University, Rome, Italy.
| | - Fabio Buttari
- Unit of Neurology, IRCCS Neuromed, Pozzilli, IS, Italy
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44
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Isaeva OI, Sharonov GV, Serebrovskaya EO, Turchaninova MA, Zaretsky AR, Shugay M, Chudakov DM. Intratumoral immunoglobulin isotypes predict survival in lung adenocarcinoma subtypes. J Immunother Cancer 2019; 7:279. [PMID: 31665076 PMCID: PMC6819482 DOI: 10.1186/s40425-019-0747-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 09/20/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The role of tumor-infiltrating B-cells (TIBs) and intratumorally-produced antibodies in cancer-immunity interactions essentially remains terra incognita. In particular, it remains unexplored how driver mutations could be associated with distinct TIBs signatures and their role in tumor microenvironment. METHODS Here we analyzed associations of immunoglobulin isotypes and clonality with survival in TCGA RNA-Seq data for lung adenocarcinoma (LUAD), stratifying patients into 12 driver mutation and phenotypic tumor subgroups. RESULTS We revealed several unexpected associations between TIBs behavior and prognosis. Abundance and high proportion of IgG1 isotype, and low proportion of IgA among all intratumorally produced immunoglobulins were specifically associated with improved overall survival for KRASmut but not KRASwt LUAD, revealing the first link between a driver mutation and B-cell response. We found specific IgG1 signature associated with long survival, which suggests that particular specificities of IgG1+ TIBs could be beneficial in KRASmut LUAD. In contrast to our previous observations for melanoma, highly clonal IgG1 production by plasma cells had no meaningful effect on prognosis, suggesting that IgG1+ TIBs may exert a beneficial effect in KRASmut cases in an alternative way, such as efficient presentation of cognate antigens or direct B cell attack on tumor cells. Notably, a high proportion of the IgG1 isotype is positively correlated with the non-silent mutation burden both in the general LUAD cohort and in most patient subgroups, supporting a role for IgG1+ TIBs in antigen presentation. Complementing the recent finding that the presence of stromal IgG4-producing cells is associated with a favorable prognosis for patients with stage I squamous cell carcinoma, we show that the abundance of IgG4-producing TIBs likewise has a strong positive effect on overall survival in STK11mut and proximal proliferative subgroups of LUAD patients. We hypothesize that the positive role of IgG4 antibodies in some of the lung cancer subtypes could be associated with reported inability of IgG4 isotype to form immune complexes, thus preventing immunosuppression via activation of the myeloid-derived suppressor cell (MDSC) phenotype. CONCLUSIONS We discover prominent and distinct associations between TIBs antibody isotypes and survival in lung adenocarcinoma carrying specific driver mutations. These findings indicate that particular types of tumor-immunity relations could be beneficial in particular driver mutation context, which should be taken into account in developing strategies of cancer immunotherapy and combination therapies. Specificity of protective B cell populations in specific cancer subgroups could become a clue to efficient targeted immunotherapies for appropriate cohorts of patients.
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Affiliation(s)
- O I Isaeva
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia.,BostonGene LLC, Lincoln, MA, USA
| | - G V Sharonov
- Laboratory of Genomics of Antitumor Adaptive Immunity, Privolzhsky Research Medical University, Nizhny Novgorod, Russia.,Genomics of Adaptive Immunity Department, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | - E O Serebrovskaya
- Genomics of Adaptive Immunity Department, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.,Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia
| | - M A Turchaninova
- Laboratory of Genomics of Antitumor Adaptive Immunity, Privolzhsky Research Medical University, Nizhny Novgorod, Russia.,Genomics of Adaptive Immunity Department, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | - A R Zaretsky
- Genomics of Adaptive Immunity Department, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.,Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia.,Evrogen JSC, Moscow, Russia
| | - M Shugay
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia.,Laboratory of Genomics of Antitumor Adaptive Immunity, Privolzhsky Research Medical University, Nizhny Novgorod, Russia.,Genomics of Adaptive Immunity Department, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.,Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia
| | - D M Chudakov
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia. .,Laboratory of Genomics of Antitumor Adaptive Immunity, Privolzhsky Research Medical University, Nizhny Novgorod, Russia. .,Genomics of Adaptive Immunity Department, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia. .,Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia.
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45
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Tuomisto AE, Mäkinen MJ, Väyrynen JP. Systemic inflammation in colorectal cancer: Underlying factors, effects, and prognostic significance. World J Gastroenterol 2019; 25:4383-4404. [PMID: 31496619 PMCID: PMC6710177 DOI: 10.3748/wjg.v25.i31.4383] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 06/07/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Systemic inflammation is a marker of poor prognosis preoperatively present in around 20%-40% of colorectal cancer patients. The hallmarks of systemic inflammation include an increased production of proinflammatory cytokines and acute phase proteins that enter the circulation. While the low-level systemic inflammation is often clinically silent, its consequences are many and may ultimately lead to chronic cancer-associated wasting, cachexia. In this review, we discuss the pathogenesis of cancer-related systemic inflammation, explore the role of systemic inflammation in promoting cancer growth, escaping antitumor defense, and shifting metabolic pathways, and how these changes are related to less favorable outcome.
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Affiliation(s)
- Anne E Tuomisto
- Cancer and Translational Medicine Research Unit, University of Oulu, Oulu 90220, Finland
- Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu 90220, Finland
| | - Markus J Mäkinen
- Cancer and Translational Medicine Research Unit, University of Oulu, Oulu 90220, Finland
- Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu 90220, Finland
| | - Juha P Väyrynen
- Cancer and Translational Medicine Research Unit, University of Oulu, Oulu 90220, Finland
- Department of Pathology, Oulu University Hospital and Medical Research Center Oulu, Oulu 90220, Finland
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, United States
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46
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IL-10-producing regulatory B cells and plasmocytes: Molecular mechanisms and disease relevance. Semin Immunol 2019; 44:101323. [DOI: 10.1016/j.smim.2019.101323] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 10/10/2019] [Indexed: 12/20/2022]
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47
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Pioli PD, Casero D, Montecino-Rodriguez E, Morrison SL, Dorshkind K. Plasma Cells Are Obligate Effectors of Enhanced Myelopoiesis in Aging Bone Marrow. Immunity 2019; 51:351-366.e6. [PMID: 31303400 DOI: 10.1016/j.immuni.2019.06.006] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 04/10/2019] [Accepted: 06/12/2019] [Indexed: 12/25/2022]
Abstract
Aging results in increased myelopoiesis, which is linked to the increased incidence of myeloid leukemias and production of myeloid-derived suppressor cells. Here, we examined the contribution of plasma cells (PCs) to age-related increases in myelopoiesis, as PCs exhibit immune regulatory function and sequester in bone marrow (BM). PC number was increased in old BM, and they exhibited high expression of genes encoding inflammatory cytokines and pathogen sensors. Antibody-mediated depletion of PCs from old mice reduced the number of myeloid-biased hematopoietic stem cells and mature myeloid cells to levels in young animals, but lymphopoiesis was not rejuvenated, indicating that redundant mechanisms inhibit that process. PCs also regulated the production of inflammatory factors from BM stromal cells, and disruption of the PC-stromal cell circuitry with inhibitors of the cytokines IL-1 and TNF-α attenuated myelopoiesis in old mice. Thus, the age-related increase in myelopoiesis is driven by an inflammatory network orchestrated by PCs.
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Affiliation(s)
- Peter D Pioli
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - David Casero
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | | | - Sherie L Morrison
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Kenneth Dorshkind
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
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48
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Perdomo-Celis F, Romero F, Salgado DM, Vega R, Rodríguez J, Angel J, Franco MA, Greenberg HB, Narváez CF. Identification and Characterization at the Single-Cell Level of Cytokine-Producing Circulating Cells in Children With Dengue. J Infect Dis 2019; 217:1472-1480. [PMID: 29390091 DOI: 10.1093/infdis/jiy053] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 01/22/2018] [Indexed: 01/10/2023] Open
Abstract
In this study, we identified, at the single-cell level, naturally induced cytokine-producing circulating cells (CPCCs) in children with dengue virus (DENV) infection ranging clinically from mild to severe disease. Tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) CPCCs were detected in children with primary or secondary acute dengue virus (DENV) infection, and the pattern of these cytokines was similar to that seen in the supernatant of cultured peripheral blood mononuclear cells and partially comparable to that found in plasma. Monocytes, B cells, and myeloid dendritic cells (mDCs) were the primary CPCCs detected, and the frequency of mDCs was significantly higher in severe disease. B cells isolated from children with dengue spontaneously secreted TNF-α, IL-6, and interleukin 10, and supernatants from cultures of purified B cells induced activation of allogeneic T cells, supporting an antibody-independent function of these cells during DENV infection. Thus, CPCCs could be a new immune parameter with potential use to evaluate pathogenesis in this infection.
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Affiliation(s)
| | - Felipe Romero
- Programa de Medicina, Facultad de Salud, Universidad Surcolombiana, Neiva.,Departamento de Pediatría, Hospital Universitario de Neiva, Bogotá, Colombia
| | - Doris M Salgado
- Programa de Medicina, Facultad de Salud, Universidad Surcolombiana, Neiva.,Departamento de Pediatría, Hospital Universitario de Neiva, Bogotá, Colombia
| | - Rocío Vega
- Programa de Medicina, Facultad de Salud, Universidad Surcolombiana, Neiva.,Departamento de Pediatría, Hospital Universitario de Neiva, Bogotá, Colombia
| | - Jairo Rodríguez
- Programa de Medicina, Facultad de Salud, Universidad Surcolombiana, Neiva.,Departamento de Pediatría, Hospital Universitario de Neiva, Bogotá, Colombia
| | - Juana Angel
- Instituto de Genética Humana, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Manuel A Franco
- Instituto de Genética Humana, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Harry B Greenberg
- Department of Medicine and Department of Microbiology and Immunology, Stanford University School of Medicine, California
| | - Carlos F Narváez
- Programa de Medicina, Facultad de Salud, Universidad Surcolombiana, Neiva
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49
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Arneth BM. Impact of B cells to the pathophysiology of multiple sclerosis. J Neuroinflammation 2019; 16:128. [PMID: 31238945 PMCID: PMC6593488 DOI: 10.1186/s12974-019-1517-1] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 06/11/2019] [Indexed: 02/07/2023] Open
Abstract
Introduction Multiple sclerosis (MS) is a chronic autoimmune disorder that affects the central nervous system and compromises the health and well-being of millions of people worldwide. B cells have been linked to MS and its progression. This review aimed to determine the role of B cells in MS development. Methods Articles used in this review were obtained from PubMed, LILACS, and EBSCO. The search terms and phrases included “multiple sclerosis,” “MS,” “B-Cells,” “pathogenesis,” and “development.” Original research studies and articles on MS and B cells published between 2007 and 2018 were included. Results Results from the selected articles showed a significant connection between B cell groups and MS. B cells act as a significant source of plasma cells, which generate antibodies while also regulating autoimmune processes and T cell production. In addition, B cells regulate the release of molecules that affect the proinflammatory actions of other immune cells. Discussion B cells play key roles in immune system functioning and MS. The findings of this review illustrate the complex nature of B cell actions, their effects on the autoimmune system, and the method by which they contribute to MS pathogenesis. Conclusion Previous research implicates biological, genetic, and environmental factors in MS pathogenesis. This review suggests that B cells contribute to MS development and advancement by influencing and regulating autoimmune processes such as T cell production and APC activity.
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Affiliation(s)
- Borros M Arneth
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, University Hospital of the Universities of Giessen and Marburg UKGM, Justus Liebig University Giessen, Feulgenstr. 12, 35392, Giessen, Germany.
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50
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Jing L, Kim S, Sun L, Wang L, Mildner E, Divaris K, Jiao Y, Offenbacher S. IL-37- and IL-35/IL-37-Producing Plasma Cells in Chronic Periodontitis. J Dent Res 2019; 98:813-821. [PMID: 31050915 DOI: 10.1177/0022034519847443] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Periodontitis is one of the most prevalent chronic inflammatory diseases and is induced by the interaction between oral microorganisms and the host immune system. Plasma cells are of special interest in chronic periodontitis (CP), as they represent ~50% of infiltrated immune cells in periodontal lesions. Plasma cells constitute the only known cell type capable of antibody production; however, recent evidence supports an emerging role for distinct sets of plasma cells in cytokine production. However, the presence of cytokine-producing plasma cells in CP is unknown. In this study, we used immunohistochemistry to detect significantly elevated levels of IL-35 and IL-37 (2 recently identified anti-inflammatory cytokines) in CP gingival tissue as compared with healthy tissue. Remarkably, we demonstrate that CD138+ CD38+ plasma cells are the major immune cell type in CP gingival tissues and that these cells produce IL-35 and IL-37. We used immunofluorescence and confocal microscopy analysis to identify a subset of plasma cells with robust cytoplasmic expression of IL-37-we denote this subset as IL-37-producing plasma cells (CD138+CD38+PIL-37). Another subset of plasma cells coproduces IL-35 and IL-37 and is denoted as IL-37/IL-35-coproducing plasma cells (CD138+CD38+PIL-35/IL-37). We determined that these 2 plasma cell subsets are IgG+plasma cells. Moreover, we show that human recombinant IL-35 and IL-37 exhibit a dose-dependent inhibition of osteoclast formation in vitro (~78.9% and 97.7% inhibition in 300 ng/mL of IL-35 and IL-37, respectively, P < 0.05). Overall, our findings suggest that PIL-37 and PIL-35/IL-37 exist as subsets of plasma cells in CP lesions and that these 2 new types of plasma cells may regulate periodontitis pathogenesis by inhibiting alveolar bone loss through directly blocking osteoclast formation. Importantly, these data suggest a novel role of plasma cells and offer potential new mechanistic and regulatory targets to be investigated in the context of periodontal health and disease.
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Affiliation(s)
- L Jing
- 1 Department of Periodontology, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - S Kim
- 1 Department of Periodontology, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - L Sun
- 1 Department of Periodontology, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - L Wang
- 2 Curriculum in Oral and Craniofacial Biomedicine, Adams School of Dentistry, University of North Carolina at Chapel Hill, NC, USA
| | - E Mildner
- 3 Curriculum in Biology, School of Medicine, Emory University, Atlanta, GA, USA
| | - K Divaris
- 4 Department of Pediatric Dentistry, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,5 Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Y Jiao
- 1 Department of Periodontology, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,6 Curriculum in Doctor of Dental Surgery, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - S Offenbacher
- 1 Department of Periodontology, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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