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Zhang JY, Li H, Zhang MJ, Sun ZJ. Lymphangiogenesis orchestrating tumor microenvironment: Face changing in immunotherapy. Biochim Biophys Acta Rev Cancer 2025; 1880:189278. [PMID: 39929379 DOI: 10.1016/j.bbcan.2025.189278] [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: 11/13/2024] [Revised: 01/22/2025] [Accepted: 02/04/2025] [Indexed: 02/19/2025]
Abstract
In the era of immunotherapy, the lymphatic system has garnered significant attention from researchers. Increasing evidence highlights the complex regulation of lymphatic vessels (LVs) within the tumor microenvironment, unveiling a paradox in tumor progression: while LVs enhance immune surveillance, they simultaneously foster immune suppression. This review summarizes the regulatory factors of lymphangiogenesis, discusses the intricate effects of LVs on immunotherapy, and emphasizes the potential connection between lymphangiogenesis and tertiary lymphoid structure. Additionally, current therapeutic strategies targeting lymphangiogenesis are critically evaluated, with a forward-looking perspective on future research directions and regulatory approaches to achieve precise targeting and optimize immunotherapy paradigms.
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Affiliation(s)
- Jun-Ye Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Centre for Immunology and Metabolism, Taikang Centre for Life and Medical Sciences, Wuhan University, Wuhan 430079, China
| | - Hao Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Centre for Immunology and Metabolism, Taikang Centre for Life and Medical Sciences, Wuhan University, Wuhan 430079, China; Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, China
| | - Meng-Jie Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Centre for Immunology and Metabolism, Taikang Centre for Life and Medical Sciences, Wuhan University, Wuhan 430079, China.
| | - Zhi-Jun Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Centre for Immunology and Metabolism, Taikang Centre for Life and Medical Sciences, Wuhan University, Wuhan 430079, China; Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, China.
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Reste M, Ajazi K, Sayi-Yazgan A, Jankovic R, Bufan B, Brandau S, Bækkevold ES, Petitprez F, Lindstedt M, Adema GJ, Almeida CR. The role of dendritic cells in tertiary lymphoid structures: implications in cancer and autoimmune diseases. Front Immunol 2024; 15:1439413. [PMID: 39483484 PMCID: PMC11526390 DOI: 10.3389/fimmu.2024.1439413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 09/23/2024] [Indexed: 11/03/2024] Open
Abstract
Tertiary Lymphoid Structures (TLS) are organized aggregates of immune cells such as T cells, B cells, and Dendritic Cells (DCs), as well as fibroblasts, formed postnatally in response to signals from cytokines and chemokines. Central to the function of TLS are DCs, professional antigen-presenting cells (APCs) that coordinate the adaptive immune response, and which can be classified into different subsets, with specific functions, and markers. In this article, we review current data on the contribution of different DC subsets to TLS function in cancer and autoimmunity, two opposite sides of the immune response. Different DC subsets can be found in different tumor types, correlating with cancer prognosis. Moreover, DCs are also present in TLS found in autoimmune and inflammatory conditions, contributing to disease development. Broadly, the presence of DCs in TLS appears to be associated with favorable clinical outcomes in cancer while in autoimmune pathologies these cells are associated with unfavorable prognosis. Therefore, it is important to analyze the complex functions of DCs within TLS in order to enhance our fundamental understanding of immune regulation but also as a possible route to create innovative clinical interventions designed for the specific needs of patients with diverse pathological diseases.
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Affiliation(s)
- Mariana Reste
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal
| | - Kristi Ajazi
- Department of Immunotechnology, Lund University, Lund, Sweden
| | - Ayca Sayi-Yazgan
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, Istanbul Technical University, Istanbul, Türkiye
- Department of Life Sciences, Centre for Inflammation Research and Translational Medicine, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
| | - Radmila Jankovic
- Faculty of Medicine, Institute of Pathology, University of Belgrade, Belgrade, Serbia
| | - Biljana Bufan
- Department of Microbiology and Immunology, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia
| | - Sven Brandau
- Experimental and Translational Research, Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany
| | - Espen S. Bækkevold
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Florent Petitprez
- Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom
| | - Malin Lindstedt
- Department of Immunotechnology, Lund University, Lund, Sweden
| | - Gosse J. Adema
- Radiotherapy & OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Catarina R. Almeida
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal
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Salvador AFM, Abduljawad N, Kipnis J. Meningeal Lymphatics in Central Nervous System Diseases. Annu Rev Neurosci 2024; 47:323-344. [PMID: 38648267 PMCID: PMC12051392 DOI: 10.1146/annurev-neuro-113023-103045] [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] [Indexed: 04/25/2024]
Abstract
Since its recent discovery, the meningeal lymphatic system has reshaped our understanding of central nervous system (CNS) fluid exchange, waste clearance, immune cell trafficking, and immune privilege. Meningeal lymphatics have also been demonstrated to functionally modify the outcome of neurological disorders and their responses to treatment, including brain tumors, inflammatory diseases such as multiple sclerosis, CNS injuries, and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review, we discuss recent evidence of the contribution of meningeal lymphatics to neurological diseases, as well as the available experimental methods for manipulating meningeal lymphatics in these conditions. Finally, we also provide a discussion of the pressing questions and challenges in utilizing meningeal lymphatics as a prime target for CNS therapeutic intervention and possibly drug delivery for brain disorders.
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Affiliation(s)
- Andrea Francesca M Salvador
- Brain Immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA;
| | - Nora Abduljawad
- Neuroscience Graduate Program, Washington University School of Medicine, St. Louis, Missouri, USA
- Brain Immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA;
| | - Jonathan Kipnis
- Neuroscience Graduate Program, Washington University School of Medicine, St. Louis, Missouri, USA
- Brain Immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA;
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Petkova M, Ferby I, Mäkinen T. Lymphatic malformations: mechanistic insights and evolving therapeutic frontiers. J Clin Invest 2024; 134:e172844. [PMID: 38488007 PMCID: PMC10940090 DOI: 10.1172/jci172844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2024] Open
Abstract
The lymphatic vascular system is gaining recognition for its multifaceted role and broad pathological significance. Once perceived as a mere conduit for interstitial fluid and immune cell transport, recent research has unveiled its active involvement in critical physiological processes and common diseases, including inflammation, autoimmune diseases, and atherosclerosis. Consequently, abnormal development or functionality of lymphatic vessels can result in serious health complications. Here, we discuss lymphatic malformations (LMs), which are localized lesions that manifest as fluid-filled cysts or extensive infiltrative lymphatic vessel overgrowth, often associated with debilitating, even life-threatening, consequences. Genetic causes of LMs have been uncovered, and several promising drug-based therapies are currently under investigation and will be discussed.
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Affiliation(s)
- Milena Petkova
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Ingvar Ferby
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Taija Mäkinen
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland
- University of Helsinki, Helsinki, Finland
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Femel J, Hill C, Illa Bochaca I, Booth JL, Asnaashari TG, Steele MM, Moshiri AS, Do H, Zhong J, Osman I, Leachman SA, Tsujikawa T, White KP, Chang YH, Lund AW. Quantitative multiplex immunohistochemistry reveals inter-patient lymphovascular and immune heterogeneity in primary cutaneous melanoma. Front Immunol 2024; 15:1328602. [PMID: 38361951 PMCID: PMC10867179 DOI: 10.3389/fimmu.2024.1328602] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 01/15/2024] [Indexed: 02/17/2024] Open
Abstract
Introduction Quantitative, multiplexed imaging is revealing complex spatial relationships between phenotypically diverse tumor infiltrating leukocyte populations and their prognostic implications. The underlying mechanisms and tissue structures that determine leukocyte distribution within and around tumor nests, however, remain poorly understood. While presumed players in metastatic dissemination, new preclinical data demonstrates that blood and lymphatic vessels (lymphovasculature) also dictate leukocyte trafficking within tumor microenvironments and thereby impact anti-tumor immunity. Here we interrogate these relationships in primary human cutaneous melanoma. Methods We established a quantitative, multiplexed imaging platform to simultaneously detect immune infiltrates and tumor-associated vessels in formalin-fixed paraffin embedded patient samples. We performed a discovery, retrospective analysis of 28 treatment-naïve, primary cutaneous melanomas. Results Here we find that the lymphvasculature and immune infiltrate is heterogenous across patients in treatment naïve, primary melanoma. We categorized five lymphovascular subtypes that differ by functionality and morphology and mapped their localization in and around primary tumors. Interestingly, the localization of specific vessel subtypes, but not overall vessel density, significantly associated with the presence of lymphoid aggregates, regional progression, and intratumoral T cell infiltrates. Discussion We describe a quantitative platform to enable simultaneous lymphovascular and immune infiltrate analysis and map their spatial relationships in primary melanoma. Our data indicate that tumor-associated vessels exist in different states and that their localization may determine potential for metastasis or immune infiltration. This platform will support future efforts to map tumor-associated lymphovascular evolution across stage, assess its prognostic value, and stratify patients for adjuvant therapy.
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Affiliation(s)
- Julia Femel
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, OR, United States
| | - Cameron Hill
- Ronald O. Perelman Department of Dermatology, New York University (NYU) Grossman School of Medicine, New York, NY, United States
| | - Irineu Illa Bochaca
- Ronald O. Perelman Department of Dermatology, New York University (NYU) Grossman School of Medicine, New York, NY, United States
| | - Jamie L. Booth
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, OR, United States
| | - Tina G. Asnaashari
- Department of Biomedical Engineering and Computational Biology Program, Oregon Health & Science University, Portland, OR, United States
| | - Maria M. Steele
- Ronald O. Perelman Department of Dermatology, New York University (NYU) Grossman School of Medicine, New York, NY, United States
| | - Ata S. Moshiri
- Ronald O. Perelman Department of Dermatology, New York University (NYU) Grossman School of Medicine, New York, NY, United States
| | - Hyungrok Do
- Department of Population Health, New York University (NYU) Grossman School of Medicine, New York, NY, United States
| | - Judy Zhong
- Department of Population Health, New York University (NYU) Grossman School of Medicine, New York, NY, United States
- Laura and Isaac Perlmutter Cancer Center, New York University (NYU) Langone Health, New York, NY, United States
| | - Iman Osman
- Ronald O. Perelman Department of Dermatology, New York University (NYU) Grossman School of Medicine, New York, NY, United States
- Laura and Isaac Perlmutter Cancer Center, New York University (NYU) Langone Health, New York, NY, United States
| | - Sancy A. Leachman
- Department of Dermatology, Oregon Health & Science University, Portland, OR, United States
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States
| | - Takahiro Tsujikawa
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, OR, United States
- Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kevin P. White
- Department of Dermatology, Oregon Health & Science University, Portland, OR, United States
| | - Young H. Chang
- Department of Biomedical Engineering and Computational Biology Program, Oregon Health & Science University, Portland, OR, United States
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States
| | - Amanda W. Lund
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, OR, United States
- Ronald O. Perelman Department of Dermatology, New York University (NYU) Grossman School of Medicine, New York, NY, United States
- Department of Biomedical Engineering and Computational Biology Program, Oregon Health & Science University, Portland, OR, United States
- Laura and Isaac Perlmutter Cancer Center, New York University (NYU) Langone Health, New York, NY, United States
- Department of Dermatology, Oregon Health & Science University, Portland, OR, United States
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States
- Department of Pathology, New York University (NYU) Grossman School of Medicine, New York, NY, United States
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Sato Y, Tamura M, Yanagita M. Tertiary lymphoid tissues: a regional hub for kidney inflammation. Nephrol Dial Transplant 2023; 38:26-33. [PMID: 34245300 DOI: 10.1093/ndt/gfab212] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Indexed: 01/26/2023] Open
Abstract
Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues that develop at sites of chronic inflammation in nonlymphoid organs. As with lymph nodes, TLTs initiate adaptive immune responses and coordinate local tissue immunity. Although virtually ignored for decades, TLTs have recently received a great deal of attention for their ability to influence disease severity, prognosis and response to therapy in various diseases, including cancer, autoimmune disorders and infections. TLTs are also induced in kidneys of patients with chronic kidney diseases such as immunoglobulin A nephropathy and lupus nephritis. Nevertheless, TLTs in the kidney have not been extensively investigated and their mechanism of development, functions and clinical relevance remain unknown, mainly because of the absence of adequate murine kidney TLT models and limited availability of human kidney samples containing TLTs. We recently found that aged kidneys, but not young kidneys, exhibit multiple TLTs after injury. Interestingly, although they are a minor component of TLTs, resident fibroblasts in the kidneys diversify into several distinct phenotypes that play crucial roles in TLT formation. Furthermore, the potential of TLTs as a novel kidney injury/inflammation marker as well as a novel therapeutic target for kidney diseases is also suggested. In this review article we describe the current understanding of TLTs with a focus on age-dependent TLTs in the kidney and discuss their potential as a novel therapeutic target and kidney inflammation marker.
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Affiliation(s)
- Yuki Sato
- Medical Innovation Center, TMK Project, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masaru Tamura
- Technology and Development Team for Mouse Phenotype Analysis, Japan Mouse Clinic, RIKEN BioResource Research Center (BRC), Tsukuba, Japan
| | - Motoko Yanagita
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
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Role of tertiary lymphoid organs in the regulation of immune responses in the periphery. Cell Mol Life Sci 2022; 79:359. [PMID: 35689679 PMCID: PMC9188279 DOI: 10.1007/s00018-022-04388-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 04/28/2022] [Accepted: 05/20/2022] [Indexed: 12/12/2022]
Abstract
Tertiary lymphoid organs (TLOs) are collections of immune cells resembling secondary lymphoid organs (SLOs) that form in peripheral, non-lymphoid tissues in response to local chronic inflammation. While their formation mimics embryologic lymphoid organogenesis, TLOs form after birth at ectopic sites in response to local inflammation resulting in their ability to mount diverse immune responses. The structure of TLOs can vary from clusters of B and T lymphocytes to highly organized structures with B and T lymphocyte compartments, germinal centers, and lymphatic vessels (LVs) and high endothelial venules (HEVs), allowing them to generate robust immune responses at sites of tissue injury. Although our understanding of the formation and function of these structures has improved greatly over the last 30 years, their role as mediators of protective or pathologic immune responses in certain chronic inflammatory diseases remains enigmatic and may differ based on the local tissue microenvironment in which they form. In this review, we highlight the role of TLOs in the regulation of immune responses in chronic infection, chronic inflammatory and autoimmune diseases, cancer, and solid organ transplantation.
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Singla B, Aithabathula RV, Kiran S, Kapil S, Kumar S, Singh UP. Reactive Oxygen Species in Regulating Lymphangiogenesis and Lymphatic Function. Cells 2022; 11:1750. [PMID: 35681445 PMCID: PMC9179518 DOI: 10.3390/cells11111750] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/18/2022] [Accepted: 05/24/2022] [Indexed: 11/17/2022] Open
Abstract
The lymphatic system is pivotal for immunosurveillance and the maintenance of tissue homeostasis. Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vessels, has both physiological and pathological roles. Recent advances in the molecular mechanisms regulating lymphangiogenesis have opened a new area of research on reparative lymphangiogenesis for the treatment of various pathological disorders comprising neurological disorders, cardiac repair, autoimmune disease, obesity, atherosclerosis, etc. Reactive oxygen species (ROS) produced by the various cell types serve as signaling molecules in several cellular mechanisms and regulate various aspects of growth-factor-mediated responses, including lymphangiogenesis. The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. Low ROS levels are essential for lymphangiogenesis. On the contrary, oxidative stress due to enhanced ROS generation and/or reduced levels of antioxidants suppresses lymphangiogenesis via promoting lymphatic endothelial cell apoptosis and death. In this review article, we provide an overview of types and sources of ROS, discuss the role of ROS in governing lymphangiogenesis and lymphatic function, and summarize the role of lymphatics in various diseases.
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Affiliation(s)
- Bhupesh Singla
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38017, USA; (R.V.A.); (S.K.); (S.K.); (U.P.S.)
| | - Ravi Varma Aithabathula
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38017, USA; (R.V.A.); (S.K.); (S.K.); (U.P.S.)
| | - Sonia Kiran
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38017, USA; (R.V.A.); (S.K.); (S.K.); (U.P.S.)
| | - Shweta Kapil
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children′s Hospital Medical Center, Cincinnati, OH 45229, USA;
| | - Santosh Kumar
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38017, USA; (R.V.A.); (S.K.); (S.K.); (U.P.S.)
| | - Udai P. Singh
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN 38017, USA; (R.V.A.); (S.K.); (S.K.); (U.P.S.)
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Ohm B, Jungraithmayr W. B Cell Immunity in Lung Transplant Rejection - Effector Mechanisms and Therapeutic Implications. Front Immunol 2022; 13:845867. [PMID: 35320934 PMCID: PMC8934882 DOI: 10.3389/fimmu.2022.845867] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 02/10/2022] [Indexed: 12/14/2022] Open
Abstract
Allograft rejection remains the major hurdle in lung transplantation despite modern immunosuppressive treatment. As part of the alloreactive process, B cells are increasingly recognized as modulators of alloimmunity and initiators of a donor-specific humoral response. In chronically rejected lung allografts, B cells contribute to the formation of tertiary lymphoid structures and promote local alloimmune responses. However, B cells are functionally heterogeneous and some B cell subsets may promote alloimmune tolerance. In this review, we describe the current understanding of B-cell-dependent mechanisms in pulmonary allograft rejection and highlight promising future strategies that employ B cell-targeted therapies.
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Affiliation(s)
- Birte Ohm
- Department of Thoracic Surgery, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Wolfgang Jungraithmayr
- Department of Thoracic Surgery, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
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Salvador AFM, Kipnis J. Immune response after central nervous system injury. Semin Immunol 2022; 59:101629. [PMID: 35753867 DOI: 10.1016/j.smim.2022.101629] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/07/2022] [Accepted: 06/13/2022] [Indexed: 01/15/2023]
Abstract
Traumatic injuries of the central nervous system (CNS) affect millions of people worldwide, and they can lead to severely damaging consequences such as permanent disability and paralysis. Multiple factors can obstruct recovery after CNS injury. One of the most significant is the progressive neuronal death that follows the initial mechanical impact, leading to the loss of undamaged cells via a process termed secondary neurodegeneration. Efforts to define treatments that limit the spread of damage, while important, have been largely ineffectual owing to gaps in the mechanistic understanding that underlies the persisting neuronal cell death. Inflammation, with its influx of immune cells that occurs shortly after injury, has been associated with secondary neurodegeneration. However, the role of the immune system after CNS injury is far more complex. Studies have indicated that the immune response after CNS injury is detrimental, owing to immune cell-produced factors (e.g., pro-inflammatory cytokines, free radicals, neurotoxic glutamate) that worsen tissue damage. Our lab and others have also demonstrated the beneficial immune response that occurs after CNS injury, with the release of growth factors such as brain-derived growth factor (BDNF) and interleukin (IL-10) and the clearance of apoptotic and myelin debris by immune cells1-4. In this review, we first discuss the multifaceted roles of the immune system after CNS injury. We then speculate on how advancements in single-cell RNA technologies can dramatically change our understanding of the immune response, how the spinal cord meninges serve as an important site for hosting immunological processes critical for recovery, and how the origin of peripherally recruited immune cells impacts their function in the injured CNS.
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Affiliation(s)
- Andrea Francesca M Salvador
- Department of Pathology & Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA.
| | - Jonathan Kipnis
- Department of Pathology & Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
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11
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Yin Y, Zhu ZX, Li Z, Chen YS, Zhu WM. Role of mesenteric component in Crohn’s disease: A friend or foe? World J Gastrointest Surg 2021; 13:1536-1549. [PMID: 35070062 PMCID: PMC8727179 DOI: 10.4240/wjgs.v13.i12.1536] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 08/01/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease (CD) is a complex and relapsing gastrointestinal disease with mesenteric alterations. The mesenteric neural, vascular, and endocrine systems actively take part in the gut dysbiosis-adaptive immunity-mesentery-body axis, and this axis has been proven to be bidirectional. The abnormalities of morphology and function of the mesenteric component are associated with intestinal inflammation and disease progress of CD via responses to afferent signals, neuropeptides, lymphatic drainage, adipokines, and functional cytokines. The hypertrophy of mesenteric adipose tissue plays important roles in the pathogenesis of CD by secreting large amounts of adipokines and representing a rich source of proinflammatory or profibrotic cytokines. The vascular alteration, including angiogenesis and lymphangiogenesis, is concomitant in the disease course of CD. Of note, the enlarged and obstructed lymphatic vessels, which have been described in CD patients, are likely related to the early onset submucosa edema and being a cause of CD. The function of mesenteric lymphatics is influenced by endocrine of mesenteric nerves and adipocytes. Meanwhile, the structure of the mesenteric lymphatic vessels in hypertrophic mesenteric adipose tissue is mispatterned and ruptured, which can lead to lymph leakage. Leaky lymph factors can in turn stimulate adipose tissue to proliferate and effectively elicit an immune response. The identification of the role of mesentery and the crosstalk between mesenteric tissues in intestinal inflammation may shed light on understanding the underlying mechanism of CD and help explore new therapeutic targets.
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Affiliation(s)
- Yi Yin
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhen-Xing Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhun Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Yu-Sheng Chen
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Ming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
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12
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-62v2kivtk' or 159=(select 159 from pg_sleep(9))--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6w8jpumgz'); waitfor delay '0:0:18' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-675tomkjw'); waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6-1); waitfor delay '0:0:18' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6inyod6yy'); waitfor delay '0:0:0' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6' and 2*3*8=6*8 and 'q4ng'='q4ng] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6uo9qdmbo' or 900=(select 900 from pg_sleep(15))--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6xjcyx5xp'; waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6kliwx55t'; waitfor delay '0:0:0' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-60"xor(if(now()=sysdate(),sleep(15),0))xor"z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6-1 waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6" and 2*3*8=6*8 and "1plv"="1plv] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-60'xor(if(now()=sysdate(),sleep(15),0))xor'z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6jpd2wffe'); waitfor delay '0:0:9' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6xkcvwszk'); waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 PMCID: PMC8371859 DOI: 10.1186/s41232-021-00175-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/05/2023] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn’s disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer’s disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6-1; waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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29
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6'||'] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-60"xor(if(now()=sysdate(),sleep(9),0))xor"z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6-1); waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6y8xz2ym5')); waitfor delay '0:0:0' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6f9cyjbik')); waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6algupclm] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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35
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-64yudfa9k'; waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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36
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6fqqx42pj'; waitfor delay '0:0:9' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6uldec7js')); waitfor delay '0:0:15' --] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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38
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Hokari R, Tomioka A. The role of lymphatics in intestinal inflammation. Inflamm Regen 2021; 41:25. [PMID: 34404493 DOI: 10.1186/s41232-021-00175-6%' and 2*3*8=6*8 and 'qtjh'!='qtjh%] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/03/2021] [Indexed: 01/29/2024] Open
Abstract
The lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn's disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer's disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.
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Affiliation(s)
- Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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39
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Atreya R, Siegmund B. Location is important: differentiation between ileal and colonic Crohn's disease. Nat Rev Gastroenterol Hepatol 2021; 18:544-558. [PMID: 33712743 DOI: 10.1038/s41575-021-00424-6] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/29/2021] [Indexed: 01/31/2023]
Abstract
Crohn's disease can affect any part of the gastrointestinal tract; however, current European and national guidelines worldwide do not differentiate between small-intestinal and colonic Crohn's disease for medical treatment. Data from the past decade provide evidence that ileal Crohn's disease is distinct from colonic Crohn's disease in several intestinal layers. Remarkably, colonic Crohn's disease shows an overlap with regard to disease behaviour with ulcerative colitis, underlining the fact that there is more to inflammatory bowel disease than just Crohn's disease and ulcerative colitis, and that subtypes, possibly defined by location and shared pathophysiology, are also important. This Review provides a structured overview of the differentiation between ileal and colonic Crohn's disease using data in the context of epidemiology, genetics, macroscopic differences such as creeping fat and histological findings, as well as differences in regard to the intestinal barrier including gut microbiota, mucus layer, epithelial cells and infiltrating immune cell populations. We also discuss the translation of these basic findings to the clinic, emphasizing the important role of treatment decisions. Thus, this Review provides a conceptual outlook on a new mechanism-driven classification of Crohn's disease.
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Affiliation(s)
- Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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40
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Yeo KP, Lim HY, Angeli V. Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis. Cells 2021; 10:cells10061344. [PMID: 34072313 PMCID: PMC8229118 DOI: 10.3390/cells10061344] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/21/2021] [Accepted: 05/26/2021] [Indexed: 02/03/2023] Open
Abstract
In recent years, lymphatic vessels have received increasing attention and our understanding of their development and functional roles in health and diseases has greatly improved. It has become clear that lymphatic vessels are critically involved in acute and chronic inflammation and its resolution by supporting the transport of immune cells, fluid, and macromolecules. As we will discuss in this review, the involvement of lymphatic vessels has been uncovered in atherosclerosis, a chronic inflammatory disease of medium- and large-sized arteries causing deadly cardiovascular complications worldwide. The progression of atherosclerosis is associated with morphological and functional alterations in lymphatic vessels draining the diseased artery. These defects in the lymphatic vasculature impact the inflammatory response in atherosclerosis by affecting immune cell trafficking, lymphoid neogenesis, and clearance of macromolecules in the arterial wall. Based on these new findings, we propose that targeting lymphatic function could be considered in conjunction with existing drugs as a treatment option for atherosclerosis.
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41
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Koscsó B, Kurapati S, Rodrigues RR, Nedjic J, Gowda K, Shin C, Soni C, Ashraf AZ, Purushothaman I, Palisoc M, Xu S, Sun H, Chodisetti SB, Lin E, Mack M, Kawasawa YI, He P, Rahman ZSM, Aifantis I, Shulzhenko N, Morgun A, Bogunovic M. Gut-resident CX3CR1 hi macrophages induce tertiary lymphoid structures and IgA response in situ. Sci Immunol 2020; 5:5/46/eaax0062. [PMID: 32276965 DOI: 10.1126/sciimmunol.aax0062] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 12/27/2019] [Accepted: 02/28/2020] [Indexed: 12/12/2022]
Abstract
Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2 +CX3CR1lo, Ccr7 +CX3CR1int (lymph migratory), and Cxcl13 +CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13 +CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7 +CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.
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Affiliation(s)
- Balázs Koscsó
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Sravya Kurapati
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.,Biomedical Sciences PhD Program, Penn State University College of Medicine, Hershey, PA, USA
| | | | - Jelena Nedjic
- Department of Pathology and Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA
| | - Kavitha Gowda
- Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA, USA
| | - Changsik Shin
- Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA, USA
| | - Chetna Soni
- Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA, USA
| | - Azree Zaffran Ashraf
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Indira Purushothaman
- PhD Program in Anatomy at Penn State College of Medicine, Penn State University College of Medicine, Hershey, PA, USA
| | - Maryknoll Palisoc
- MD/PhD Medical Scientist Training Program, Penn State University College of Medicine, Hershey, PA, USA
| | - Sulei Xu
- Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA, USA
| | - Haoyu Sun
- Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA, USA
| | - Sathi Babu Chodisetti
- Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA, USA
| | - Eugene Lin
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Matthias Mack
- Department of Internal Medicine/Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Yuka Imamura Kawasawa
- Department of Pharmacology and Biochemistry and Molecular Biology, Institute of Personalized Medicine, Penn State University College of Medicine, Hershey, PA, USA
| | - Pingnian He
- Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA, USA
| | - Ziaur S M Rahman
- Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA, USA
| | - Iannis Aifantis
- Department of Pathology and Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA
| | - Natalia Shulzhenko
- College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA
| | - Andrey Morgun
- College of Pharmacy, Oregon State University, Corvallis, OR, USA
| | - Milena Bogunovic
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA. .,Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA, USA.,Inflammatory Bowel Disease Center, Milton S. Hershey Medical Center, Hershey, PA, USA
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42
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Cohen M, Giladi A, Raposo C, Zada M, Li B, Ruckh J, Deczkowska A, Mohar B, Shechter R, Lichtenstein RG, Amit I, Schwartz M. Meningeal lymphoid structures are activated under acute and chronic spinal cord pathologies. Life Sci Alliance 2020; 4:4/1/e202000907. [PMID: 33277355 PMCID: PMC7723261 DOI: 10.26508/lsa.202000907] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/27/2020] [Accepted: 10/28/2020] [Indexed: 12/01/2022] Open
Abstract
We found that acute insult to the central nervous system induces the formation of lymphocyte aggregates reminiscent of tertiary lymphoid structures within the spinal cord meninges. Unlike draining CNS-cervical lymph nodes, meningeal lymphocytes are locally activated during neuro-inflammtion and neurodegeneration. Tertiary lymphoid structures (TLS) are organized aggregates of B and T cells formed ectopically during different stages of life in response to inflammation, infection, or cancer. Here, we describe formation of structures reminiscent of TLS in the spinal cord meninges under several central nervous system (CNS) pathologies. After acute spinal cord injury, B and T lymphocytes locally aggregate within the meninges to form TLS-like structures, and continue to accumulate during the late phase of the response to the injury, with a negative impact on subsequent pathological conditions, such as experimental autoimmune encephalomyelitis. Using a chronic model of spinal cord pathology, the mSOD1 mouse model of amyotrophic lateral sclerosis, we further showed by single-cell RNA-sequencing that a meningeal lymphocyte niche forms, with a unique organization and activation state, including accumulation of pre-B cells in the spinal cord meninges. Such a response was not found in the CNS-draining cervical lymph nodes. The present findings suggest that a special immune response develops in the meninges during various neurological pathologies in the CNS, a possible reflection of its immune privileged nature.
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Affiliation(s)
- Merav Cohen
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Amir Giladi
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Catarina Raposo
- Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
| | - Mor Zada
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Baoguo Li
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Julia Ruckh
- Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
| | | | - Boaz Mohar
- Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
| | - Ravid Shechter
- Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
| | - Rachel G Lichtenstein
- Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beersheba, Israel
| | - Ido Amit
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Michal Schwartz
- Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel .,Klarman Cell Observatory, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
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Guedj K, Abitbol Y, Cazals-Hatem D, Morvan M, Maggiori L, Panis Y, Bouhnik Y, Caligiuri G, Corcos O, Nicoletti A. Adipocytes orchestrate the formation of tertiary lymphoid organs in the creeping fat of Crohn's disease affected mesentery. J Autoimmun 2019; 103:102281. [PMID: 31171476 DOI: 10.1016/j.jaut.2019.05.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/14/2019] [Accepted: 05/14/2019] [Indexed: 12/21/2022]
Abstract
The formation of tertiary lymphoid organs (TLOs) is orchestrated by the stromal cells of tissues chronically submitted to inflammatory stimuli, in order to uphold specific adaptive immune responses. We have recently shown that the smooth muscle cells of the arterial wall orchestrate the formation of the TLOs associated with atherosclerosis in response to the local release of TNF-α. Observational studies have recently documented the presence of structures resembling TLOs the creeping fat that develops in the mesentery of patients with Crohn's disease (CD), an inflammatory condition combining a complex and as yet not elucidated infectious and autoimmune responses. We have performed a comprehensive analysis of the TLO structures in order to decipher the mechanism leading to their formation in the mesentery of CD patients, and assessed the effect of infectious and/or inflammatory inducers on the potential TLO-organizer functions of adipocytes. Quantitative analysis showed that both T and B memory cells, as well as plasma cells, are enriched in the CD-affected mesentery, as compared with tissue from control subjects. Immunohistochemistry revealed that these cells are concentrated within the creeping fat of CD patients, in the vicinity of transmural lesions; that T and B cells are compartmentalized in clearly distinct areas; that they are supplied by post-capillary high endothelial venules and drained by lymphatic vessels indicating that these nodules are fully mature TLOs. Organ culture showed that mesenteric tissue samples from CD patients contained greater amounts of adipocyte-derived chemokines and the use of the conditioned medium from these cultures in functional assays was able to actively recruit T and B lymphocytes. Finally, the production of chemokines involved in TLO formation by 3T3-L1 adipocytes was directly elicited by a combination of TNF-α and LPS in vitro. We therefore propose a mechanism in which mesenteric adipocyte, through their production of key chemokines in response to inflammatory/bacterial stimuli, may orchestrate the formation of functional TLOs developing in CD-affected mesentery.
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Affiliation(s)
- Kevin Guedj
- Université de Paris, UMRS1148, INSERM, DHU Fire, Hôpital Bichat, 46 rue Henri Huchard, 75018, Paris, France; APHP, Department of Gastroenterology, IBD and Intestinal Failure, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110, Clichy, France
| | - Yaël Abitbol
- Université de Paris, UMRS1148, INSERM, DHU Fire, Hôpital Bichat, 46 rue Henri Huchard, 75018, Paris, France; APHP, Department of Gastroenterology, IBD and Intestinal Failure, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110, Clichy, France
| | - Dominique Cazals-Hatem
- APHP, Department of Pathology, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110, Clichy, France
| | - Marion Morvan
- Université de Paris, UMRS1148, INSERM, DHU Fire, Hôpital Bichat, 46 rue Henri Huchard, 75018, Paris, France
| | - Léon Maggiori
- APHP, Department of Colorectal Surgery, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110, Clichy, France; DHU Unity - Paris 7 Diderot University, 5 rue Thomas Mann, 75013, Paris, France
| | - Yves Panis
- APHP, Department of Colorectal Surgery, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110, Clichy, France; DHU Unity - Paris 7 Diderot University, 5 rue Thomas Mann, 75013, Paris, France
| | - Yoram Bouhnik
- DHU Unity - Paris 7 Diderot University, 5 rue Thomas Mann, 75013, Paris, France; APHP, Department of Gastroenterology, IBD and Intestinal Failure, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110, Clichy, France
| | - Giuseppina Caligiuri
- Université de Paris, UMRS1148, INSERM, DHU Fire, Hôpital Bichat, 46 rue Henri Huchard, 75018, Paris, France
| | - Olivier Corcos
- Université de Paris, UMRS1148, INSERM, DHU Fire, Hôpital Bichat, 46 rue Henri Huchard, 75018, Paris, France; DHU Unity - Paris 7 Diderot University, 5 rue Thomas Mann, 75013, Paris, France; APHP, Department of Gastroenterology, IBD and Intestinal Failure, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110, Clichy, France
| | - Antonino Nicoletti
- Université de Paris, UMRS1148, INSERM, DHU Fire, Hôpital Bichat, 46 rue Henri Huchard, 75018, Paris, France.
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44
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Nowocin AK, Meader L, Brown K, Elgueta R, Wong W. Characterizing the B-Cell and Humoral Response in Tertiary Lymphoid Organs in Kidney Allografts. EXP CLIN TRANSPLANT 2019; 17:330-338. [PMID: 30880652 DOI: 10.6002/ect.2017.0261] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Tertiary lymphoid organs are formed at sites of chronic inflammation and are thought to contribute to the immune response. Here, we aimed to characterize the structure and function of tertiary lymphoid organs in a model of murine kidney allotransplant to understand their role in alloimmunity. MATERIALS AND METHODS We transplanted 4 C57BL/6 mouse kidneys (isograft group) and 17 DBA/2 mouse kidneys into C57BL/6 mouse recipients. Three DBA/2-to-C57BL/6 transplant mice that rejected their grafts acutely (before 10 days posttransplant) were excluded from the study. The 14 surviving DAB2 grafts were retrieved at day 45 posttransplant and evaluated histologically. The presence of antibody-secreting cells and circulating levels of donor-specific antibodies were also evaluated. RESULTS We found that tertiary lymphoid organs can be associated with a beneficial response in a kidney allotransplant model. Characterization of B-cell subsets within tertiary lymphoid organs in mouse kidney allografts revealed naive, plasma, and memory B cells, which were mostly grouped within or in close proximity of tertiary lymphoid organs. Staining for intracellular immunoglobulin G showed that many of the B cells within tertiary lymphoid organs were capable of producing antibodies. Although allospecific antibodies were found in the serum of recipient mice and were deposited in the transplanted kidneys, graft function was not affected in this model. CONCLUSIONS B cells within tertiary lymphoid organs are functional and contribute to the humoral arm of the alloresponse. However, tertiary lymphoid organs are not necessarily associated with graft rejection, suggesting that protective mechanisms are at play.
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Affiliation(s)
- Anna K Nowocin
- From the MRC Centre for Transplantation, King's College London School of Medicine at Guy's, King's and St. Thomas' Hospitals, London, United Kingdom
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45
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Pipi E, Nayar S, Gardner DH, Colafrancesco S, Smith C, Barone F. Tertiary Lymphoid Structures: Autoimmunity Goes Local. Front Immunol 2018; 9:1952. [PMID: 30258435 PMCID: PMC6143705 DOI: 10.3389/fimmu.2018.01952] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Accepted: 08/07/2018] [Indexed: 12/18/2022] Open
Abstract
Tertiary lymphoid structures (TLS) are frequently observed in target organs of autoimmune diseases. TLS present features of secondary lymphoid organs such as segregated T and B cell zones, presence of follicular dendritic cell networks, high endothelial venules and specialized lymphoid fibroblasts and display the mechanisms to support local adaptive immune responses toward locally displayed antigens. TLS detection in the tissue is often associated with poor prognosis of disease, auto-antibody production and malignancy development. This review focuses on the contribution of TLS toward the persistence of the inflammatory drive, the survival of autoreactive lymphocyte clones and post-translational modifications, responsible for the pathogenicity of locally formed autoantibodies, during autoimmune disease development.
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Affiliation(s)
- Elena Pipi
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.,Experimental Medicine Unit, Immuno-Inflammation Therapeutic Area, GSK Medicines Research Centre, Stevenage, United Kingdom
| | - Saba Nayar
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - David H Gardner
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | | | - Charlotte Smith
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Francesca Barone
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
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Mueller CG, Nayar S, Gardner D, Barone F. Cellular and Vascular Components of Tertiary Lymphoid Structures. Methods Mol Biol 2018; 1845:17-30. [PMID: 30141005 DOI: 10.1007/978-1-4939-8709-2_2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Inflammatory immune cells recruited at the site of chronic inflammation form structures that resemble secondary lymphoid organs (SLO). These are characterized by segregated areas of prevalent T- or B-cell aggregation, differentiation of high endothelial venules, and local activation of resident stromal cells, including lymphatic endothelial cells. B-cell proliferation and affinity maturation toward locally displayed autoantigens have been demonstrated at these sites, known as tertiary lymphoid structures (TLS). TLS formation during chronic inflammation has been associated with local disease persistence and progression, as well as increased systemic manifestations. While bearing a similar histological structure to SLO, the signals that regulate TLS and SLO formation can diverge and a series of pro-inflammatory cytokines have been ascribed as responsible for TLS formation at different anatomical sites. Moreover, for a long time the structural compartment that regulates TLS homeostasis, including survival and recirculation of leucocytes has been neglected. In this chapter, we summarize the novel data available on TLS formation, structural organization, and the functional and anatomical links connecting TLS and SLOs.
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Affiliation(s)
- Christopher George Mueller
- Laboratoire d'Immunologie, Immunopathologie et Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire (IBMC), CNRS UPR 3572, University of Strasbourg, Strasbourg, France
| | - Saba Nayar
- Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK
| | - David Gardner
- Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK
| | - Francesca Barone
- Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
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Alloimmune-induced intragraft lymphoid neogenesis promotes B-cell tolerance breakdown that accelerates chronic rejection. Curr Opin Organ Transplant 2017; 21:368-74. [PMID: 27258579 DOI: 10.1097/mot.0000000000000329] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW Antibody-mediated rejection (AMR) has emerged as a leading cause of allograft loss in solid organ transplantation. A better understanding of AMR immunopathology is a prerequisite to improve its management. RECENT FINDINGS The prevalent dogma considers that AMR is the consequence of a thymo-dependent B-cell response against donor-specific polymorphic antigens (mainly mismatched human leukocyte antigen molecules).Nevertheless, antibodies directed against nonpolymorphic antigens expressed by the graft are also generated during chronic rejection and can contribute to allograft destruction. This implies that a breakdown of self-tolerance occurs during chronic rejection. Accumulating evidence suggests that this event occurs inside the ectopic 'tertiary' lymphoid tissue that develops within rejected allografts.Thus, AMR should be viewed as a complex interplay between allo- and autoimmune humoral responses. SUMMARY The interplay between allo- and autoimmune humoral responses in chronic rejection highlights several unmet medical issues like better diagnosis tools are needed to screen recipients for nonhuman leukocyte antigen alloantibodies and autoantibodies, therapeutic strategies shall aim at blocking the response against alloantigens but also the breakdown of self-tolerance that occurs within tertiary lymphoid tissue.
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Al-Kofahi M, Yun JW, Minagar A, Alexander JS. Anatomy and roles of lymphatics in inflammatory diseases. ACTA ACUST UNITED AC 2017. [DOI: 10.1111/cen3.12400] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Mahmoud Al-Kofahi
- Department of Experimental and Clinical Pharmacology; College of Pharmacy; University of Minnesota; Minneapolis MN USA
| | - J. Winny Yun
- Department of Molecular and Cellular Physiology; Louisiana State University Health Sciences Center Shreveport; Shreveport LA USA
| | - Alireza Minagar
- Department of Neurology; Louisiana State University Health Sciences Center Shreveport; Shreveport LA USA
| | - J. Steven Alexander
- Department of Molecular and Cellular Physiology; Louisiana State University Health Sciences Center Shreveport; Shreveport LA USA
- Department of Neurology; Louisiana State University Health Sciences Center Shreveport; Shreveport LA USA
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S1P Provokes Tumor Lymphangiogenesis via Macrophage-Derived Mediators Such as IL-1 β or Lipocalin-2. Mediators Inflamm 2017; 2017:7510496. [PMID: 28804221 PMCID: PMC5539930 DOI: 10.1155/2017/7510496] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 06/15/2017] [Indexed: 12/17/2022] Open
Abstract
A pleiotropic signaling lipid, sphingosine-1-phosphate (S1P), has been implicated in various pathophysiological processes supporting tumor growth and metastasis. However, there are only a few descriptive studies suggesting a role of S1P in tumor lymphangiogenesis, which is critical for tumor growth and dissemination. Corroborating own data, the literature suggests that apoptotic tumor cell-derived S1P alters the phenotype of tumor-associated macrophages (TAMs) to gain protumor functions. However, mechanistically, the role of TAM-induced lymphangiogenesis has only been poorly described, mostly linked to the production of lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C) and VEGF-D, or transdifferentiation into lymphatic endothelial cells. Recent findings highlight a rather underappreciated role of S1P in tumor lymphangiogenesis, referring to the production of interleukin-1β (IL-1β) and lipocalin-2 (LCN2) by a tumor-promoting macrophage phenotype. In this review, we aim to provide to the readers with the current understanding of the molecular mechanism how apoptotic cell-derived S1P triggers TAMs to promote lymphangiogenesis.
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TNFΔARE Mice Display Abnormal Lymphatics and Develop Tertiary Lymphoid Organs in the Mesentery. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:798-807. [PMID: 28183530 DOI: 10.1016/j.ajpath.2016.12.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 11/25/2016] [Accepted: 12/01/2016] [Indexed: 01/25/2023]
Abstract
Chronic inflammatory diseases are associated with a persistent and enhanced response to environmental antigens. As an adaptive response to this exaggerated immune state, affected tissue typically develops tertiary lymphoid organs. Studies of Crohn disease (CD), a chronic inflammatory disease of the intestinal tract, report tertiary lymphoid organs present within the mucosal wall, along with other lymphatic diseases, such as lymphangiogenesis and obstructed lymphatic vessels. These observations suggest that downstream mesenteric lymphatic vessels and lymph drainage into mesenteric lymph nodes may be compromised. However, information is lacking on the morphologic features and functional status of mesenteric lymphatics in CD. Using confocal imaging, PCR, flow cytometry, and functional strategies, we addressed these questions in the established TNFΔARE mouse model of CD and found that this mouse model had many lymphatic abnormalities reminiscent of human CD. These abnormalities include intestinal lymphangiectasia, mesenteric lymph node lymphadenopathy, and lymphangiogenesis in both the mesentery and mucosa. Critically, TNFΔARE mice also present mesenteric tertiary lymphoid organs and have altered lymphatic transport of dendritic cells to mesenteric lymph nodes, two features likely to actively modulate immunity. Our findings provide key insights into lymphatic remodeling in the TNFΔARE mouse model. They shed light on the involvement of these lymphatic changes in immune dysfunctions observed in CD and suggest the lymphatic system as new target for therapeutic options.
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