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Frontiers in B-cell immunology

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Cellular & Molecular immunology 2013年第2期10卷 95-96页

作者： Liwei Lu department of pathology and center for infection and immunology The University of Hong Kong Hong Kong China

During the last several decades, significant progress has been made in understanding the roles of B cells inimmunity and autoimmunity. B-cell development, occurring in the bone marrow, is a complex dynamic process involving immunoglobulin （Ig） gene rearrangement and B-cell receptor （BCR） expression. Early progenitor B （pro-B） cells initiate DNA rearrangement at their Ig heavy chain loci, resulting in the synthesis of μ-chains in the cytoplasm and the assembly of the precursor B-cell receptor （pre-BCR）. Following successful rearrangement of light chain genes, these precursor B （pre-B） cells differentiate into immature B cells when whole IgM mole- cules are expressed as the functional BCR on the cell surface.

关键词：变态反应和免疫学骨髓基因基因重排理解力免疫球蛋白类细胞质原癌基因

Regulatory B cells in autoimmune diseases

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Cellular & Molecular immunology 2013年第2期10卷 122-132页

作者： Min Yang Ke Rui Shengjun Wang Liwei Lu department of pathology and center for infection and immunology The University of Hong Kong Hong Kong China department of immunology School of Medical Science and Laboratory Medicine Jiangsu University Zhenjiang China These authors contributed equally to this work.

B cells are generally considered to be positive regulators of the immune response because of their capability to produce antibodies, including autoantibodies. The production of antibodies facilitates optimal CD4＋ T-cell activation because B cells serve as antigen-presenting cells and exert other modulatory functions in immune responses. However, certain B cells can also negatively regulate the immune response by producing regulatory cytokines and directly interacting with pathogenic T cells via cell-to-cell contact. These types of B Cells are defined as regulatory B （Breg） cells. The regulatory function of Breg cells has been demonstrated in mouse models of inflammation, cancer, transplantation, and particularly in autoimmunity. In this review, we focus on the recent advances that lead to the understanding of the development and function of Breg cells and the implications of B cells in human autoimmune diseases.

关键词： autoimmune disease interleukin-lO regulatory B cells

Role of B1 cells in autoimmunity

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Role of B1 cells in autoimmunity

Targeting innate sensing in the tumor microenvironment to improve immunotherapy

第十届全国免疫学学术大会

作者： Liwei Lu Department of Pathology and Center of Infection and Immunology The University of Hong Kong

B1 cells are distinguished from conventional B2 cells by their developmental origin,self-renewal capacity,anatomical location and phenotypic feature,which mainly reside in the peritoneal and pleural cavities.Although there is increasing evidence that B1 cells,especially B1a cell subset,play a pathogenic role in autoimmunity,it has remained largely unclear

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Cellular & Molecular immunology 2020年第1期17卷 13-26页

作者： Zhida Liu Yang-Xin Fu department of pathology UT Southwestern Medical CenterDallasTX 75235USA department of immunology UT Southwestern Medical CenterDallasTX 75235USA

The innate immune sensing pathways play critical roles in the defense against pathogen infection,but their roles in cancer immunosurveillance and cancer therapies are less defined.We propose that defective innate immune sensing inside the tumor microenvironment might limit T-cell responses to immunotherapy.A recent mechanistic understanding of conventional therapies revealed that both innate immune sensing and T-cell responses are essential for optimal antitumor efficacy.T-cell-based immunotherapy,particularly immune checkpoint blockade,has achieved great success in reactivating antitumor immune responses to lead to tumor regression,but only in a small fraction of patients.Therefore,incorporating conventional therapy that can increase innate sensing and immunotherapy should lead to promising strategies for cancer patients.Here,we review the innate sensing pathways related to cancer initiation/progression and therapies,summarize the recent key findings in innate immune sensing related to conventional therapies,evaluate current combination strategies,and highlight the potential issues of combinational therapies in terms of antitumor efficacy and toxicities.

关键词： Innate immune sensing Conventional therapy Immunotherapy

A critical role of IL-17 in modulating the B-cell response during H5N1 influenza virus infection

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Cellular & Molecular immunology 2011年第6期8卷 462-468页

作者： Xiaohui Wang Chris CS Chan Min Yang Jun Deng Vincent KM Poon Virtual HC Leung King-Hung Ko Jie Zhou Kwok Yung Yuen Bo-Jian Zheng Liwei Lu department of pathology The University of Hong KongHong KongChina department of Microbiology The University of Hong KongHong KongChina center of infection and immunology The University of Hong KongHong KongChina

Interleukin-17(IL-17),a member of the IL-17 cytokine family,plays a crucial role in mediating the immune response against extracellular bacteria and fungi in the lung.Although there is increasing evidence that IL-17 is involved in protective immunity against H1 and H3 influenza virus infections,little is known about the role of IL-17 in the highly pathogenic H5N1 influenza virus infection.In this study,we show that H5N1-infected IL-17 knockout(KO)mice exhibit markedly increased weight loss,more pronounced lung immunopathology and significantly reduced survival rates as compared with infected wild-type controls.Moreover,the frequency of B cells in the lung were substantially decreased in IL-17 KO mice after virus infection,which correlated with reduced CXCR5 expression in B cells and decreased CXCL13 production in the lung tissue of IL-17 KO mice.Consistent with this observation,B cells from IL-17 KO mice exhibited a significant reduction in chemokine-mediated migration in culture.Taken together,these findings demonstrate a critical role for IL-17 in mediating the recruitment of B cells to the site of pulmonary influenza virus infection in mice.

关键词： B cell H5N1 influenza virus IL-17 lung infection

Leptin Signaling Protects NK Cells from Apoptosis During Development in Mouse Bone Marrow

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Cellular & Molecular immunology 2009年第5期6卷 353-360页

作者： Cherry Kam Chun Lo Queenie Lai Kwan Lam Min Yang King-Hung Ko Lingyun Sun Rui Ma Shengjun Wang Huaxi Xu Sidney Tam Chang-You Wu Bo-Jiang Zheng Liwei Lu departments of pathology and Microbiology Center of Infection andImmunology The University of Hong Kong Hong Kong China department of Rheumatology Drum Tower Hospital Nanjing UniversityMedical School Nanjing China department of immunology School of Medical Science and LaboratoryMedicine Jiangsu University. Zhenjiang China epartment of pathology Queen Mary Hospital Hong Kong China department of immunology Sun Yat-Sen University Guangzhou China These authors contributed equally to this work Department of Pathology and Center of Infection and Immunology The University of Hong Kong Pokfulam Road Hong Kong China

Increasing evidence indicates a role of leptin in immune response, but it remains largely unclear whether leptin signaling is involved in regulating NK cell development in the bone marrow （BM）. In this study, we have characterized NK cell differentiation and maturation in the BM of leptin-receptor deficient db/db mice at a prediabetic stage. Although the BM cellularity was similar to the control value, the total number of NK cells was severely reduced in mutant mice. Flow cytometric analysis of db/db BM cells revealed significantly decreased frequencies of developing NK cells at various stages of differentiation. BM db/db NK cells displayed markedly increased apoptosis but maintained normal cell cycling status and proliferative capacity. Moreover, recombinant leptin could significantly enhance the survival of NK cells from wild-type mice in cultures. Further examination on NK cell functional activity showed that db/db NK cells exhibited normal intrinsic cytotoxicity with significantly increased IL-10 production. Taken together, our findings suggest that leptin signaling regulates NK cell development via enhancing the survival of immature NK cells in mouse BM.

关键词： NK cell bone marrow lymphocyte development

Supplying the trip to antibody production-nutrients,signaling,and the programming of cellular metabolism in the mature B lineage

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Cellular & Molecular immunology 2022年第3期19卷 352-369页

作者： Mark R.Boothby Shawna K.Brookens Ariel L.Raybuck Sung Hoon Cho department of pathology Microbiology&ImmunologyMolecular Pathogenesis DivisionVanderbilt University Medical CenterNashvilleTN37232USA department of Medicine Rheumatology&Immunology DivisionVanderbilt University Medical CenterNashvilleTN37232USA Cancer Biology Program Vanderbilt UniversityNashvilleTN37232USA Vanderbilt Institute of infection Inflammationand ImmunologyNashvilleTN37232USA

The COVID pandemic has refreshed and expanded recognition of the vital role that sustained antibody(Ab)secretion plays in our immune defenses against microbes and of the importance of vaccines that elicit Ab protection against infection.With this backdrop,it is especially timely to review aspects of the molecular programming that govern how the cells that secrete Abs arise,persist,and meet the challenge of secreting vast amounts of these glycoproteins.Whereas plasmablasts and plasma cells(PCs)are the primary sources of secreted Abs,the process leading to the existence of these cell types starts with naive B lymphocytes that proliferate and differentiate toward several potential fates.At each step,cells reside in specific microenvironments in which they not only receive signals from cytokines and other cell surface receptors but also draw on the interstitium for nutrients.Nutrients in turn influence flux through intermediary metabolism and sensor enzymes that regulate gene transcription,translation,and metabolism.This review will focus on nutrient supply and how sensor mechanisms influence distinct cellular stages that lead to PCs and their adaptations as factories dedicated to Ab secretion.Salient findings of this group and others,sometimes exhibiting differences,will be summarized with regard to the journey to a distinctive metabolic program in PCs.

关键词： B lymphocyte Plasma cell Intermediary metabolism Glucose Glutamine Fatty acid Signal transduction

Type 3 innate lymphoid cell-derived lymphotoxin prevents microbiota-dependent inflammation

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Cellular & Molecular immunology 2018年第7期15卷 697-709页

作者： Yuan Zhang Tae-Jin Kim Joanna A Wroblewska Vera Tesic Vaibhav Upadhyay Ralph R Weichselbaum Alexei V Tumanov Hong Tang Xiaohuan Guo Haidong Tang Yang-Xin Fu department of pathology University of ChicagoChicagoIL 60637USA department of Biochemistry and Molecular Biology Korea University College of MedicineSeoul 02841Korea Committee on immunology Department of PathologyUniversity of ChicagoChicagoIL 60637USA department of Radiation and Cellular Oncology and The Ludwig center for Metastasis Research University of ChicagoChicagoIL 60637USA department of Microbiology Immunology and Molecular GeneticsUniversity of Texas Health Science Center San AntonioSan AntonioTX 78229USA Chinese Academy of Sciences Key Laboratory for infection and Immunity Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Institute of immunology Tsinghua University School of MedicineBeijing 100084China department of pathology University of Texas Southwestern Medical CenterDallasTX 75390USA

Splenomegaly is a well-known phenomenon typically associated with inflammation.However,the underlying cause of this phenotype has not been well characterized.Furthermore,the splenomegaly phenotype seen in lymphotoxin(LT)signaling-deficient mice is characterized by increased numbers of splenocytes and splenic neutrophils.Splenomegaly,as well as the related phenotype of increased lymphocyte counts in non-lymphoid tissues,is thought to result from the absence of secondary lymphoid tissues in LT-deficient mice.We now present evidence that mice deficient in LTα1β2 or LTβR develop splenomegaly and increased numbers of lymphocytes in non-lymphoid tissues in a microbiota-dependent manner.Antibiotic administration to LTα1β2-or LTβR-deficient mice reduces splenomegaly.Furthermore,re-derived germ-free Ltbr−/−mice do not exhibit splenomegaly or increased inflammation in non-lymphoid tissues compared to specific pathogen-free Ltbr−/−mice.By using various LTβ-and LTβR-conditional knockout mice,we demonstrate that retinoic acid-related orphan receptorγT-positive type 3 innate lymphoid cells provide the required active LT signaling to prevent the development of splenomegaly.Thus,this study demonstrates the importance of LT-mediated immune responses for the prevention of splenomegaly and systemic inflammation induced by microbiota.

关键词： germ-free lymphotoxin microbiota splenomegaly type 3 innate lymphoid cells

Olfactory ecto-mesenchymal stem cells possess immunoregulatory function and suppress autoimmune arthritis

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Cellular & Molecular immunology 2016年第3期13卷 401-408页

作者： Ke Rui Zhijiang Zhang Jie Tian Xiang Lin Xiaohui Wang Jie Ma Xinyi Tang Huaxi Xu Liwei Lu Shengjun Wang department of Laboratory Medicine The Affiliated People's Hospital Jiangsu University Zhenjiang China Institute of Laboratory Medicine and department of Histology Jiangsu Key Laboratory of Laboratory Medicine Jiangsu University Zhenjiang China department of pathology and center for infection and immunology The University of Hong Kong Hong Kong China

Recent studies have identified olfactory ecto-mesenchymal stem cells （OE-MSCs） as a new type of resident stem cell in the olfactory lamina propria. However, it remains unclear whether OE-MSCs possess any immunoregulatory functions. In this study, we found that mouse OE-MSCs expressed higher transforming growth factor-beta and interleukin-10 levels than bone marrow-derived MSCs. In culture, OE-MSCs exerted their immunosuppressive capacity via directly suppressing effector T-cell proliferation and increasing regulatory T （Treg） cell expansion. In mice with collagen-induced arthritis, adoptive transfer of OE-MSCs markedly suppressed arthritis onset and disease severity, which was accompanied by increased Treg cells and reduced Th1/Th17 cell responses in vivo. Taken together, our findings identified a novel function of OE-MSCs in regulating T-cell responses, indicating that OE-MSCs may represent a new cell therapy for the treatment of rheumatoid arthritis and other autoimmune diseases.

关键词： CIA olfactory ecto-mesenchymal stem cells Treg cell