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Annual Review of Immunology Apr 2023Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways,... (Review)
Review
Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy.
Topics: Humans; Animals; Interferons; Lupus Erythematosus, Systemic; B-Lymphocytes; T-Lymphocytes, Helper-Inducer; Autoantibodies
PubMed: 36854182
DOI: 10.1146/annurev-immunol-101921-042422 -
Frontiers in Immunology 2022Liver fibrosis is a common pathological feature of end stage liver failure, a severe life-threatening disease worldwide. Nonalcoholic fatty liver disease (NAFLD),... (Review)
Review
Liver fibrosis is a common pathological feature of end stage liver failure, a severe life-threatening disease worldwide. Nonalcoholic fatty liver disease (NAFLD), especially its more severe form with steatohepatitis (NASH), results from obesity, type 2 diabetes and metabolic syndrome and becomes a leading cause of liver fibrosis. Genetic factor, lipid overload/toxicity, oxidative stress and inflammation have all been implicated in the development and progression of NASH. Both innate immune response and adaptive immunity contribute to NASH-associated inflammation. Innate immunity may cause inflammation and subsequently fibrosis danger-associated molecular patterns. Increasing evidence indicates that T cell-mediated adaptive immunity also provokes inflammation and fibrosis in NASH cytotoxicity, cytokines and other proinflammatory and profibrotic mediators. Recently, the single-cell transcriptome profiling has revealed that the populations of CD4 T cells, CD8 T cells, γδ T cells, and TEMs are expanded in the liver with NASH. The activation of T cells requires antigen presentation from professional antigen-presenting cells (APCs), including macrophages, dendritic cells, and B-cells. However, since hepatocytes express MHCII molecules and costimulators, they may also act as an atypical APC to promote T cell activation. Additionally, the phenotypic switch of hepatocytes to proinflammatory cells in NASH contributes to the development of inflammation. In this review, we focus on T cells and in particular CD4 T cells and discuss the role of different subsets of CD4 T cells including Th1, Th2, Th17, Th22, and Treg in NASH-related liver inflammation and fibrosis.
Topics: CD8-Positive T-Lymphocytes; Diabetes Mellitus, Type 2; Disease Progression; Fibrosis; Humans; Inflammation; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; T-Lymphocytes, Regulatory
PubMed: 36032141
DOI: 10.3389/fimmu.2022.967410 -
Zhongguo Dang Dai Er Ke Za Zhi =... Mar 2018Infectious diseases can be caused by multiple pathogens, which can produce specific immune response in human body. The immune response produced by T cells is cellular... (Review)
Review
Infectious diseases can be caused by multiple pathogens, which can produce specific immune response in human body. The immune response produced by T cells is cellular immunity, which plays an important role in the anti-infection process of human body, and can participate in immunological protection and cause immunopathology. The outcome of various infectious diseases is closely related to cellular immune function, especially the function of T cells. Jurkat cells belong to the human acute T lymphocyte leukemia cell line. Jurkat cell model can simulate the function T lymphocytes, so it is widely used in the in vitro studies of T cell signal transduction, cytokines, and receptor expression, and can provide reference and guidance for the treatment of various infectious diseases and the research on their pathogenesis. The Jurkat cell model has been widely used in the in vitro studies of viral diseases and atypical pathogens, but parasitic infection studies using the Jurkat cell model are still rare. This article reviews advances in the application of Jurkat cell model in the research on infectious diseases.
Topics: Communicable Diseases; Deltaretrovirus Infections; Enterovirus A, Human; Enterovirus Infections; Epstein-Barr Virus Infections; HIV Infections; Humans; Jurkat Cells; T-Lymphocytes
PubMed: 29530126
DOI: 10.7499/j.issn.1008-8830.2018.03.014 -
Frontiers in Immunology 2019The increasingly recognized role of different types of B cells and plasma cells in protective and pathogenic immune responses combined with technological advances have... (Review)
Review
The increasingly recognized role of different types of B cells and plasma cells in protective and pathogenic immune responses combined with technological advances have generated a plethora of information regarding the heterogeneity of this human immune compartment. Unfortunately, the lack of a consistent classification of human B cells also creates significant imprecision on the adjudication of different phenotypes to well-defined populations. Additional confusion in the field stems from: the use of non-discriminatory, overlapping markers to define some populations, the extrapolation of mouse concepts to humans, and the assignation of functional significance to populations often defined by insufficient surface markers. In this review, we shall discuss the current understanding of human B cell heterogeneity and define major parental populations and associated subsets while discussing their functional significance. We shall also identify current challenges and opportunities. It stands to reason that a unified approach will not only permit comparison of separate studies but also improve our ability to define deviations from normative values and to create a clean framework for the identification, functional significance, and disease association with new populations.
Topics: Animals; B-Lymphocytes; B-Lymphocytes, Regulatory; Cytokines; Humans; Immunity, Humoral; Immunoglobulin D; Immunoglobulin M; Immunologic Memory; Plasma Cells
PubMed: 31681331
DOI: 10.3389/fimmu.2019.02458 -
Clinical Journal of the American... Feb 2016Immunosuppressive agents are commonly used in the nephrologist's practice in the treatment of autoimmune and immune-mediated diseases and transplantation, and they are... (Review)
Review
Immunosuppressive agents are commonly used in the nephrologist's practice in the treatment of autoimmune and immune-mediated diseases and transplantation, and they are investigational in the treatment of AKI and ESRD. Drug development has been rapid over the past decades as mechanisms of the immune response have been better defined both by serendipity (the discovery of agents with immunosuppressive activity that led to greater understanding of the immune response) and through mechanistic study (the study of immune deficiencies and autoimmune diseases and the critical pathways or mutations that contribute to disease). Toxicities of early immunosuppressive agents, such as corticosteroids, azathioprine, and cyclophosphamide, stimulated intense investigation for agents with more specificity and less harmful effects. Because the mechanisms of the immune response were better delineated over the past 30 years, this specialty is now bestowed with a multitude of therapeutic options that have reduced rejection rates and improved graft survival in kidney transplantation, provided alternatives to cytotoxic therapy in immune-mediated diseases, and opened new opportunities for intervention in diseases both common (AKI) and rare (atypical hemolytic syndrome). Rather than summarizing clinical indications and clinical trials for all currently available immunosuppressive medications, the purpose of this review is to place these agents into mechanistic context together with a brief discussion of unique features of development and use that are of interest to the nephrologist.
Topics: Animals; Antibodies, Monoclonal; Autoimmune Diseases; B-Lymphocytes; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Molecular Targeted Therapy; Signal Transduction; T-Lymphocytes; Treatment Outcome
PubMed: 26170177
DOI: 10.2215/CJN.08570814 -
Clinical Reviews in Allergy & Immunology Oct 2017B lymphocytes are critical for effective immunity; they produce antibodies and cytokines, present antigens to T lymphocytes and regulate immune responses. However,... (Review)
Review
B lymphocytes are critical for effective immunity; they produce antibodies and cytokines, present antigens to T lymphocytes and regulate immune responses. However, because of the inherent randomness in the process of generating their vast repertoire of antigen-specific receptors, B cells can also cause diseases through recognizing and reacting to self. Therefore, B lymphocyte selection and responses require tight regulation at multiple levels and at all stages of their development and activation to avoid diseases. Indeed, newly generated B lymphocytes undergo rigorous tolerance mechanisms in the bone marrow and, subsequently, in the periphery after their migration. Furthermore, activation of mature B cells is regulated through controlled expression of co-stimulatory receptors and intracellular signalling thresholds. All these regulatory events determine whether and how B lymphocytes respond to antigens, by undergoing apoptosis or proliferation. However, defects that alter regulated co-stimulatory receptor expression or intracellular signalling thresholds can lead to diseases. For example, autoimmune diseases can result from altered regulation of B cell responses leading to the emergence of high-affinity autoreactive B cells, autoantibody production and tissue damage. The exact cause(s) of defective B cell responses in autoimmune diseases remains unknown. However, there is evidence that defects or mutations in genes that encode individual intracellular signalling proteins lead to autoimmune diseases, thus confirming that defects in intracellular pathways mediate autoimmune diseases. This review provides a synopsis of current knowledge of signalling proteins and pathways that regulate B lymphocyte responses and how defects in these could promote autoimmune diseases. Most of the evidence comes from studies of mouse models of disease and from genetically engineered mice. Some, however, also come from studying B lymphocytes from patients and from genome-wide association studies. Defining proteins and signalling pathways that underpin atypical B cell response in diseases will help in understanding disease mechanisms and provide new therapeutic avenues for precision therapy.
Topics: Animals; Autoimmunity; B-Lymphocytes; Humans; Immunity, Humoral; Immunomodulation; Intracellular Signaling Peptides and Proteins; Signal Transduction
PubMed: 28456914
DOI: 10.1007/s12016-017-8609-4 -
Frontiers in Immunology 2022A series of rheumatoid arthritis (RA) studies established a PD-1CXCR5CD4 T-cell subset that was coined peripheral helper T (Tph) cells. CXCL13 production is a key... (Review)
Review
A series of rheumatoid arthritis (RA) studies established a PD-1CXCR5CD4 T-cell subset that was coined peripheral helper T (Tph) cells. CXCL13 production is a key feature of Tph cells and may contribute to the formation of tertiary lymphoid structures (TLS) in inflamed tissues. In addition, Tph cells provide help to B cells as efficiently as follicular helper T (Tfh) cells, and these features would implicate Tph cells in the pathogenesis of RA. Subsequent studies have revealed that Tph cells are involved in various human diseases such as autoimmune diseases, infectious diseases, and cancers. Although the analysis of human immunity has various limitations, accumulating evidence demonstrated the expansion of B cells with low somatic hypermutation and a link between TLS and immune functions in these diseases. We discuss about the emerging roles of the Tph cell and its relevant immune responses in peripheral tissues including B-cell expansion with atypical features.
Topics: Arthritis, Rheumatoid; B-Lymphocytes; Humans; Receptors, CXCR5; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer
PubMed: 35880181
DOI: 10.3389/fimmu.2022.946786 -
Biochemical and Biophysical Research... Jan 2021T-cells play key roles in immunity to COVID-19 as well as the development of severe disease. T-cell immunity to COVID-19 is mediated through differentiated CD4 T-cells...
T-cells play key roles in immunity to COVID-19 as well as the development of severe disease. T-cell immunity to COVID-19 is mediated through differentiated CD4 T-cells and cytotoxic CD8 T-cells, although their differentiation is often atypical and ambiguous in COVID-19 and single cell dynamics of key genes need to be characterized. Notably, T-cells are dysregulated in severe COVID-19 patients, although their molecular features are still yet to be fully revealed. Importantly, it is not clear which T-cell activities are beneficial and protective and which ones can contribute to the development of severe COVID-19. In this article, we examine the latest evidence and discuss the key features of T-cell responses in COVID-19, showing how T-cells are dysregulated in severe COVID-19 patients. Particularly, we highlight the impairment of FOXP3 induction in CD4 T-cells and how the impaired FOXP3 expression can lead to the differentiation of abnormally activated (hyperactivated) T-cells and the dysregulated T-cell responses in severe patients. Furthermore, we characterise the feature of hyperactivated T-cells, showing their potential contribution to T-cell dysregulation and immune-mediated tissue destruction (immunopathology) in COVID-19.
Topics: CD4-Positive T-Lymphocytes; COVID-19; Cytokines; Forkhead Transcription Factors; Humans; Lymphocyte Activation; SARS-CoV-2; T-Lymphocytes, Cytotoxic
PubMed: 33220925
DOI: 10.1016/j.bbrc.2020.10.079 -
Poultry Science Aug 2021A description of standard and atypical heterophils, lymphocytes, and 2 types of giant cells found in the circulation of 17 wk commercial ducks (N = 24) in apparent...
A description of standard and atypical heterophils, lymphocytes, and 2 types of giant cells found in the circulation of 17 wk commercial ducks (N = 24) in apparent good health is the subject. Heterophils were sorted as either "classic" (HC) having red rod-shaped cytoplasmic granules, "typical" (HT) having weakly stained granules providing a reticular cytoplasmic appearance, or rarely as "variant" types (HV) having orange spherical granules. Atypical HT's and HC's were in 14 of 24 (58%) of the ducks. Small lymphocytes (Ls), reactive lymphocytes and plasmacytes (Lm) were routinely found. Giant cells, also present, were placed with Lm or monocytes (Mn) depending on cytology. Two counts of 200 leukocytes gave the total white count (TWBC) and 2 heterophil/lymphocyte ratios. H/L 1 = (HT + HC +HV) / Ls; and H/L 2 = (HT + HC + HV) / (Ls + Lm). The results showed that TWBC were normal (~ 23,000 /μL) but both H/L ratios were highly variable. HT were differentiated from HC on nuclear and cytoplasmic criteria. Many HT and HC exhibited signs of deterioration. Some giant cells likely represented developmental stages. Multiple nucleoli were evident in others suggesting polyploidy. The more common lymphoid giants were usually round whereas monocyte types were irregular. Mn types were actively phagocytic often consuming thrombocytes or rarely erythrocytes (RBC). Giant cells of either type were in 13 of 24 (54%) of the duck hemograms. Conidiospores were detected in the blood smears of 4 ducks and bacteria in 2 with 1 duck having both. As all ducks were in apparent good health the blood born microorganisms likely represented low grade infections. Presumably the atypical cells were a response to the presence of toxins of bacterial and fungal origin. The presence of atypical heterophils and lymphocytes complicates interpretation of H/L ratios traditionally used to establish stress. As atypical cells can be found in the context of normal TWBC or nonstress H/L values cytological observations attain additional importance. Moreover, giant cells may be useful indicators of infection even without direct microscopic observation or isolation of the offending organisms.
Topics: Animals; Blood Cell Count; Chickens; Ducks; Leukocytes; Plasma Cells
PubMed: 34225201
DOI: 10.1016/j.psj.2021.101248 -
Thrombosis and Haemostasis Oct 2016The immune response to heparin is one of the most common drug-induced allergies, and yet, atypical for a drug hypersensitivity reaction. Whereas most drug-induced... (Review)
Review
The immune response to heparin is one of the most common drug-induced allergies, and yet, atypical for a drug hypersensitivity reaction. Whereas most drug-induced allergies are rare, idiosyncratic and life-long, the allergic response to heparin is common, predictable in certain clinical settings and transient. Advances in the last decade with regards to structural characterisation of the PF4/heparin antigenic complex, contributions of innate immunity and development of animal models have provided insights into the distinctive features of the HIT immune response. Recent descriptions of the crystal structure of the PF4/heparin complex, alongside other biophysical studies, have clarified the structural requirements for immunogenicity and heparin-dependency of antibody formation. Studies of interactions of PF4 with bacterial cell walls as well as epidemiologic associations of anti-PF4/heparin antibody formation and infection suggest a role for immune priming and explain the rapid evolution of an isotype-switched immune response in sensitised patients. Murine models have greatly facilitated investigations of cellular basis of the HIT response and identified a major role for T-cells and marginal zone B-cells, but key findings have yet to be validated in human disease. This chapter will summarise recent investigations of the HIT immune response in the context of major pathways of immune activation and identify areas of uncertainty.
Topics: Adaptive Immunity; Animals; Antibody Formation; Antigen-Presenting Cells; B-Lymphocytes; Bacterial Infections; Heparin; Humans; Immunity, Innate; Mice; Platelet Factor 4; T-Lymphocytes; Thrombocytopenia; Toll-Like Receptors
PubMed: 27465274
DOI: 10.1160/TH16-01-0074