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Molecular Cell Apr 2014Clustered regularly interspaced short palindromic repeats (CRISPR), and associated proteins (Cas) comprise the CRISPR-Cas system, which confers adaptive immunity against... (Review)
Review
Clustered regularly interspaced short palindromic repeats (CRISPR), and associated proteins (Cas) comprise the CRISPR-Cas system, which confers adaptive immunity against exogenic elements in many bacteria and most archaea. CRISPR-mediated immunization occurs through the uptake of DNA from invasive genetic elements such as plasmids and viruses, followed by its integration into CRISPR loci. These loci are subsequently transcribed and processed into small interfering RNAs that guide nucleases for specific cleavage of complementary sequences. Conceptually, CRISPR-Cas shares functional features with the mammalian adaptive immune system, while also exhibiting characteristics of Lamarckian evolution. Because immune markers spliced from exogenous agents are integrated iteratively in CRISPR loci, they constitute a genetic record of vaccination events and reflect environmental conditions and changes over time. Cas endonucleases, which can be reprogrammed by small guide RNAs have shown unprecedented potential and flexibility for genome editing and can be repurposed for numerous DNA targeting applications including transcriptional control.
Topics: Adaptive Immunity; Bacteriophages; CRISPR-Associated Proteins; Clustered Regularly Interspaced Short Palindromic Repeats; DNA, Bacterial; Inverted Repeat Sequences; Prokaryotic Cells
PubMed: 24766887
DOI: 10.1016/j.molcel.2014.03.011 -
Journal For Immunotherapy of Cancer Sep 2020To prevent the destruction of tissues owing to excessive and/or inappropriate immune responses, immune cells are under strict check by various regulatory mechanisms at... (Review)
Review
To prevent the destruction of tissues owing to excessive and/or inappropriate immune responses, immune cells are under strict check by various regulatory mechanisms at multiple points. Inhibitory coreceptors, including programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), serve as critical checkpoints in restricting immune responses against self-tissues and tumor cells. Immune checkpoint inhibitors that block PD-1 and CTLA-4 pathways significantly improved the outcomes of patients with diverse cancer types and have revolutionized cancer treatment. However, response rates to such therapies are rather limited, and immune-related adverse events are also observed in a substantial patient population, leading to the urgent need for novel therapeutics with higher efficacy and lower toxicity. In addition to PD-1 and CTLA-4, a variety of stimulatory and inhibitory coreceptors are involved in the regulation of T cell activation. Such coreceptors are listed as potential drug targets, and the competition to develop novel immunotherapies targeting these coreceptors has been very fierce. Among such coreceptors, lymphocyte activation gene-3 (LAG-3) is expected as the foremost target next to PD-1 in the development of cancer therapy, and multiple clinical trials testing the efficacy of LAG-3-targeted therapy are underway. LAG-3 is a type I transmembrane protein with structural similarities to CD4. Accumulating evidence indicates that LAG-3 is an inhibitory coreceptor and plays pivotal roles in autoimmunity, tumor immunity, and anti-infection immunity. In this review, we summarize the current understanding of LAG-3, ranging from its discovery to clinical application.
Topics: Adaptive Immunity; Amino Acids; Caenorhabditis elegans Proteins; Humans; Immunotherapy; Transcription Factors
PubMed: 32929051
DOI: 10.1136/jitc-2020-001014 -
Nature Reviews. Immunology Feb 2019Dendritic cells (DCs) can be viewed as translators between innate and adaptive immunity. They integrate signals derived from tissue infection or damage and present... (Review)
Review
Dendritic cells (DCs) can be viewed as translators between innate and adaptive immunity. They integrate signals derived from tissue infection or damage and present processed antigen from these sites to naive T cells in secondary lymphoid organs while also providing multiple soluble and surface-bound signals that help to guide T cell differentiation. DC-mediated tailoring of the appropriate T cell programme ensures a proper cascade of immune responses that adequately targets the insult. Recent advances in our understanding of the different types of DC subsets along with the cellular organization and orchestration of DC and lymphocyte positioning in secondary lymphoid organs over time has led to a clearer understanding of how the nature of the T cell response is shaped. This Review discusses how geographical organization and ordered sequences of cellular interactions in lymph nodes and the spleen regulate immunity.
Topics: Adaptive Immunity; Animals; Cell Differentiation; Dendritic Cells; Humans; Immunity, Innate; Lymph Nodes; Lymphocyte Activation; Spleen; T-Lymphocytes
PubMed: 30464294
DOI: 10.1038/s41577-018-0088-1 -
Science China. Life Sciences Jul 2023With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between... (Review)
Review
With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between environmental and genetic factors. In a nutshell, etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage. In recent years, population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity, providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways. In this review, we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics. An overview of the genetic basis of autoimmunity is followed by 3 chapters detailing susceptibility genes involved in innate immunity, adaptive immunity and inflammatory cell death processes respectively. With such attempts, we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the 'usual suspects' of a limited subset of validated therapeutic targets.
Topics: Humans; Autoimmune Diseases; Immunity, Innate; Autoimmunity; Adaptive Immunity; Genetic Predisposition to Disease
PubMed: 36738430
DOI: 10.1007/s11427-021-2187-3 -
Essays in Biochemistry Oct 2016All organisms are connected in a complex web of relationships. Although many of these are benign, not all are, and everything alive devotes significant resources to... (Review)
Review
All organisms are connected in a complex web of relationships. Although many of these are benign, not all are, and everything alive devotes significant resources to identifying and neutralizing threats from other species. From bacteria through to primates, the presence of some kind of effective immune system has gone hand in hand with evolutionary success. This article focuses on mammalian immunity, the challenges that it faces, the mechanisms by which these are addressed, and the consequences that arise when it malfunctions.
Topics: Adaptive Immunity; Animals; Humans; Immune System; Immune System Diseases; Immunologic Memory; Infections
PubMed: 27784777
DOI: 10.1042/EBC20160017 -
Journal of Medicinal Food Dec 2014The human gut microbiome impacts human brain health in numerous ways: (1) Structural bacterial components such as lipopolysaccharides provide low-grade tonic stimulation... (Review)
Review
The human gut microbiome impacts human brain health in numerous ways: (1) Structural bacterial components such as lipopolysaccharides provide low-grade tonic stimulation of the innate immune system. Excessive stimulation due to bacterial dysbiosis, small intestinal bacterial overgrowth, or increased intestinal permeability may produce systemic and/or central nervous system inflammation. (2) Bacterial proteins may cross-react with human antigens to stimulate dysfunctional responses of the adaptive immune system. (3) Bacterial enzymes may produce neurotoxic metabolites such as D-lactic acid and ammonia. Even beneficial metabolites such as short-chain fatty acids may exert neurotoxicity. (4) Gut microbes can produce hormones and neurotransmitters that are identical to those produced by humans. Bacterial receptors for these hormones influence microbial growth and virulence. (5) Gut bacteria directly stimulate afferent neurons of the enteric nervous system to send signals to the brain via the vagus nerve. Through these varied mechanisms, gut microbes shape the architecture of sleep and stress reactivity of the hypothalamic-pituitary-adrenal axis. They influence memory, mood, and cognition and are clinically and therapeutically relevant to a range of disorders, including alcoholism, chronic fatigue syndrome, fibromyalgia, and restless legs syndrome. Their role in multiple sclerosis and the neurologic manifestations of celiac disease is being studied. Nutritional tools for altering the gut microbiome therapeutically include changes in diet, probiotics, and prebiotics.
Topics: Adaptive Immunity; Brain; Diet; Gastrointestinal Tract; Humans; Hypothalamo-Hypophyseal System; Immunity, Innate; Microbiota; Neurosecretory Systems; Pituitary-Adrenal System
PubMed: 25402818
DOI: 10.1089/jmf.2014.7000 -
Nutrients Jul 2013Vitamin D metabolizing enzymes and vitamin D receptors are present in many cell types including various immune cells such as antigen-presenting-cells, T cells, B cells... (Review)
Review
Vitamin D metabolizing enzymes and vitamin D receptors are present in many cell types including various immune cells such as antigen-presenting-cells, T cells, B cells and monocytes. In vitro data show that, in addition to modulating innate immune cells, vitamin D also promotes a more tolerogenic immunological status. In vivo data from animals and from human vitamin D supplementation studies have shown beneficial effects of vitamin D on immune function, in particular in the context of autoimmunity. In this review, currently available data are summarized to give an overview of the effects of vitamin D on the immune system in general and on the regulation of inflammatory responses, as well as regulatory mechanisms connected to autoimmune diseases particularly in type 1 diabetes mellitus.
Topics: Adaptive Immunity; Animals; Autoimmune Diseases; Diabetes Mellitus, Type 1; Dietary Supplements; Humans; Immune System; Immunity, Innate; Nutritional Status; Randomized Controlled Trials as Topic; Receptors, Calcitriol; Seasons; Vitamin D
PubMed: 23857223
DOI: 10.3390/nu5072502 -
Frontiers in Immunology 2020Coeliac disease is a common small bowel enteropathy arising in genetically predisposed individuals and caused by ingestion of gluten in the diet. Great advances have... (Review)
Review
Coeliac disease is a common small bowel enteropathy arising in genetically predisposed individuals and caused by ingestion of gluten in the diet. Great advances have been made in understanding the role of the adaptive immune system in response to gluten peptides. Despite detailed knowledge of these adaptive immune mechanisms, the complete series of pathogenic events responsible for development of the tissue lesion remains less certain. This review contributes to the field by discussing additional mechanisms which may also contribute to pathogenesis. These include the production of cytokines such as interleukin-15 by intestinal epithelial cells and local antigen presenting cells as a pivotal event in the disease process. A subset of unconventional T cells called gamma/delta T cells are also persistently expanded in the coeliac disease (CD) small intestinal epithelium and recent analysis has shown that these cells contribute to pathogenic inflammation. Other unconventional T cell subsets may play a local immunoregulatory role and require further study. It has also been suggested that, in addition to activation of pathogenic T helper cells by gluten peptides, other peptides may directly interact with the intestinal mucosa, further contributing to the disease process. We also discuss how myofibroblasts, a major source of tissue transglutaminase and metalloproteases, may play a key role in intestinal tissue remodeling. Contribution of each of these factors to pathogenesis is discussed to enhance our view of this complex disorder and to contribute to a wider understanding of chronic immune-mediated disease.
Topics: Adaptive Immunity; Celiac Disease; Humans; Immunity, Innate
PubMed: 32733456
DOI: 10.3389/fimmu.2020.01374 -
Frontiers in Immunology 2020Not only do Adipocytes have energy storage and endocrine functions, but they also play an immunological role. Adipocytes are involved in adaptive immunity to mediate the... (Review)
Review
Not only do Adipocytes have energy storage and endocrine functions, but they also play an immunological role. Adipocytes are involved in adaptive immunity to mediate the pathological processes of a variety of chronic inflammatory diseases and autoimmune syndromes. The adaptive immune response consists of T cell-mediated cellular immunity and B cell-mediated humoral immunity. Obese adipocytes overexpress MHC class II molecules and costimulators to act as antigen-presenting cells (APCs) and promote the activation of CD4 T cells. In addition, various adipokines secreted by adipocytes regulate the proliferation and differentiation of T cells. Adipokines are also involved in B cell generation, development, activation, and antibody production. Therefore, adipocytes play an important role in B cell-mediated adaptive immunity. This review describes how adipocytes participate in adaptive immunity from the perspective of T cells and B cells, and discusses their role in the pathogenesis of various diseases.
Topics: Adaptive Immunity; Adipocytes; Adipokines; Animals; Antigen Presentation; Antigen-Presenting Cells; B-Lymphocytes; Biomarkers; Energy Metabolism; Humans; Immunomodulation; Lymphocyte Activation; T-Lymphocytes
PubMed: 33329579
DOI: 10.3389/fimmu.2020.593058 -
Cancer Cell Jun 2017Immunotherapy has changed the landscape of cancer treatment. Checkpoint blockade therapies unleash breaks in the immune system and induce long-lasting responses....
Immunotherapy has changed the landscape of cancer treatment. Checkpoint blockade therapies unleash breaks in the immune system and induce long-lasting responses. However, a significant number of patients do not respond (innate resistance), and a subset progress after responding (acquired resistance). A better understanding of the molecular mechanisms underlying checkpoint blockade therapies will facilitate the design of novel strategies to treat and prevent resistance. To view this SnapShot, open or download the PDF.
Topics: Adaptive Immunity; Cell Cycle Checkpoints; Drug Resistance, Neoplasm; Humans; Immunotherapy; Interferons; Neoplasms
PubMed: 28609660
DOI: 10.1016/j.ccell.2017.05.010