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Nature Reviews. Immunology May 2017Immune tolerance hinders the potentially destructive responses of lymphocytes to host tissues. Tolerance is regulated at the stage of immature B cell development... (Review)
Review
Immune tolerance hinders the potentially destructive responses of lymphocytes to host tissues. Tolerance is regulated at the stage of immature B cell development (central tolerance) by clonal deletion, involving apoptosis, and by receptor editing, which reprogrammes the specificity of B cells through secondary recombination of antibody genes. Recent mechanistic studies have begun to elucidate how these divergent mechanisms are controlled. Single-cell antibody cloning has revealed defects of B cell central tolerance in human autoimmune diseases and in several human immunodeficiency diseases caused by single gene mutations, which indicates the relevance of B cell tolerance to disease and suggests possible genetic pathways that regulate tolerance.
Topics: Animals; B-Lymphocytes; Humans; Immune Tolerance; MicroRNAs; Receptors, Immunologic; Superantigens
PubMed: 28368006
DOI: 10.1038/nri.2017.19 -
Immunity Aug 2022While inbred mice have informed most of what we know about the immune system in the modern era, they have clear limitations with respect to their ability to be... (Review)
Review
While inbred mice have informed most of what we know about the immune system in the modern era, they have clear limitations with respect to their ability to be informative regarding genetic heterogeneity or microbial influences. They have also not been very predictive as models of human disease or vaccination results. Although there are concerted attempts to compensate for these flaws, the rapid rise of human studies, driven by both technical and conceptual advances, promises to fill in these gaps, as well as provide direct information about human diseases and vaccination responses. Work on human immunity has already provided important additional perspectives on basic immunology such as the importance of clonal deletion to self-tolerance, and while many challenges remain, it seems inevitable that "the human model" will continue to inform us about the immune system and even allow for the discovery of new mechanisms.
Topics: Animals; Clonal Deletion; Humans; Immune System; Mice; Self Tolerance; Vaccination
PubMed: 35947979
DOI: 10.1016/j.immuni.2022.07.008 -
Frontiers in Immunology 2022The quest to understand how allogeneic transplanted tissue is not rejected and how tolerance is induced led to fundamental concepts in immunology. First, we review the... (Review)
Review
The quest to understand how allogeneic transplanted tissue is not rejected and how tolerance is induced led to fundamental concepts in immunology. First, we review the research that led to the Clonal Deletion theory in the late 1950s that has since dominated the field of immunology and transplantation. At that time many basic mechanisms of immune response were unknown, including the role of lymphocytes and T cells in rejection. These original observations are reassessed by considering T regulatory cells that are produced by thymus of neonates to prevent autoimmunity. Second, we review "operational tolerance" induced in adult rodents and larger animals such as pigs. This can occur spontaneously especially with liver allografts, but also can develop after short courses of a variety of rejection inhibiting therapies. Over time these animals develop alloantigen specific tolerance to the graft but retain the capacity to reject third-party grafts. These animals have a "split tolerance" as peripheral lymphocytes from these animals respond to donor alloantigen in graft versus host assays and in mixed lymphocyte cultures, indicating there is no clonal deletion. Investigation of this phenomenon excludes many mechanisms, including anti-donor antibody blocking rejection as well as anti-idiotypic responses mediated by antibody or T cells. This split tolerance is transferred to a second immune-depleted host by T cells that retain the capacity to effect rejection of third-party grafts by the same host. Third, we review research on alloantigen specific inhibitory T cells that led to the first identification of the CD4CD25T regulatory cell. The key role of T cell derived cytokines, other than IL-2, in promoting survival and expansion of antigen specific T regulatory cells that mediate transplant tolerance is reviewed. The precise methods for inducing and diagnosing operational tolerance remain to be defined, but antigen specific T regulatory cells are key mediators.
Topics: Animals; Antigens; Clonal Deletion; Immune Tolerance; Isoantigens; Swine; T-Lymphocytes, Regulatory; Transplantation Tolerance
PubMed: 35529847
DOI: 10.3389/fimmu.2022.810798 -
Frontiers in Immunology 2019The liver is an immunologically tolerant organ that is uniquely equipped to limit hypersensitivity to food-derived antigens and bacterial products through the portal... (Review)
Review
The liver is an immunologically tolerant organ that is uniquely equipped to limit hypersensitivity to food-derived antigens and bacterial products through the portal vein and can feasibly accept liver allografts. The adaptive immune response is a major branch of the immune system that induces organ/tissue-localized and systematic responses against pathogens and tumors while promoting self-tolerance. Persistent infection of the liver with a virus or other pathogen typically results in tolerance, which is a key feature of the liver. The liver's immunosuppressive microenvironment means that hepatic adaptive immune cells become readily tolerogenic, promoting the death of effector cells and the "education" of regulatory cells. The above mechanisms may result in the clonal deletion, exhaustion, or inhibition of peripheral T cells, which are key players in the adaptive immune response. These tolerance mechanisms are believed to be responsible for almost all liver diseases. However, optimal protective adaptive immune responses may be achieved through checkpoint immunotherapy and the modulation of hepatic innate immune cells in the host. In this review, we focus on the mechanisms involved in hepatic adaptive immune tolerance, the liver diseases caused thereby, and the therapeutic strategies needed to overcome this tolerance.
Topics: Adaptive Immunity; Animals; Humans; Immune Tolerance; Liver; Liver Diseases; T-Lymphocytes
PubMed: 31787967
DOI: 10.3389/fimmu.2019.02525 -
Trends in Immunology Nov 2017Immune responses to allografts represent a major barrier in organ transplantation. Immune tolerance to avoid chronic immunosuppression is a critical goal in the field,... (Review)
Review
Immune responses to allografts represent a major barrier in organ transplantation. Immune tolerance to avoid chronic immunosuppression is a critical goal in the field, recently achieved in the clinic by combining bone marrow transplantation (BMT) with kidney transplantation following non-myeloablative conditioning. At high levels of chimerism such protocols can permit central deletional tolerance, but with a significant risk of graft-versus-host (GVH) disease (GVHD). By contrast, transient chimerism-based tolerance is devoid of GVHD risk and appears to initially depend on regulatory T cells (Tregs) followed by gradual, presumably peripheral, clonal deletion of donor-reactive T cells. Here we review recent mechanistic insights into tolerance and the development of more robust and safer protocols for tolerance induction that will be guided by innovative immune monitoring tools.
Topics: Animals; Bone Marrow Transplantation; Chimerism; Clonal Deletion; Humans; Kidney Transplantation; T-Lymphocytes, Regulatory; Transplantation Chimera; Transplantation Conditioning; Transplantation Immunology; Transplantation Tolerance
PubMed: 28826941
DOI: 10.1016/j.it.2017.07.008 -
Cellular & Molecular Immunology Jun 2020In contrast to the previous belief that autoreactive B cells are eliminated from the normal repertoire of B cells, many autoreactive B cells actually escape clonal... (Review)
Review
In contrast to the previous belief that autoreactive B cells are eliminated from the normal repertoire of B cells, many autoreactive B cells actually escape clonal deletion and develop into mature B cells. These autoreactive B cells in healthy individuals perform some beneficial functions in the host and are homeostatically regulated by regulatory T and B cells or other mechanisms to prevent autoimmune diseases. Autoreactive B-1 cells constitutively produce polyreactive natural antibodies for tissue homeostasis. Recently, autoreactive follicular B cells were reported to participate actively in the germinal center reaction. Furthermore, the selection and usefulness of autoreactive marginal zone (MZ) B cells found in autoimmune diseases are not well understood, although the repertoire of MZ B-cell receptors (BCRs) is presumed to be biased to detect bacterial antigens. In this review, we discuss the autoreactive B-cell populations among all three major B-cell subsets and their regulation in immune responses and diseases.
Topics: Animals; Antibody Formation; B-Lymphocytes; Disease; Health; Homeostasis; Humans; Immunity
PubMed: 32382130
DOI: 10.1038/s41423-020-0445-4 -
Annual Review of Immunology Apr 2018Recent progress in both conceptual and technological approaches to human immunology have rejuvenated a field that has long been in the shadow of the inbred mouse model.... (Review)
Review
Recent progress in both conceptual and technological approaches to human immunology have rejuvenated a field that has long been in the shadow of the inbred mouse model. This is a healthy development both for the clinical relevance of immunology and for the fact that it is a way to gain access to the wealth of phenomenology in the many human diseases that involve the immune system. This is where we are likely to discover new immunological mechanisms and principals, especially those involving genetic heterogeneity or environmental influences that are difficult to model effectively in inbred mice. We also suggest that there are likely to be novel immunological mechanisms in long-lived, less fecund mammals such as human beings since they must remain healthy far longer than short-lived rodents in order for the species to survive.
Topics: Animals; B-Lymphocytes; Biological Evolution; Biological Variation, Population; Clonal Deletion; Host-Pathogen Interactions; Humans; Immune System; Immunity; Immunologic Memory; Models, Animal; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 29490162
DOI: 10.1146/annurev-immunol-042617-053206 -
Mikrobiyoloji Bulteni Jul 2016Superantigens (SAgs) are microbial proteins produced by various microorganisms that elicit excessive and strong stimulation of T cells via an unconventional mechanism.... (Review)
Review
Superantigens (SAgs) are microbial proteins produced by various microorganisms that elicit excessive and strong stimulation of T cells via an unconventional mechanism. They cause polyclonal activation of T cells in a non-specific manner, by binding to a particular variable-beta (Vβ) chain of T-cell receptor (TCR) and MHC class II molecule, in unprocessed form and outside of peptide-binding cleft, forming a bridge between the antigen presenting cell and the T cell. SAgs are classified into three groups, namely 1) exogenous (soluble proteins and exotoxins secreted by microorganisms), 2) endogenous (transmembrane proteins encoded by viruses which are integrated into the genome) and 3) B-cell SAgs (proteins which stimulate predominantly B cells). The best characterized and mostly studied SAgs are staphylococcal and streptococcal exotoxins, however it is well-known that many other microorganisms also possess SAg activities. Despite the presence of several viruses that cause severe infections in humans, the number of viruses that have proteins identified with SAg property in their pathogenesis, is relatively low. To date, the defined viruses that encoded SAgs are as follows; mouse mammary tumor virus (MMTV) (Marrack, et al. 1991), rabies virus (Lafon, et al. 1992), Epstein-Barr virus (EBV) (Sutkowski, et al. 1996), human endogenous retrovirus (HERV) (Conrad, et al. 1997), human immunodeficiency virus (HIV) (Posnett, et al. 1995; Torres, et al. 1996; Townsley-Fuchs, et al. 1997) and Ebola virus (Leroy, et al. 2011). SAgs were first described in the MMTV, a polymorphic B-type retrovirus that is either contained in the genome as an endogenous provirus (germline transmission) or exogenous infectious virus that transmits vertically via breast milk. Both MMTV forms encode SAgs. The SAg-mediated massive T cell activation is required for the spread of exogenous MMTV from intestines to mammary glands, facilitating the transmission of infectious virus. On the other hand, expression of endogenous SAgs leads to thymic deletion of responding T cells (bearing Vβ6-9+ TCR) due to self-tolerance induction during the fetal life, and protects the host against future exogenous MMTV infections. The SAg of rabies virus is the N protein found in nucleocapsid structure and stimulates Vβ8+TCR-bearing T cells. The SAg-induced polyclonal activation of T cells leads to turn-off the specific immune response, to enhance the immunopathogenesis and facilitates viral transmission from the initial site of infection (the muscle tissue) to the nerve endings. In case of EBV-associated SAg that activates Vβ13+TCR-bearing T cells, it was detected that the SAg activity was not encoded by EBV itself, but instead was due to the transactivation of HERV-K18 by EBV latent membrane proteins, whose env gene encodes the SAg (Sutkowski, et al. 2001). It has been denoted that EBV-induced SAg expression plays a role in the long-term persistence and latency of virus in memory B cells, in the development of autoimmune diseases and in the oncogenesis mechanisms. The proteins which are identified as SAgs of HIV are Nef and gp120. It is believed that, the massive activation of CD4+ T cells (selectively with Vβ-12+, Vβ-5.3+ and Vβ-18+ TCRs) in early stages of infection and clonal deletion, anergy and apoptosis of bystander T cells in the late stages may be due to SAg property of Nef protein, as well as the other mechanisms. However there are some studies indicating that Nef does not act as a SAg (Lapatschek, et al. 2001). HIV gp120 glycoprotein is a B-cell SAg that binds to VH3-expressing B cell receptors and causes polyclonal B cell activation. In addition, binding of gp120 to IgE on the surface of basophiles and mast cells causes activation of those cells, secretion of high level proinflammatory mediators leading to allergic reactions and tissue damage. In a recent study, the depletion (anergy or deletion) of T cell populations bearing Vβ12+, Vβ13+ and Vβ17+ TCR have been shown, in patients infected with Zaire Ebola virus, whatever the clinical outcome (death or recovery), these results also suggest the presence of SAg activity. In this review article, following a brief description of the general characteristics of SAgs, virus-encoded SAgs and their roles in the diseases have been discussed.
Topics: Animals; Humans; Mice; Superantigens; Viruses
PubMed: 27525406
DOI: 10.5578/mb.24250 -
Journal of Theoretical Biology Jun 2015In this article, I trace the historic background of clonal deletion and molecular mimicry, two major pillars underlying our present understanding of autoimmunity and...
In this article, I trace the historic background of clonal deletion and molecular mimicry, two major pillars underlying our present understanding of autoimmunity and autoimmune disease. Clonal deletion originated as a critical element of the clonal selection theory of antibody formation in order to explain tolerance of self. If we did have complete clonal deletion, there would be major voids, the infamous "black holes", in our immune repertoire. For comprehensive, protective adaptive immunity, full deletion is necessarily a rare event. Molecular mimicry, the sharing of epitopes among self and non-self antigens, is extraordinary common and provides the evidence that complete deletion of self-reactive clones is rare. If molecular mimicry were not common, protective adaptive immunity could not be all-encompassing. By taking a fresh look at these two processes together we can envision their evolutionary basis and understand the need for regulatory devices to prevent molecular mimicry from progressing to autoimmune disease.
Topics: Animals; Autoantigens; Autoimmune Diseases; Autoimmunity; Clonal Deletion; Epitopes; Homeostasis; Humans; Immune Tolerance; Lymphocytes; Models, Biological; Molecular Mimicry
PubMed: 25172771
DOI: 10.1016/j.jtbi.2014.08.034