Transforming Growth Factor-β: A Cytokine Paradigm
Thomas F. Kresina in Immune Modulating Agents, 2020
Immunological tolerance is a basic property of the immune system that allows for protection of the host from external pathogens without reacting against self. Autoimmune disease results when there is a breakdown in tolerance, leading to self-reactivity and subsequent destruction of tissues. Characteristic clinical presentations of autoimmune disorders include increased lymphocyte activation, increased major histocompatibility complex (MHC) expression, production of inflammatory cytokines, and presence of both polyclonal and autoreactive antibodies, resulting in a chronic inflammatory state. Since TGF-β plays a critical role in the maintenance of normal immune function, dysregulation of this growth factor may play a role in autoimmune pathogenesis, as has been observed in transgenic mice in which the TGF-β1 gene has been functionally deleted or is overexpressed [37–40], Because TGF-β appears to be such a pivotal cytokine in the regulation of immune function and autoimmune diseases, many approaches have been undertaken to modulate immune pathogenesis by manipulating TGF-β. These approaches include neutralization of excess TGF-β activity by neutralizing antibodies [41] and use of binding proteins such as decorin [42,43]. Alternatively, to promote immune suppression, increased TGF-β is required; that increase can be achieved through systemic exogenous administration of TGF-β [44], as well as augmentation of endogenous production through agents such as tamoxifen [45] or through induction of oral tolerance.
Immunologically Mediated Diseases and Allergic Reactions
Julius P. Kreier in Infection, Resistance, and Immunity, 2022
The central role of the immune system is to discriminate self from nonself. Competent lymphocytes must recognize and respond to foreign antigens, yet remain nonresponsive to self-antigens. In order to avoid autoreactivity, the immune system functions within the confines of self-tolerance, which is defined simply as the unresponsiveness of the immune system to a self-antigen. Tolerance mechanisms actively prevent the maturation and expansion of potentially self-reactive lymphocytes to maintain a self-tolerant repertoire of mature immune cells, as discussed in chapter 8. Self-tolerance mechanisms include (1) the deletion of all self-reactive lymphocytes during their maturation, (2) the preferential inactivation of helper T cells specific for self-antigens, and (3) the suppression of self-reactive T cells by regulatory cells. How then is it possible that autoimmune responses are generated in light of the fact that control mechanisms are working to prevent such occurrences? Autoimmune responses result from a breakdown of immunological tolerance. There may be an abnormal selection of self-reactive lymphocytes or an inappropriate stimulation of normally nonresponsive or anergic T cells. A breakdown in tolerance may also occur as a result of inhibiting suppressive surveillance mechanisms, or there may be a release of antigens that are normally inaccessible to immune recognition. A number of factors may be responsible for breaking self-tolerance, including genetic predispositions, infections, or immunological anomalies.
Dopamine in the Immune and Hematopoietic Systems
Nira Ben-Jonathan in Dopamine, 2020
Autoimmunity is a complex condition where the immune system does not distinguish between self and nonself antigens, as a result of a loss of immune tolerance. To date, as many as 80 autoimmune diseases have been identified, with an overall prevalence of 5%, thus constituting a serious health issue. As detailed in several reviews [1,2,44,45], dopaminergic pathways are considered as key regulators in multiple sclerosis (MS), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and basal ganglia encephalitis. In addition, a number of neurological and psychiatric disorders in which DA is involved are associated with abnormalities of specific immune cell subpopulations. The neurological disorders include PD, Alzheimer’s disease (AD), HIV-related encephalitis, and migraine. Psychiatric disorders include schizophrenia, anxiety disorders, and Tourette’s syndrome.
An overview of tolerogenic immunotherapies based on plant-made antigens
Published in Expert Opinion on Biological Therapy, 2019
Dania O. Govea-Alonso, Jaime I. Arevalo-Villalobos, Verónica A. Márquez-Escobar, Sornkanok Vimolmangkang, Sergio Rosales-Mendoza
Immune tolerance relies on complex physiological mechanisms that are dependent on several factors, including the dose and time of antigen exposure as well as the administration route. Genetics as well as composition and metabolic activity of the microbiome also exert an important influence on immune tolerance [14]. In particular, oral tolerance is induced in the gut-associated lymphoid tissues (GALT), which comprise several different organized lymphoid structures that include Peyer’s patches (PPs) and isolated lymphoid tissue (ILF) being critical for the initiation of intestinal IgA responses [15]. The induction of tolerance primarily comprises the suppression of antigen-specific effector T- and B-cell responses by the induction of T-cell deletion (anergy) and the activation of Treg cells [16].
Locked and loaded: engineering and arming oncolytic adenoviruses to enhance anti-tumor immune responses
Published in Expert Opinion on Biological Therapy, 2022
Immune tolerance can be imposed during B and T cell ontogeny by central tolerance. However, the balance between immune activation and immune tolerance is also modulated later by innate immune cells, antigen-presenting cells (APCs), and other types of immune cells in the peripheral [94]. Innate immune cells can be activated by receptors of PAMPs and DAMPs to recognize pathogens [3]. These pattern recognition systems are good at detecting strange external invaders but less useful in detecting neoplastic cells as they lack these patterns. In the absence of innate immune triggers, long-term exposure of tumor antigens to T cells can gradually convert T cells into an anergic or dysfunctional state (Figure 4) [90]. Thus, slow growth in the absence of innate cell danger signals can allow tumor cells to evade T cell recognition. In other cases, inflammation itself can assist in the tumorigenesis [95], but this is a different discussion.
Oral delivery of the intracellular domain of the insulinoma-associated protein 2 (IA-2ic) by bacterium-like particles (BLPs) prevents type 1 diabetes mellitus in NOD mice
Published in Drug Delivery, 2022
Ruifeng Mao, Menglan Yang, Rui Yang, Yingying Chen, Enjie Diao, Tong Zhang, Dengchao Li, Xin Chang, Zhenjing Chi, Yefu Wang
Apart from preventing invasion of pathogens, the immune response plays an important role in preventing reactivity to self-antigens, thereby preventing the development of autoimmunity by complicated suppression tolerance mechanisms. Immune tolerance, including central and peripheral tolerance, relies on complicated clonal deletion/anergy of T and B cells as well as suppression by regulatory immune cells (Issa & Wood, 2012; Wambre & Jeong, 2018). Tolerance induction can be achieved by introducing proteins or peptides through various methods, such as intravenous injection, intranasal administration, skin administration as well as oral administration (Wang & Tisch, 2008; Xu et al., 2013; Mao et al., 2020a, 2020b). As a result of its ability to induce systemic unresponsiveness to orally administered antigens and its non-invasiveness, oral tolerance has been intensively investigated (Sricharunrat et al., 2018). Most of these oral tolerance studies performed in animals and human clinical trials aim to prevent and treat allergies, transplantation rejection as well as autoimmune disorders, including type 1 diabetes mellitus (T1DM).
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