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Immunologic Tolerance
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
As discussed above, negative selection in the thymus cannot account for the absence of autoimmunity, since autoreactive clones exist in the periphery. The concept of clonal anergy was advanced to explain the dormant state of these autoreactive clones. Clonal anergy is primarily a mechanism of peripheral tolerance, although it also may be induced within the thymus.
Shifting Paradigms in Peripheral Tolerance
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Jonathan D. Powell, Ronald H. Schwartz
Although anergy occurs when T cells are stimulated via the TCR in the absence of costimulation, it does not appear that costimulation alone directly inhibits anergy induction. Rather, TCR stimulation in the presence of costimulation leads to IL-2 production, which leads to T cell proliferation as well as the prevention of anergy induction.45,46 Hence, it is the action of IL-2 that prevents anergy induction. In fact, T cell clonal anergy can be reversed if the cells are cultured in IL-2 and allowed to proliferate. Recent work has clearly linked cell cycle progression and the prevention of anergy.47-50 Anergic cells are arrested in G1 and inhibiting cell cycle progression in the presence of signal 1 leads to anergy. In our own in vitro model, we have been able to show that the drug rapamycin, which blocks IL-2-induced cell cycle progression from G1 to S, can promote anergy even in the presence of costimulation. We have been able to exploit this property of rapamycin in an in vivo bone marrow transplantation model. If we give minimally conditioned (300 cGray Total Body Irradiation) B strain parents (BxD)F1 bone marrow under the cover of rapamycin for 4 weeks, we can induce durable long term chimer-ism in the absence of continued immunosuppression (Powell and Tisdale, manuscript in preparation).
Tolerance and autoimmunity
Published in Gabriel Virella, Medical Immunology, 2019
George C. Tsokos, Gabriel Virella
By definition, anergic clones lack the ability to respond to stimulation with the corresponding antigen. Thus, the most obvious manifestation of clonal anergy is the inability to respond to proper stimulation. Anergic B cells carry IgM autoreactive antibody in their membrane but are not activated when they encounter antigen. Anergic T cells express TCR for the tolerizing antigen but fail to properly express the IL-2 and IL-2 receptor genes and to proliferate in response to antigenic stimulation.
Beyond the amyloid hypothesis: how current research implicates autoimmunity in Alzheimer’s disease pathogenesis
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Miyo K. Chatanaka, Dorsa Sohaei, Eleftherios P. Diamandis, Ioannis Prassas
The immune system is a sophisticated organ that orchestrates the fight against foreign pathogens. The B cells of the humoral response of the adaptive immune system, showcase an almost infinite number of different receptors that can bind to pathogenic molecules, leading to their eventual destruction [1]. As explained in detail previously [2], B cells undergo a selection process in the thymus that filters out any cells that cannot distinguish “self” from “non-self” antigens. The T cells of the cell-mediated arm of adaptive immunity undergo a similar process in the thymus that establishes a central tolerance by eliminating naive T cells with T cell receptors (TCRs) that recognize “self” antigens [3,4]. In addition, any autoreactive T cells that escape thymic selection are further subjected to clonal anergy, deletion, and ignorance, and regulatory T cells (Tregs) assist in the tight regulation of these dangerous B and T cells [3]. Through various processes and physiological aging, however, this intricate system frequently deteriorates and the regenerative capacity of the organs that create immune cells progressively reduces their functional capabilities (see [5,6]). This allows for autoantibodies (antibodies directed against self-antigens) to initiate a chain reaction that leads to misdirected and harmful immune responses [7]. Therefore, autoimmunity is a biological process whereby the organism loses its immune tolerance and mounts attacks against self-antigens (autoantigens).
Chronic immune thrombocytopenia in a child with X-linked agammaglobulinemia-an uncommon phenotype
Published in Platelets, 2022
Jing Yin, Jijun Ma, Xiaoxue Liu, Jingyue Xia, Qi Ai, Chongwei Li
During the early B-cell development, Ig gene recombination produces many autoreactive B cells that are effectively removed by immune tolerance mechanisms such as apoptosis, clonal anergy, and receptor editing. However, the elimination of these autoreactive B cells fails when BCR signaling is impaired. A study by Eric Meffre et al. concluded that central B-cell tolerance checkpoints are abrogated in the absence of BTK, and the antibodies expressed by XLA B cells are self-reactive and highly polyreactive [11]. Robbins et al., (1969) reported autoimmune hemolytic anemia in a 6-year-old boy with congenital sex-linked hypogammaglobulinemia [12]. Further, this child developed a positive Coombs test for two years and responded well to corticosteroids, although he relapsed when corticosteroids were discontinued [12], which is similar to our patient.
Suppression of the CD28/B7 pathway reduces the occurrence and development of myasthenia gravis and cytokine levels
Published in International Journal of Neuroscience, 2021
Zhan-Xia Xue, Yong-Shan Gao, Xue-Liang Wu
We initially found that the increased lymphocyte proliferation of EAMG rats could be negated by CTLA4-Ig treatment. T regulatory cells were identified due to their crucial role in the development of self-tolerance and in the pathogenesis of MG [29]. CD28 is essential to promote T cell proliferation and cytokine production, while CTLA4 acts as a negative regulator for the activation of T cells [10]. CTLA4-Ig inhibits immune reactions by blocking the T-cell costimulatory CD28-CD80-86 pathway [30]. CTLA4-Ig is homologous CD28, where both ligands can bind B7-1 and B7-2 on antigen-presenting cells. It has been found that CTLA4 binds B7-1 and B7-2 with a greater affinity than CD28, thus enabling it to outcompete CD28 for its ligands, eventually transmitting inhibitory signals to T cells [15, 31, 32]. Previous studies have demonstrated that CD28/B7 interactions can co-stimulate T cell activation and prevent T cell clonal anergy [33]. CD28 could potentially deliver a costimulatory signal in the process of T cell activation, where it delivers TCR-independent autonomous signals that regulate the expression of pro-inflammatory cytokines and chemokines [34]. T cell activation can be mediated through co-stimulatory factors delivered by LFA 1/ICAM, LFA 3/CD2, CTLA4/CD40, CD28/B7 and ICOS/ICOSL interactions [35].