Shifting Paradigms in Peripheral Tolerance
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
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).
Clinical Studies In Acute and Chronic Inflammation
Siegfried Matzku, Rolf A. Stahel in Antibodies in Diagnosis and Therapy, 2019
Anti-CD3 (muromonal-CD3, Orthoclone OKT3) therapy has been extensively used as an immunosuppressive agent in transplantation (reviewed in Parlevliet and Schellekens, 1992 and in Sgro, 1995) and is one of the most widely used therapies for transplant rejection. Treatment with anti-CD3 results in a rapid and profound lymphocytopenia possibly due to several mechanisms including complement-dependent cytolysis, cell-mediated antibody-dependent cytolysis, opsonization and phagocytosis by macrophages and inhibition of T cells interacting with antigen presenting cells (Bonnefoy-Berard and Revillard, 1996). Long lasting effects may be due to induction of clonal anergy resulting in long lasting specific unresponsiveness.
Tolerance and autoimmunity
Gabriel Virella in Medical Immunology, 2019
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.
Checkpoint inhibitors and acute myelogenous leukemia: promises and challenges
Published in Expert Review of Hematology, 2018
Mansour Alfayez, Gautam Borthakur
T cells get activated normally once they encounter and recognize an antigen, presented on MHC molecule, through their T-cell receptor (TCR) (Figure 1). This natural interaction is, however, insufficient to establish optimal clinical responses. A second ‘co-stimulatory’ signal is required for full activation of T cells. The best recognized co-stimulatory signal is CD28 on T cell and CD80 or CD86 on antigen-presenting cells (APCs). CD80 and CD86 are upregulated on activated APCs as ‘danger signals’ as they present microbial antigens to efficiently stimulate T cell. Stimulating T cell in the absence of CD28-CD80/86 co-stimulatory signal result in hyporesponsive state or ‘clonal anergy’ [19]. Although structurally similar to CD28 expressed on activated T cells, CTLA-4 binds to CD80/CD86 with higher affinity than CD28, thereby inhibiting T-cell response. A modulated T-cell response is therefore dependent on a balanced interaction between co-stimulatory and co-inhibitory signals. In the setting of an immune reaction induced by exposure to pathogens, these inhibitory checkpoints intervene to attenuate the inflammatory reaction while maintaining self-tolerance protecting surrounding tissues from excessive damage. In the context of cancer, on the other hand, ‘anergy’ can be an important mechanism for tumors to be ‘invisible’ to the immune system, which makes it a potential therapeutic target [20].
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).
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].
Related Knowledge Centers
- Immune Tolerance
- Immunology
- Peripheral Tolerance
- Virus
- Immune System
- Lymphocyte
- Pathogen
- Immune Response
- Antigen
- Clonal Deletion