The Use of Placenta-Derived Cells in Autoimmune Disorders
Ornella Parolini, Antonietta Silini in Placenta, 2016
Central tolerance is induced in self-reactive, immature lymphocytes in the thymus and bone marrow, thus acting as a safeguard to ensure that the repertoire of mature lymphocytes is inept in responding to local, self-antigens. Potent, self-antigen recognition by immature lymphocytes has several consequences. The cells may die due to a process that selects self-reactive clones (through clonal deletion or negative selection), making the cells apoptotic (Kyewski and Klein 2006; Palmer 2003; Starr et al. 2003). Or, in the case of CD4+ T cells, they can even differentiate into regulatory cells that migrate to the periphery and block immune reactions to selfantigens, through, for example, the production of inhibitory cytokines, or by direct, contact-mediated blockade of costimulatory molecules on antigen-presenting cells. In B cells, receptor editing can occur whereby the B cell receptor is rearranged so that it is no longer able to recognize self-antigen (Goodnow et al. 1990).
Pathophysiology and Clinical Management of Diabetes and Prediabetes
Jeffrey I. Mechanick, Elise M. Brett in Nutritional Strategies for the Diabetic & Prediabetic Patient, 2006
T1DM is caused by T-cell mediated destruction of pancreatic insulin-producing β-cells. Tian et al. [116] have found a novel way to restore central tolerance in NOD mice using hematopoietic stem cells retrovirally transduced to express a protective form of the MHC class II β-chain. As a result, autoreactive T-cells will be killed in the thymus and never get to the pancreatic β-cells [116]. Central tolerance refers to mechanisms of tolerance acting in the thymus or bone marrow, in contrast to peripheral tolerance which occurs in immune cells after they have left the primary lymphoid organs. Pre-clinical studies must be completed before stem cells can be successfully given to humans with T1DM. Some drugs may be synthesized so that they exert their effect only within the areas of inflammation. One example is an engineered TGF-1β that can become activated locally within areas of β-cell inflammation [117,118].
Autoimmune endocrine disease
Philip E. Harris, Pierre-Marc G. Bouloux in Endocrinology in Clinical Practice, 2014
Autoimmunity continues to represent a poorly understood set of processes where “self” is misrecognized as foreign. When left unchecked, this misidentification can activate host defense systems that, in turn, result in tissue dysfunction and disruption.1 Thyroid immunity in many respects resembles analogous, fundamental events occurring in other tissues. Although immune surveillance is critical to organism survival, its overzealous activity can result in devastating diseases as these play themselves out in the thyroid. To regulate the intensity and specificity of immune reactivity, the body has several safeguards in place. Within the thymus, central tolerance is imposed by positive and negative B- and T-cell selection. Thymic epithelial cells express many of the so-called “tissue-specific” proteins that are known to behave as autoantigens. In the periphery, the vast array of cytokines generated by immune cells leads to polarization of T cells and can down regulate autoreactivity. In addition, the discovery of cell types that can down regulate immune reactivity, such as CD4+CD25+FOXp3+ regulatory T cells, has provided a partial explanation for how local reactivity can be controlled.2 These regulatory T cells are in turn influenced by multiple cytokines, such as interleukin (IL)-27, and other molecular and cellular factors. Better understanding of the defects underlying autoimmune thyroid diseases should allow the development of better treatments, such as those that are antigen specific.
How do nuclear factor kappa B (NF-κB)1 and NF-κB2 defects lead to the incidence of clinical and immunological manifestations of inborn errors of immunity?
Published in Expert Review of Clinical Immunology, 2023
Nazanin Fathi, Hanieh Mojtahedi, Marzieh Nasiri, Hassan Abolhassani, Mahsa Yousefpour Marzbali, Marzie Esmaeili, Fereshte Salami, Furozan Biglari, Nima Rezaei
T-cell proliferation, viability, stimulation, and especially CD4 T helper maturation are significantly influenced by NF-κBs. In general, NF-κBs are involved in T-cell central tolerance, thymocyte positive and negative selection, and lymphopoiesis. Central tolerance happens in the thymus on T lymphocytes derived from bone marrow. In double-negative (DN) CD4-CD8- cells undergo gene rearrangement to αß or γθ TCR. Then, double-positive (DP) CD4+ CD8+ cells are created. Next, thymocytes in the form of CD4 or CD8 single-positives (SP) with relative affinity to self-peptide-MHC complexes are selected as positive selection processes. These cells express the chemokine receptor (CCR7) and migrate into the medulla of the thymus, where medullary thymic epithelial cells (mTECs) highly express ligands for CCR7. There, CD8+ or CD4+ T cells make interactions with antigen-presenting cells (APCs) such as dendritic cells or mTECs to the exclusion of autoreactive T cells as negative selection processes.
Targeting the RANK/RANKL pathway in autoimmune disease and malignancy: future perspectives
Published in Expert Review of Clinical Immunology, 2021
Finally, little is known about how the immune response against cancer is inhibited by central tolerance, and a pharmacologic strategy to modulate key role central tolerance is not yet available. Key thymic pathways that restrict antitumor immunity have been recently identified and described. Importantly, it is now accepted that the autoimmune regulator (aire) gene plays a crucial role in preventing antitumor immunity [18,19]. Interestingly, a synergistic antitumor effect of central Aire-mediated tolerance and peripheral checkpoint proteins have been recently highlighted and are leading to growing interest in using RANKL blockage (denosumab), to enhance peripherally acting checkpoint inhibition. However, the potential benefic effects of RANKL blockade in cancer need to be carefully validated under the various tumor conditions in humans and possible adverse effects need to be carefully excluded [20].
Cellular mechanisms and clinical applications for phenocopies of inborn errors of immunity: infectious susceptibility due to cytokine autoantibodies
Published in Expert Review of Clinical Immunology, 2023
Rui Sun, Yating Wang, Hassan Abolhassani
The abnormal negative selection also underly the autoAbs production in thymoma and myasthenia gravis (MG associated with Good’s syndrome), this IEI is also featured with a high level of anti-type I IFN autoAbs production, but the underlying germline genetic cause has not been yet identified [14,15]. Besides MG, thymoma is highly related to autoimmune encephalitis [16,17], acquired neuromyotonia [18,19]. Among these clinical conditions, MG is the single most common thymoma-associated neurological autoimmune disease (~30–40%) caused by autoAbs against neuromuscular-associated proteins. One explanation regarding the dysfunctional negative selection can be attributed to abnormalities of the thymus, in which immature thymocytes are dysregulated during their maturation toward CD4+ or CD8+ T cells, thus contributing to the failed central tolerance and development of a variety of autoimmune symptoms [20]. Moreover, both thymoma and AIRE mutations seem to lead to a severer and broader range of autoAbs profiles than that of the local tissue-specific autoimmune diseases, this could be explained by the irreplaceable central negative selection role of thymus T cells on B cell immunoglobulin (Ig) production and autoAbs de novo generation.
Related Knowledge Centers
- B Cell
- Immunology
- Peptide
- Peripheral Tolerance
- Thymus
- Lymphatic System
- Bone Marrow
- Immune System
- T Cell
- Reactive Lymphocyte