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Basics of Allergy
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Rafeul Alam, Dipa K Sheth, Magdalena M Gorska
The elimination of auto-reactive T and B cells in the thymus and bone marrow, respectively, through negative selection is called central tolerance (Walker and Abbas 2002). There is evidence that some self-reactive T and B cells manage to escape the negative selection; their receptors may recognize MHC/self-peptide with an affinity that is not high enough to elicit negative selection. Despite the presence of auto-reactive cells, autoimmunity does not develop due to peripheral tolerance. DCs expressing self-peptides are not activated and therefore have very low levels of co-stimulatory molecules. They also secrete IL-10, so the majority of lymphocytes become anergic instead of being activated. Presentation of self-antigens in the absence of co-stimulation may also lead to clonal deletion through apoptosis. Auto-reactive cells as well as inflammatory cells in the peripheral organs are suppressed by a population of CD4+CD25+FoxP3+ cells, called regulatory T cells (Tregs) (Shevach et al. 2001). These cells secrete IL-10 and TGFb and block proliferation of lymphocytes.
Death Receptor-Mediated Apoptosis and Lymphocyte Homeostasis
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Lixin Zheng, Richard M. Siegel, Jagan R. Muppidi, Felicita Hornung, Michael J. Lenardo
Because of positive selection, all peripheral T cells are “educated” to recognize antigen in the context of self-MHC. To avoid generating strongly self-reactive T cells that can cause autoimmune disorders, the thymus specifically eliminates self-reactive T cells by negative selection. In this instance, clonotypic thymocyte apoptosis is triggered whenever the TCRs of developing thymocytes encounter self-peptide/MHC complexes at high avidity.14, 19 It is believed that self-tolerance of the immune system is largely dependent on thymic deletion of strong self-reactive T cells at an early stage of T cell development, a process called “central tolerance”.18
Tolerance and autoimmunity
Published in Gabriel Virella, Medical Immunology, 2019
George C. Tsokos, Gabriel Virella
At the cellular level, tolerance can result from clonal deletion or clonal anergy. Clonal deletion involves different processes for T and B lymphocytes. T lymphocytes are massively produced in the thymus and once generated will not rearrange their receptors. Memory T cells are long lived, and there is no clear evidence that new ones are generated after the thymus ceases to function in early adulthood. Therefore, elimination of autoreactive T cells has been postulated to occur at the production site (thymus) at the time the cells are differentiating their T-cell receptor (TCR) repertoire. Clonal deletion of T lymphocytes in the thymus is not a completely efficient process. The clones most likely to be eliminated are those that express T-cell receptors that interact with high affinity with self peptides associated with major histocompatibility complex (MHC) molecules. This process assumes that autoantigens are expressed in the thymus. Truly, mutation of the gene AIRE (autoimmune regulator) in both humans and mice results in the “autoimmune polyendocrinopathy syndrome.” AIRE protein is responsible for the expression in the thymus of proteins typically seen in peripheral organs. T cells that are specific for antigens not expressed in the thymus escape negative selection (central tolerance) and move to the periphery where they may attack tissues and organs.
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.
Dysregulated translational factors and epigenetic regulations orchestrate in B cells contributing to autoimmune diseases
Published in International Reviews of Immunology, 2023
Ming Yang, Ping Yi, Jiao Jiang, Ming Zhao, Haijing Wu, Qianjin Lu
Pemphigus, a kind of skin and/or mucous membrane involved autoimmune disease, is characterized with acantholysis resulted from pathogenic autoantibody IgG against desmoglein (Dsg) 1/3 in the epidermis. TF Aire plays an essential part in the production of self-antigens like Dsg1/3 in thymus, which induces negative selection of B cells in central tolerance [237]. Ectopic lymphoid-like structures (ELSs) were diffusely distributed in the lesions of pemphigus vulgaris (PV) and pemphigus foliaceus (PF), which consisted of differentially differentiated B cells featured with elevated mRNA level of TFs Blimp1, IRF4 and Bcl6, as well as chemokines and its receptors [238]. Global DNA methylation and Dnmt1 expression were increased, while histone methylation and acetylation were decreased due to upregulated HDAC1/2 and downregulated SUV39H1 and EZH2 in PBMCs of PV patients [44]. Remarkably, variants in KDM4C gene and the other three genes encoding HMTs (SETD7/KMT7, MECOM/KMT8E and PRDM16/KMT8F) were associated with RF risk, indicating that histone (de)methylation plays a major part in epigenetic regulations of PF, rather than DNA (de)methylation [47].
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.