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The Thymic Defect
Published in Miroslav Holub, Immunology of Nude Mice, 2020
Since the applied monoclonals label also the epidermal cells (keratinocytes) in the basal stratum of the skin and of other squamous epithelial linings11 it may be suggested that the endocrine epithelial thymic cells are of ectodermal origin and that they migrate into the endodermal thymic anlage at different times of organ development. Haynes11 proposes a similar maturation pathway for human thymic epithelial cells and keratinocytes: in addition to the shared surface antigens both contain keratin and have similar growth requirements in vitro. Thymic medullary epithelial cells forming Hassall’s corpuscles undergo the same surface antigen changes with basal keratinocytes maturing into stratum granulosum and stratum spinosum cells. This agrees also with the morphological suggestions that medullary thymic epithelial cells have a potential for differentiation similar to skin epithelial cells.12
Immunologic Tolerance
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Mice containing a class I antigen (Kb) transgene whose expression is controlled by a keratin gene promoter, express the transgene in keratinocytes and in medullary thymic epithelial cells, but not in the thymic cortex. When these mice were mated with another transgenic line expressing a T cell receptor specific for Kb, the CD8+/receptor+ cells were not deleted. Rather, they were rendered anergic. Thus, thymic medullary epithelial cells may have a role in the induction of anergy of mature (single-positive) thymocytes. Further support for this idea comes from experiments in which lethally-irradiated (A X B)F1 mice are reconstituted with bone marrow from a strain A mouse. Peripheral T cells are tolerant to strain B alloantigens, even though T cells with B-allospecific receptors are present in the circulation. Clearly, deletion in the thymus has not occurred, and the T cells are anergic. Since the bone marrow-derived cells in the thymus express only strain A antigens, thymic epithelial cells remain as the only candidate cells which still express strain B MHC and can induce anergy.
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
As the details of lymphocyte development became better elucidated, this concept of a critical “self/nonself” learning period became refined. Whereas Burnet and others emphasized a developmental period in terms of the organism, it is clear that the model might be applied to a critical developmental period in the life of a lymphocyte. For example, precursors to T cells home to the thymus where they are educated to self through the processes of positive and negative selection. Using T-cell receptor (TCR)-specific antibodies, Kappler and Marrack formally demonstrated the phenomenon of thymic negative selection, whereby autoreactive T lymphocytes are deleted prior to their emergence into the peripheral circulating lymphocyte pool.5 As such, the education process to self takes place during a critical period of T cell development. Interestingly, it has been recently shown that a myriad of ostensibly peripheral self proteins are expressed in medullary thymic epithelial cells.6-9 This “promiscuous gene expression” of self antigens, which includes insulin, somatostatin, elastase, trypsin2 (among others), appears to be general in that it is not limited to a particular set of functional genes or even exclusively secluded proteins. Since many of these genes do not have any obvious function in the thymus and are not expressed by epithelial cells elsewhere in the body, one can hypothesize that their expression in the thymus is for the purpose of inducing tolerance. Indeed, if thymic deletion could be demonstrated for most peripheral antigens, then it might be argued that mechanisms of peripheral tolerance are only minor fail-safes with the bulk of the self/nonself discrimination process taking place in the thymus.
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
The NF-κB pathway may be activated by TCRs, costimulatory CD28, TNF-like receptor signals, and different stimuli during T cell development and activity. The different effector subsets of activated CD4 + T cells such as type 1 T helper (Th1), Th2, Th9, Th17, Tfh, and Treg cells each have distinctive functions that are depending on TCR signaling. TCR stimulation is also necessary for the proliferation and differentiation of activated naïve CD8 + T cells into effector and memory cells. TCR activates the canonical NF-κB pathway. The non-canonical NF-κB2 pathway is crucial for controlling differentiation but not for the initial activation of T cells through TCR signaling. The majority of T cell-autonomous effects via CD28 signaling are tightly controlled by NF-κB. In particular, the NF-κB p65/p52-dependent upregulation of Bcl-xL is one survival function of CD28 [50]. Treg cells are an essential subgroup of lymphocytes that suppress self-reactive T cells so escape negative selection. They limit the immunological responses relying on T cells and preventing autoimmune diseases. Treg development depends on the TCR and CD28 signaling by stimulating the NF-κB1 pathway [51]. Autoimmune regulator (AIRE) is an essential transcriptional regulator, expression in the medullary thymic epithelial cells (mTECs). AIRE induces developing Tregs to establish central immune tolerance and eliminates autoreactive T cells by managing the expression of several tissue-specific antigens in mTECs [52].
Repurposing denosumab in lung cancer beyond counteracting the skeletal related events: an intriguing perspective
Published in Expert Opinion on Biological Therapy, 2020
Maria V. Deligiorgi, Dimitrios T. Trafalis
Although the discovery of RANKL expressed on osteoblasts is deemed to revolutionize our understanding of bone biology and oncology [9], RANKL is a pleiotropic molecule, ubiquitously expressed. Besides bones, RANKL is expressed in lymph nodes, thymus, intestine, lung, mammary glands, spleen, kidney, liver, brain, heart, skin, and skeletal muscles. Various cells express RANKL beyond osteoblasts, such as bone marrow stromal cells, activated T cells, B cells, fibroblasts, endothelial cells, chondrocytes, and mammary epithelial cells [19]. Interestingly, RANKL had been discovered as a cytokine expressed on T cells stimulating the survival of RANK-expressing dendritic cells (DCs) and enhancing the ability of DCs to trigger the proliferation of naive T-cell prior to its identification as OPG ligand [20,21]. The RANKL/RANK interplay has been shown to inhibit the immune response through multiple mechanisms, involving: (i) stimulation of development of medullary thymic epithelial cells (mTECs); (ii) promotion of generation of regulatory T cells (Tregs), and (iii) induction of T-cell tolerance and deletion [22,23].
Repurposing denosumab in breast cancer beyond prevention of skeletal related events: Could nonclinical data be translated into clinical practice?
Published in Expert Review of Clinical Pharmacology, 2020
Maria V. Deligiorgi, Mihalis I. Panayiotidis, Dimitrios T. Trafalis
Expressed mainly on activated CD4+ and CD8+ T cells and natural killer (NK) cells, RANKL stimulates various processes-landmark of immunity, including DCs survival and maturation, T-cell activation, and NK function [37]. Based on in vitro and in vivo data, the clinical significance of the RANKL/RANK interplay in immunity is highly divergent. It enhances the immune response through: (i) control of T- and B-lymphocyte development; (ii) orchestration of lymph-node organogenesis; (iii) increased DCs survival; (iv) stimulation of cytokine expression; and (iv) reinforcement of T-cell responses. On the other hand, the RANKL/RANK interplay inhibits immunity through: (i) stimulation of development of medullary thymic epithelial cells (mTECs), which are key players of T-cell self-tolerance; (ii) reinforcement of tolerance in Peyer’s Patch; (iii) promotion of generation of regulatory T cells (Tregs); and (iv) induction of T-cell tolerance and deletion. The factors that skew the balance toward inhibition or enhancement of immunity are yet to be illuminated [37].