Early loss of thymic function may be crucial for the development of immune-mediated diseases. According to this concept premature collapse of thymic output is compensated by homeostatic proliferation of peripheral T-cells, driven by recognition of self antigens and finally resulting in the expansion of autoreactive, senescent T-cell clones. Such senescent T-cells are characterized by the loss of the co-stimulatory receptor CD28 and the gain of new immunomodulatory molecules such as natural killer cell receptors and toll-like receptors. The immune system may compensate for these changes by regulatory mechanisms, including the evolvement of regulatory T-cells. However, the aging process may also affect these regulatory T-cells leading to a second “hit” of the immune system. Current therapeutic approaches in patients with immune-mediated diseases target common end pathways of inflammation, driven by proinflammatory cytokines and effector cells. Future directions will include the aim to reset the immune system, by restoring the ability to repopulate the immune system with young and adaptable lymphocytes as well as by strengthening the effect of regulatory T-cells.
Keywords: CD28, aging, regulatory T-lymphocyte, cellular senescence, thymus, autoimmune disease, T-Cells, natural killer cell, toll-like receptors, immune system, inflammation, cytokines, homeostasis, rheumatoid arthritis, innate immune system, thymopoesis, autoimmune regulator, juvenile idiopathic arthritis, haematopoietic progenitor cells, major histocompatibility complex M, MHC II, HLA-DR4, thymic atrophy, autoimmune diseases, Epstein Barr Virus, EBV, CD4, CD8, CD27, IFN, perforin, granzyme B, CCR-5, CCR-7, Ankylosing spondylitis, Dermatomyositis, 50
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