CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.
Proposed role of EBV infection in the development of chronic autoimmune diseases. During primary infection EBV infects autoreactive baby B cells in the tonsil, driving them to enter lymph gland follicles where antibody producing cells are made, where they proliferate and differentiate into latently infected autoreactive memory B cells (path 1) which then exit from the tonsil and circulate in the blood (path 2). The number of EBV-infected B cells is normally controlled by EBV-specific cytotoxic CD8+ T cells, which kill proliferating and lytically infected B cells, but not if there is a defect in this defence mechanism. Surviving EBV-infected autoreactive memory B cells enter the target organ where they take up residence and produce oligoclonal IgG (making the oligoclonal bands) and pathogenic autoantibodies which attack components of the target organ (path 3). Autoreactive T cells that have been activated in peripheral lymphoid organs by cross-reacting foreign antigens circulate in the blood and enter the target organ where they are reactivated by EBV-infected autoreactive B cells presenting target organ peptides (Tp) bound to major histocompatibility complex (MHC) molecules (path 4). These EBV-infected B cells provide survival signals (B7) to the CD28 receptor on the autoreactive T cells and thereby inhibit the activation-induced T-cell death which normally occurs when autoreactive T cells enter the target organ and interact with antigen-presenting cells (APCs) which do not express B7 costimulatory molecules (Path 6). After the autoreactive T cells have been reactivated by EBV-infected autoreactive B cells, they produce cytokines such as interleukin-2 (IL2), interferon-γ (IFNγ) and tumour necrosis factor-β (TNFβ) and orchestrate an autoimmune attack on the target organ (Path 5). BCR = B cell receptor; TCR = T cell receptor.
Therefore the course to autoimmunity is a sequential cascade of events and genetics and vitamin D may be one of the tipping points that effect CD8 T cell levels. Although HLA class I genes that are recognition elements for CD8 T cells are associated with MS susceptibility, HLA-D which controls CD4 function is best linked with MS susceptibility.
This hypothesis centres on the CD8 T cell and to accept this you need to agree that T cells are central to the problems of MS. You also have to convince yourself that there is indeed a deficiency of CD8 positive T cells in autoimmune diseases. Many people would not agree with this. Treatment of EBV would break this cycle, lets see what the Charcot Project gives us.
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This is just one idea of the problem of MS. There are others.