Pender MP. CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis. Autoimmune Dis. 2012;2012:189096.
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.
This article is free to download and read at your leisure.
This is just one idea of the problem of MS. There are others.


Is this suggesting that EBV gets into the lymph nodes via the tonsils? Are they the doorway to the body? Lots of people used to have tonsillectomies due to repeat bouts of tonsillitis. If the tonsils were removed prior to EBV infection, would this effect the hypothesis?
ReplyDeleteAn interesting question, would it affect the hypothesis? Probably but it is really for Dr Pender to think about this.
ReplyDeleteBut there is an answer to your question I think
Tonsillectomy and infectious mononucleosis. Sumaya et al. Am J Epidemiol. 1978;107:65-70
An association between tonsillectomy and glandular fever was performed in a college student population (n =328).
"Although it was determined that the development of glandular fever during college years was statistically less common in tonsillectomized students, the difference was not very large and "probably had no significant biologic meaning".
Broadley SA et al. Multiple sclerosis and tonsillectomy: no evidence for an influence on the development of disease or clinical phenotype. Mult Scler. 2000 ;6:121-3.
So maybe chinks in the Pender idea but what is the route of infection
Thank you MD for a comment on this (as I asked a fortnight ago).
ReplyDeleteI also asked about vertigo - any current treatments available that work? Or any future ones in the pipeline?
Treatments....thats prof Gs department
ReplyDelete"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" :
ReplyDeleteSo is there a deficiency? That sounds likes a question that should have a clear yes/no answer
I guess, the question remains whether the CD8 T-cell deficiency is there before the body encounters the virus or whether the vial encounter has this kind of effect on the immune system.
ReplyDeleteWe know from HIV that constant fighting has an impact on CD8 T cells - they become exhausted, fatigued and less good at killing infected cells.
Obviously EBV is less challenging for our immune system than HIV, but still the virus has to be controlled for life.
Remembering some data from Pender lab from top of my head so could be wrong but Healthy control CD8 responding to EBV count 22 plus or minus 1, MSer 19 plus or minus 1. There was a statistical reduction but is this biologically significant?
ReplyDeleteIs this a deficiency?..Probably not in terms of absolute numbers in my mind, in someone elses mind yes.
Science is often not black and white but shades of grey. But the answer might be black and white is the question is restrictive enough
Re: "I also asked about vertigo - any current treatments available that work? Or any future ones in the pipeline."
ReplyDeleteThere are some treatments that work for vertigo, but not very well; e.g. cinnarazine and betahistine. The problem is that they delay central adaptation of the brain; i.e. the slow down the recovery so we don't like using them. Most of the trials on the clinicaltrials.gov website are rehabilitation trials. I am aware of two new drugs under development that are targeting vertigo, but they are in early stage development.