The genes identified in the new research include those that influence specific cells of the immune system, either through controlling interleukins (messenger chemicals that help immune cells communicate) or T-cells, which help the body fight off intruders. About a third of the genes identified are also linked to other autoimmune diseases, such as Crohn's disease, rheumatoid arthritis and type 1 diabetes.
Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
CVfactor wrote:The evidence is becoming conclusive that MS is an autoimmune disease:
http://www.webmd.boots.com/news/20110812/new-genetic-clues-multiple-sclerosisThe genes identified in the new research include those that influence specific cells of the immune system, either through controlling interleukins (messenger chemicals that help immune cells communicate) or T-cells, which help the body fight off intruders. About a third of the genes identified are also linked to other autoimmune diseases, such as Crohn's disease, rheumatoid arthritis and type 1 diabetes.
And another new article:
http://www.nature.com/nature/journal/v476/n7359/full/nature10251.htmlImmunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Attention has recently focused on environmental factors associated with the increase in the incidence of several classes of disease in the industrially developed nations. The concept, forming the basis of the emerging discipline of “Darwinian medicine” , is that hygiene-related factors isolate the human population from micro-organisms, both pathogens and, probably more importantly, commensals, that are crucial to the establishment of beneficial immunoregulatory networks. Thus, in principle, an “interkingdom cross-talk” between microbes and the human host can establish patterns of immune reactivity that prevent various allergic, autoimmune, and inflammatory diseases while a failure of such cross-talk can facilitate them . One consequence of improved hygiene is that certain infections that were previously regularly encountered in infancy now occur at a much later time in life and after other infections may have altered the patterns of immune responsiveness. Infection by EBV is a good example, and it has been postulated that various other infections acquired before EBV may affect immunoregulatory networks, thereby leading to an attrition or eclipse of those regulatory T cells (Tregs) that would otherwise protect against MS . In this context, Tregs, though essential to immune function, may in some circumstances induce harmful effects and have therefore been termed a “dangerous necessity” .
Accordingly, a critical determinant of MS risk could be a compromised number or activity of protective Tregs [61, 62]. During an active and specific T cell-mediated immune response there could well be a competition with other kinds of T cells, most likely T-helper-cells, recognising the same epitope as the Tregs or epitopes closely spatially situated on the relevant antigen(s). As a consequence certain T-helper cell populations, that induce production of specific antibody, could become expanded and, thus, account for the diverse rise in antibody levels as epiphenomena with little or no pathologic importance. Notwithstanding, the local production of measles, varicella, or rubella-specific antibodies in the central nervous system can be useful for diagnosis [28–30], and the production of anti-HERV antibodies may become of use as prognostic factor for MS disease [4, 63].
Uncertainty exists as to whether similar or different mechanisms contribute to the pathogenesis of different subtypes of multiple sclerosis (MS). Detailed analysis of naive T cell homeostasis shows that patients with relapsing-remitting MS (RRMS) and with primary progressive MS (PPMS) have early-onset thymic involution that causes reduced thymic output. The reduced thymic output leads to secondary peripheral homeostatic alterations in naïve CD4 T-cells, which closely mimic T-cell alterations observed in an experimental animal model of diabetes mellitus. Homeostatic T-cell receptor (TCR) signalling and proliferation of naïve T cells are induced by self-peptides. Consequently, the findings of increased TCR signalling of naïve CD4 T-cells, without increased proliferation, in PPMS, and the increased homeostatic proliferation of naïve CD4 T-cells in RRMS favour the development of autoimmunity. Thus, it seems highly likely that peripheral T-cell alterations secondary to a thymic abnormality contribute to the pathogenesis of both MS subtypes.
One study of immunoablation/autologous stem cell transplantation as a treatment of MS showed that the post transplant MS patients “rebooted” their immune system such that the thymus produced new T cells having a diverse TCR repertoire [36 ].
In keeping with the observation that specific T cells that have been primed by pathogens and cross-react with self antigens can cause autoimmunity in animal models, patients with autoimmune diseases such as SLE, rheumatoid arthritis and multiple sclerosis have been found to have higher frequencies and activation states and/or less co-stimulatory requirements of self-reactive lymphocytes 27-30. In multiple sclerosis, receptor analysis of T and B cells in CNS tissue and in the cerebrospinal fluid (CSF) showed clonal expansions in both populations, indicating that there is clonal reactivity to a restricted number of disease-relevant antigens 31-33. In addition, longitudinal studies provided evidence for long-term persistence of individual myelin-specific T-cell clones tracked over several years in the blood of patients with multiple sclerosis 34-36, indicating a strong, persisting memory response and/or ongoing autoantigen exposure at least for a subset of myelin-reactive T cells in multiple sclerosis.
We suggest that these memory responses reflect, at least in part, persisting clonal expansions of polyspecific T cells recognizing both self and virus antigens that have been found associated with human autoimmune diseases. For example, high viral loads that occur during symptomatic primary EBV infection, resulting in infectious mononucleosis, are associated with an increased risk of developing multiple sclerosis 37-39, and could prime these polyspecific T-cell responses.
In addition to autoimmune responses that are initially primed by APCs and stimulated by bystander activation, additional autoantigen-specific T or B cells can be primed through epitope spreading 45 — a situation in which an immune response that is initiated by various stimuli, including microbial infection, trauma, transplanted tissue or autoimmunity, ‘spreads’ to include responses directed against a different portion of the same protein (intramolecular spreading) or a different protein (intermolecular spreading). Activating a broader set of T cells through epitope spreading is helpful in an antipathogen or antitumour immune response, because the pathogen or tumour cannot easily escape immune control with a single mutation in an immunogenic epitope. However, disease potentially arises when spread to and within self proteins occurs subsequent to the destruction of self tissue.
CVfactor wrote:George, I think that the CD4+/CD8+ balance may be reversed because CD4+ t cells come out of the thymus as naive cells and then are activated by antigen presenting cells as they are encountered (MHC II) molecules. CD8+ t cells may be already antigen specific to MHC class I antigens but are not yet activated. So, maybe it takes longer for CD4+ T cells to accumulate in their diversity as they encounter antigen presenting cells. This is my guess.
georgegoss wrote:CVfactor wrote:George, I think that the CD4+/CD8+ balance may be reversed because CD4+ t cells come out of the thymus as naive cells and then are activated by antigen presenting cells as they are encountered (MHC II) molecules. CD8+ t cells may be already antigen specific to MHC class I antigens but are not yet activated. So, maybe it takes longer for CD4+ T cells to accumulate in their diversity as they encounter antigen presenting cells. This is my guess.
Sound like as good of an explanation as I've heard. You still have a future as an immunologist if you decide to go that route!
CVfactor wrote:But I'm curious to know if with the non-myeloablative protocal do you also see a reversal of the CD4+/CD8+ T cell profile?
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