It is conceivable that antigen presentation to na?ve T cells occurs in the lymph nodes, and, thus, DC have either to collect the antigen within the CNS and then to travel to the draining lymphoid tissue, or to trap a soluble antigen which is transported through lymph vessels. redox processes involved in MS initiation; (ii) the role of reactive species in inflammation; (iii) prooxidative changes responsible for neurodegeneration; and (iv) the potential of antioxidative therapy. (IVAVT?T) and (Thr17Ala), and environmental factors affecting vitamin D3 levels, converge in order to alter branching of Asn (N)-linked glycans (323). Importantly, branching reduction results in T-cell hyperactivity and promotes spontaneous inflammatory demyelination and neurodegeneration in the MS animal model (176). N-glycan branching is positively regulated by the Golgi enzymes Mgat1 and/or Mgat5. Down-regulation of Mgat1 by (IVAVT?T) and vitamin D3, which optimizes branching and mitigates the risk of MS when combined with enhanced N-glycosylation of CTLA-4. Therefore, various genetic and environmental factors regulate a final common pathwayN-glycosylationwhich is highly relevant for MS pathogenesis. In addition, it has been shown that vitamin D directly stimulates the expression of Glc(1,4)Glc()] (114). Axo-glial proteins, such as neurofascin and contactin-2, are also important molecular targets in MS (114). Modification of self-molecule antigenicity as a consequence of redox changes in the CNS might be essential for the initiation of autoimmunity in MS pathogenesis, as discussed in detail in section II.J.1. Finally, microbes might be involved in the primal activation of encephalitogenic T cells. There are at least three mechanisms of activation of self-reactive T cells involving microbes: molecular mimicry, superantigens, and bystander activation. These Pranlukast (ONO 1078) are described in detail in Figure 3. Open in a separate window FIG. 3. The activation of autoreactive T cells by microbes. The examples of possible contribution of microbes to the activation of self-reactive T cells are presented. Molecular mimicry is a process in which T cells are activated with microbial antigen, but since its TCR also recognizes a certain autoantigen, the same T cell will be reactivated with this autoantigen. It is important to understand that when we say that TCR has a single specificity, it does not imply that it recognizes only one peptide. It is actually recognizing the physical, rather than chemical, structure of a Pranlukast (ONO 1078) peptide, lipid, or saccharide (88). Therefore, if there are two different peptides with a highly similar shape, TCR will not be able to tell them apart. Some examples of microbial and self-antigens relevant for MS that are recognized by the same TCR are given (EBV PolEpstein-Barr virus DNA polymerase). Superantigens are microbial products that activate many clones of T cells. A superantigen is not recognized by T Pranlukast (ONO 1078) cells in a classical way (enterotoxin E; SEB, enterotoxin B; V, variable region of chain of TCR. C.?The immune privilege of the central nervous system Although autoreactive T cells exist in the immune repertoire, they are no guarantee for the induction of immune response against the CNS components. It was shown, about 30 years earlier, that peripheral blood of healthy individuals contains T cells that are specific for myelin antigens (MBP) (63). Moreover, the frequency of myelin-reactive T cells in the blood of Mouse monoclonal to Histone 3.1. Histones are the structural scaffold for the organization of nuclear DNA into chromatin. Four core histones, H2A,H2B,H3 and H4 are the major components of nucleosome which is the primary building block of chromatin. The histone proteins play essential structural and functional roles in the transition between active and inactive chromatin states. Histone 3.1, an H3 variant that has thus far only been found in mammals, is replication dependent and is associated with tene activation and gene silencing. MS patients is not increased compared with that of healthy controls (44). Bearing in mind the incidence of MS, it is obvious that the activation of the autoreactive cells is more of an exemption than a rule. The base for the impediment of CNS-directed autoimmune reactivity lies in the fact that CNS is not an ordinary system in relation to the immune system, because it is immune privileged (Fig. 4). Open in a separate window FIG. 4. The elements of the CNS immune privilege. (A) VL, vessel lumen; EC, endothelial cells; EpC, epithelial cells of choroid plexus; EnC, ependymal cells; EBL, endothelial basal lamina; EpBL, epithelial basal lamina; VRS, Virchow-Robin space; PBL, parenchymal basal lamina; AEF, astrocytic end-feet; CSF, cerebrospinal fluid; P, parenchyma. TJ are essential elements of these barriers, and they are present among EC in BBB and among EpC in BCSFB. The EC of BCSFB form fenestrated walls, and they are not particularly important for the barrier function. In order to enter CNS parenchyma, immune cells have to pass EC, EBL and PBL of BBB or EC, EBL, EpBL, EpC, and EnC of BCSFB. (B) Afferent and efferent connections of a lymph node and the skin (as an example of a classical.