These articles [Chaudhuri, 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15617877); Behan et al., 2002: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=Behan+Chaudhuri+Roep+%22THE+PATHOGENESIS+OF+MULTIPLE+SCLEROSIS+REVISITED%22); VanAmerongen et al., 2004: (http://www.direct-ms.org/pdf/VitDMS/VanAmerongenVitDMSreview.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/15054436); Cepok et al., 2005: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1077174)(http://www.ncbi.nlm.nih.gov/pubmed/15841210); Diesel et al., 2005: (http://clincancerres.aacrjournals.org/cgi/content/full/11/15/5370)(http://www.ncbi.nlm.nih.gov/pubmed/16061850); Sanders et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8799216); Prokova et al., 2002: (http://www.jbc.org/cgi/content/full/277/11/9342)(http://www.ncbi.nlm.nih.gov/pubmed/11781310?dopt=Abstract); Koch et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/17050217)] are really good, and Chaudhuri (2005) suggests that vitamin D repletion during brain development may protect against abnormal astrocyte apoptosis later in life and thereby confer protection against multiple sclerosis. This is interesting and is similar to the vitamin D hypothesis of schizophrenia [McGrath and colleagues: (http://scholar.google.com/scholar?q=%22vitamin+D%22+schizophrenia&hl=en&lr=)], in the sense that there's this concept of vitamin D deficiency, during development, creating abnormalities in brain development that do not manifest themselves until relatively later in life than one might expect them to. For example, vitamin D depletion during brain development drastically decreases the expression and protein content of the low-affinity neurotrophin receptor (p75NTR), which binds all of the neurotrophins and plays crucial roles in the regulation of not only apoptosis or protection against apoptosis, by NGF and other neurotrophins (NT-3, NT-4, BDNF, etc.), but in the trophic effects of NGF in the adult brain.
Holmoy (2008) suggested that vitamin D repletion could protect against brain damage due to late Epstein-Barr Virus (EBV) infection (i.e. after early childhood, when infection is often asymptomatic or less destructive to the brain), which tends to produce an expansion of autoreactive T-cell populations [Holmoy, 2008: (http://www.ncbi.nlm.nih.gov/pubmed/17574770)]. There's actually research showing that EBV can infect astrocytes [Menet et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10438862)] and monocytes and other cells of the monocyte-macrophage lineage [Savard et al., 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10684275); (http://scholar.google.com/scholar?num=100&hl=en&lr=&cites=16392233215499070431)], which means that EBV may very well infect microglia and perivascular macrophages, etc. There still seems to be a popular sentiment that EBV only infects B-cells and epithelial cells, but there is overwhelming evidence that this is not the case and that EBV infects cells in the brain en masse during infectious mononucleosis (the term mononucleosis refers to the characteristic finding of monouclear phagocyte, or monocyte, infiltration of tissues infected by EBV; most cases of infectious mono are the result of primary EBV infection, although some can be from primary CMV infection or EBV infection that causes polyclonal, EBV-infected B-cells to start producing anti-CMV IgM and make it look like a person who had previously been infected with CMV has a primary CMV infection). I don't feel like going through papers and discussing them, but here are some hastily-done searches showing vast numbers of articles on the subject (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=mononucleosis+brain+OR+encephalitis+OR+encephalopathy+OR+meningitis+OR+meningeoencephalitis); (http://scholar.google.com/scholar?q=mononucleosis++brain+OR+encephalitis+OR+encephalopathy+OR+meningitis+OR+meningeoencephalitis&num=100&hl=en&lr=&scoring=r&as_ylo=2004)]. The pro-inflammatory response during infectious mono is massive, and the notion that the blood-brain barrier would be impermeable to infiltration by EBV-infected, polyclonal B-cells is not reasonable. Also, an important distinguishing feature of infectious mono is enlargement or lymphadenopathy in the posterior cervical lymph nodes that provide lymphatic drainage to the brain, producing a stiff neck, etc. The oligoclonal IgG antibodies in the CSF of people with multiple sclerosis have repeatedly been shown to bind EBV proteins (Cepok et al., 2005), and Cepok et al. (2005) go into all the research showing that type of thing. It's possible that the immune response is being directed against other latently-infected B-cells, etc., but the evidence is pretty substatial that late EBV infection plays some role in the etiology of multiple sclerosis, in my opinion. To think that astrocytes and probably microglia and other cell types in the central nervous system would be spared infection makes no sense to me. So it probably occurs in many or most people who are infected with EBV (90-95 percent of the US population, by age 26-27), and one might look for some differences in the degree of ongoing damage or in the pattern of gene expression by EBV (i.e. the latency pattern) in astrocytes or microglia, etc. (discussed below) of people who go on to develop multiple sclerosis, in comparison to controls.
Behan et al. (2002) discuss a lot of evidence that inappropriate astrocytic cell-cycle re-entry plays a prominent role in the etiology of multiple sclerosis, and the authors, one of whom is Chaudhuri (see Chaudhuri, 2005), also discuss the association of multiple sclerosis with glioblastoma multiforme and with rare, diffuse forms of gliomas, etc. That article is superb and is really brilliant, and yet it's not even indexed in Medline. The fact that vitamin D analogs have been used to treat glioblastoma multiforme is interesting, and the effects of vitamin D receptor (VDR) ligands, including calcitriol itself, on the astrocytic cell cycle could suggest that they could protect against astrocytic cell cycle re-entry and apoptosis in people with multiple sclerosis. I tend to think they wouldn't be all that effective in that regard and that the focus of Chaudhuri (2005) on the developing brain makes more sense. But the focus on astrocytes (Chaudhuri, 2005; Behan et al., 2005) is really intriguing, and it suggests to me that other measures might protect against abnormal astrocyte proliferation and apoptosis (i.e. guanosine and other intravenously-administered purine nucleotides or those in combination with energy substrates, etc.). That's just my opinion. It's interesting that VDR activation leads to very complex interactions with the transforming growth factor-beta signalling cascade, such as by forming heterodimers with Smad3 and potentiating many Smad3-induced transcriptional changes (VanAmerongen et al., 2004), and that the EBV latent membrane protein-1 suppresses Smad3-dependent transcriptional changes (Prokova et al., 2002). Smad3 is phosphorylated by type I TGFbeta receptors and is thereby activated as a transcription factor. Smad3 interacts with many proteins, but the suppression by LMP1 of the TGFbeta-induced and Smad3-mediated increase in p21WAF1/Cip1 expression (Prokova et al., 2002) is a relatively specific intersection with the transcriptional program that tends to be induced by VDR activation. The p21WAF1/Cip1 gene is a major cell-cycle-regulatory gene whose expression is responsive to and increased by VDR activation. The gene product allows for enhanced DNA repair before cell division, etc., and contributes to the antiproliferative and differentiating effects of VDR activation. That's just one example, but it lends credence to the hypothesis of Holmoy (2008) and suggests that the interactions of VDR-ligand-induced transcriptional changes with EBV-induced transcriptional changes may be relatively direct and may go beyond the realm of VDR-ligand-induced increases in interleukin-10 output from monocytes, etc. It might be possible to look for the effects of vitamin D or its analogs on EBV-infected, cultured monocytes or astrocytes or to look for associations of 25-hydroxyvitamin D levels with the incidences of glioblastoma among patients with multiple sclerosis? That sounds pretty difficult. There are some recent articles discussing all the problems with detecting herpesviruses in the brain during autopsies. Serafini et al. (2007) [Serafini et al., 2007: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2118531)(http://www.ncbi.nlm.nih.gov/pubmed/17984305)] found that cells in perivascular regions of the brains of people with multiple sclerosis were immunoreactive for LMP1 and other latency-associated EBV proteins, and it doesn't sound like that can be casually attributed to infiltrating, EBV-infected B-cells, etc. Someone could look for an association between 25-hydroxyvitamin D levels at death and the latency pattern of EBV infection in the brains of people with MS (or just look for different latency patterns in people with MS). I'm just thinking out loud with this.
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