This is Marie-
MS is a gentic disease--or at least some people think it is.
We may wonder how strong is this genetic component to MS and what might it mean for CCSVI?
BACKGROUND: Every cell has antigens--proteins--on the outside of them that are unique to that cell. In a individual immune system there is tolerance of one's own antigens. The cell that wears a self antigen is ignored.
The name of the receptor on the outside of cells which holds this antigen is the MHC (major histocompatibility complex) type I. In humans it is called the HLA (human leukocyte antigen). The immune system cells in the body are the ones that inspect the antigens in the MHC receptor on the outside of other cells and then decide if that cell is an OK cell that belongs in the body--or a foreigner to be attacked and removed with immune activity.
When an immune cell identifies a foreign antigen it takes some of that cell's protein and puts it in a receptor on on its own (immune cell) surface called an MHC type II receptor. When other immune system cells, like T cells, see a foreign antigen in a MHC/HLA type II receptor, then become targeted against that protein as presented.
The common wisdom is that MS is a genetic disease and this has its basis in the fact that some research shows that MS patients have a certain kind of HLA type: HLA DRB1-1501. The idea is that because these immune system components are key to antigen recognition, the fact that more people with MS have this genotype suggests that this type is prone to genetically triggered autoimmunity.
Here are some studies related to HLA types:
In this study ( http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038867/pdf/pone.0016802.pdf ) they tested people in the BNAC CCSVI study for HLA types. The MS patients had this HLA type 51.9% of the time---normals had it 31.6% of the time. In this study there were seemingly normals with CCSVI and the HLA type was not the deciding factor as to who had CCSVI. The conclusions of this group was that since the HLA was not strongly correlated with CCSVI, the relevence of CCSVI to MS should be cautiously interpreted. The reason for this caution is that the HLA factor is widely considered to be a important clue in MS because people with MS more often have this genotype. This is an association of this HLA type to ms....
But is HLA always present in MS? the answer is no, as the study above shows only about half had it. The other half didn't, but they still had MS.
Here's another perspective on the HLA issues
quote:
CONCLUSIONS: The model suggests that combinations of only a small number of genetic loci in a "susceptible allelic state" produce MS-susceptibility. Nevertheless, genome-wide associations studies with hundreds of thousands of SNPs, are plagued by both false-positive and false-negative identifications and, consequently, emphasis has been rightly placed on the replicability of findings. Nevertheless, because genome-wide screens don't distinguish between true susceptibility-loci and disease-modifying-loci, and because only true susceptibility-loci are constrained by the model, unraveling the two will not be possible using this approach.The model also suggests that HLA DRB1 may not be as uniquely important for MS-susceptibility as currently believed. Thus, this allele is only one among a hundred or more loci involved in MS susceptibility. Even though the "frequency of susceptibility" at the HLA DRB1 locus is four-fold that of other loci, the penetrance of those susceptible genotypes that include this allele is no different from those that don't. Also, almost 50% of genetically-susceptible individuals, lack this allele. Moreover, of those who have it, only a small fraction (= 5.2%) are even susceptible to getting MS.
found here:http://www.ncbi.nlm.nih.gov/pubmed/21029420
These guys are saying there are many other genetic loci (locations on the genome) that seem to add risk for MS including many alleles (which are little parts of DNA not whole genes). They also say that some of these genes probably have something to do with disease modification and not susceptibility and these can't be untangled simply by looking for them in people with MS. They suggest that the HLA factors are only part of the story and that we do not understand this genetic issue in MS well yet.
There are many studies on the HLA types in MS patients. Here's another one:
Thus, despite HLA DRB1*1501 being the most consistently identified genetic marker of MS-susceptibility (being present in over 50% of northern MS patient populations), only about 1% of individuals with this allele are even genetically susceptible to getting MS. Moreover, because genetic susceptibility seems so similar throughout North America and Europe, environmental differences principally determine the regional variations in disease characteristics. Additionally, despite 75% of MS-patients being women, men are 60% more likely to be genetically-susceptible than women. Also, men develop MS at lower levels of environmental exposure than women. Nevertheless, women are more responsive to the recent changes in environmental-exposure (whatever these have been). This explains both the changing sex-ratio and the increasing disease prevalence (which has increased by a minimum of 32% in Canada over the past 35 years). As noted, environmental risk seems to result from three sequential components of environmental exposure. The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future.
found here:http://www.ncbi.nlm.nih.gov/pubmed/19242548
This one says that HLA types are part of a multi-pronged issue. Only 50% with MS have this HLA type, but if you are a guy with MS then you are 60% likely to have this genotype, so a little more relevence there. They aren't sure what the environmental issues are (viruses or bacteria or vitamin D or whatever) but they think these intereact with the genetic type in some poeple.
Overall the HLA issue is considered part of the current autommune story: there is an assumption that since this HLA type is more common in MS, about 50% compared to 30% in normals, and it is the gene that codes the immune system's part that recognizes what to attack, this type must somehow be more likely to make mistakes than other genetic HLA types. However since HLA DRB1 is only present in hakf of MS patients and is present in many healthy people, it is assumed that it must be only part of the MS story and a certain environmental factor must also be needed for MS to be triggered. That's the idea.
In terms of venous issues Ferlini et al (fondazionehilarescere) did a paper in which they noticed that in 15 people with MS and CCSVI there were more copy number variations areas that had to do with angiogenesis (blood vessel creation) and immune function in this same area of the genome that is the above related HLA area.
Quote:
"Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region"
There is more work to be done but we can ask ourselves if we think this HLA issue is a deal breaker for CCSVI. In my thinking it doesn't seem that it is to me. I am not super impressed with the idea that 30% of the normal population has this genotype and do not have MS (that is a LOT of people the vast majority of which probably had EBV at some point had low vitamin d at some point etc.), and what do you say to the person who doesn''t have that gene and does have MS? you don't have autoimmune MS? Yours is different ? what does it mean?
the dogmatic assertion that MS is a genetically determined autoimmune disease is a bit of a leap in my mind. The association with HLA DRB1 is there but it is not a black and white thing and there are a whole lot of gentic codes in that area of the genome. The idea that some of these have to do with blood vessel creation is intrguing. I look forwad to more research with anticipation--it is like a mystery novel that is going on right now!
--marie
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