The problem we all have - when experts such as Dr. Compston come forward with statements that the immune system is responsible for MS as shown by genetic evidence-is that most of us (including reporters) do not have the faintest understanding of genetics. So, we take these experts, and their opinions, at face value. Who's going to question Dr. Compston?
I've written many times, that the most confused I've ever been in my life, was listening to Dr. Ferlini explain her genetics study in people with MS and CCSVI at the Bologna conference. But this confusion made me dig a bit deeper, so I could understand the implications. And now, I'd like to share this with y'all. Because if we hope to counter the pharma sponsored "MS specialists" in the press and within the MS community, we need to learn their language. So, here goes. Genetics 101.
Genetics is the study of the genes. All living organisms have genes. Viruses and bacteria have genes. Genes are made up of molecules, and the pattern and sequence of the chains of these molecules makes up specific genes, which is how they are categorized and studied. Genes are inherited and make us who we are. Within genes, there can be variations, called "alleles." Alleles give us different traits, such as hair or eye color. They are a variaton or alternative form of a gene.
There is a special location, or "locus", in the human genetic system where the genes that create the immune system are found. This location is called a "super locus" because it is so large and variable in different ethnic groups. The locus for the human immune system is called "HLA" for Human Leukocyte Antigen.
This is the part of the immune system that decides whether or not to attack an outside invader.
Most of us have read about the HLA-DRB1 gene and alleles (or variations) of the gene in relationship with multiple sclerosis. Surely, this gene MUST be the real marker for MS? Right?? Actually, wrong. This gene shows up in 30% of the normal population and about 50% of those with MS. Not exactly a smoking gun.
Marie wrote up a wonderful note on the HLA types in MS, and I'm going to quote from it now, since we have the vocabulary straight, it might not seem as daunting. Deep breath. You are going to understand genetics.
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This is Marie-
MS is a gentic disease--or at least some people think it is.
Every cell has antigens--or 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 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.
from a recent study:
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.
http://www.ncbi.nlm.nih.gov/pubmed/19242548
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 half 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.
https://www.facebook.com/note.php?note_id=10150128129502211
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Now, I have Dr. Compston's new earth-shattering research, his Letter from Nature Magazine in front of me. It is titled,
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
The study population was drawn from European ancestry. Every single genetic study was done on a pwMS who had a northern European genetic background. Why is this important? Because we already know that 30% of all northern Europeans show the HLA genetic marker associated with MS.
and here is the earth shattering new discovery.....
Using this approach we found that DRB1*15:01 has the strongest association with multiple sclerosis among all classical and SNP alleles, with a consistent effect between cohorts (P , 1 3 102320; Fig. 4a). The data are consistent with an additive effect on the log-odds scale for each additional allele. Conditioning on DRB1*15:01, we confirmed the presence of a protective class I allele and identified the signal as being driven by HLA-A*02:01 (as previously suggested21), with a consistent effect size across cohorts (P 5 9.1 3 10223; Fig. 4a). Again, we found no strong evidence for departure from additivity on the log-odds scale or statistical interaction with DRB1*15:01.
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Here is some of the scientific press from this one paper...which was picked up all over the world--
“We now know just how complex multiple sclerosis is,” said Jonathan Haines, Ph.D., director of the CHGR and one of the principal researchers in this effort. “These new genes give us many new clues as to what is happening in MS and will guide our research efforts for years to come.”
Researchers studied the DNA from 9,772 individuals with multiple sclerosis and 17,376 unrelated healthy controls. (again, all were northern European)
They were able to confirm 23 previously known genetic associations and identified a further 29 new genetic variants (and an additional five that are strongly suspected) conferring susceptibility to the disease.
Many genes implicated in the study are relevant to the immune system, shedding light onto the immunological pathways that underlie the development of multiple sclerosis.
One-third of the genes identified in the study have previously been implicated in playing a role in other autoimmune diseases such as Crohn’s disease and type 1 diabetes, Haines said.
Previous studies have also suggested a link between vitamin D deficiency and an increased risk of multiple sclerosis; researchers in this study identified two genes involved in the metabolism of vitamin D, providing additional insight into a possible link between genetic and environmental risk factors.
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Yes, they did find new genes associated with MS, but the one with the strongest association was still good ole DRB1*15:01. And all of these genes are only found in half of those with MS.
The same, exact result...the same exact HLA locus as all the other research. The same genetic locus that is found within 30% of the general population of those with European ancestry.
Wow.
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Anyone want to guess what the HLA DRB locus is also being associated with?
Stroke in kids with sickle cell disease and cardiovascular disease in those with RA, due to inflammation.
I'd say that qualifies as a vascular connection.
In recent years, evidence for human leukocyte antigen (HLA)-linked susceptibility for stroke has been found for the class I HLA-B and class II HLA-DRB loci in children with SCD. Hoppe and her co-workers[58] used a candidate gene approach in patients screened with MRI as part of the US-based CSSCD. Dividing patients on the basis of the MRI findings into three groupsthose with normal imaging, those with infarction clearly involving the territories of the large vessels (with or without additional small-vessel involvement), and those with infarction not involving the territories of the large vessels (presumed small-vessel disease)the authors found that polymorphisms in specific HLA types and in genes involved in inflammation, cellular adhesion, blood pressure regulation and lipid metabolism were differentially associated with the two stroke phenotypes. Another group has demonstrated that large-vessel disease in SCD is related to variations in genes that code for factors involved in the responses to inflammation, hypoxia, adhesion and coagulation.
http://www.medscape.com/viewarticle/556304_5
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Cardiovascular (CV) disease is the most common cause of mortality in patients with rheumatoid arthritis (RA). We assessed the contribution of epidemiologic features, clinical features, routine laboratory markers of inflamma- tion, and HLA–DRB1 alleles to CV mortality in patients with RA prospectively followed at a single referral center in Spain. Methods. Patients fulfilling the 1987 American College of Rheumatology classification criteria for RA seen at the rheumatology outpatient clinic of Hospital Xeral-Calde, Lugo between March and September 1996 were included. HLA–DRB1 phenotype, epidemiologic data, and clinical data were assessed at that time. Patients were prospectively followed and clinical records were examined until patient’s death or September 1, 2005.
Patients with HLA–DRB1*04 shared epitope alleles (HR 4.15, P 0.030), in particular those HLA–DRB1*0404 positive (HR 6.65, P 0.002), had increased risk of CV mortality. Increased risk of CV events was also associated with CRP level (HR 1.09, P 0.001), ESR (HR 1.03, P 0.003), and HLA–DRB1*0404 (HR 4.47, P 0.002).
Conclusion. Our results suggest that a chronically high inflammatory response in genetically predisposed individuals promotes an increased risk of CV events and CV mortality in RA.
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How does Dr. Compston hope to stop research into the vascular paradigm of MS by telling the world he can prove MS is an autoimmune disease with genetics? He obviously is counting on the fact that people are threatened by the language and won't read his research. Because, if they do...they will see that the emperor has no genetic clothing.
Joan
