One of the major criticisms of the field of immunology is that the majority of information we have is based on mouse studies, and mouse studies in many times can represent what the scientist wants them to represent. For example, they say that if we were mice, cancer would have been cured decades ago!
This is why it is reassuring to see that ideas developed in the immunological world sometimes are correlated by independent fields of study. This happened recently with two publications that attracted international attention in the area of multiple sclerosis clinical genetics.
The first paper written by the Australia and New Zealand Multiple Sclerosis Genetics Consortium (Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nature Genetics 2009 Jun 14) assessed the whole genome of 1,618 patients with multiple sclerosis and used 3.413 healthy volunteers as controls in the first set of experimentation, and subsequently replicated it with 2,256 patients and 2,310 controls. They identified 2 unique chromosomal regions, one being very close to immune gene CD40 that is associated with multiple sclerosis. Additionally, they confirmed previous data that specific types of immunological genes such as HLA-DR15, IL2RA, and IL7R are associated with multiple sclerosis.
The second paper (De Jager et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nature Genetics 2009 Jun 14) looked at the genomes of 2,624 multiple sclerosis patients and 7,220 healthy controls. This was then replicated on an additional 2,215 multiple sclerosis patients and 2,116 healthy controls. They found specific variants (alleles) of the immunological genes TNFRSF1A, IRF8 and CD6. This seemed to be associated with increased interferon alpha signaling.
So what does all this mean?
In the first study, CD40 is a costimulatory molecule that is found on dendritic cells. It is important in activation of the T cell, but also in the ability of the T cell to send a reciprocal activation signal to the dendritic cell. So it would make sense that if CD40 activity is increased then people may have more susceptibility to multiple sclerosis. HLA molecules are the ones that present antigens to T cells. Various types of HLA-molecules have previously been demonstrated to associate with autoimmune diseases. IL-2 receptor alpha and IL-7 receptor are involved in activation of T cells. Yet again it would make sense that if multiple sclerosis is indeed an immunological disease that these genes may be affected.
In the second study the gene TNFRSF1A is a receptor for the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha). Abnormal responses to TNF may cause more inflammation than usual and therefore contribute to loss of “self tolerance”. IRF8 is a transcription factor that mediates the effects of interferon alpha. This cytokine is usually part of the body’s responses to viruses but plays many functions, including upregulating ability of cells to present antigens. This may be associated with cells in the central nervous system of multiple sclerosis patients activating T cell responses, cells such as macrophages and dendritic cells.
Of both papers, perhaps the most interesting is the finding that CD6 polymorphisms are associated with multiple sclerosis. CD6 is a receptor found on lymphocytes that can “sense” various innate danger signals. For example a publication (Sarrias et al. CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock. Proc Natl Acad Scien 2007 Jul 10;104(28):11724-9. Epub 2007 Jun 29) demonstrated that administration of artificial CD6 can protect mice from the lethal immune activation associated with sepsis. Given that few molecules have this potential, in our opinion, CD6 in the context of multiple sclerosis deserves further study.