To T or not to T

I have always wondered why the genomic experts in the field of MS haven’t been able to sort out why specific human leukocyte antigen (HLA) subtypes increase your risk of getting MS and others don’t.

HLA or human leukocyte antigens are the so-called signposting proteins that antigen presenting cells (APCs) use to communicate with T-cells. The APCs continuously sample the environment and present small peptides in their HLA molecules to T-cells. The HLA molecules interact with the so-called T-cell receptor (TCR) and if the peptide (message) that has been loaded in the HLA groove (signpost) and TCR, which acts as a molecular reader, fit perfectly it tells the T-cell that it should go on the attack. In the context of MS, this attack is considered to autoimmune or dysfunctional and against a self-peptide. However, the attack could be entirely appropriate and targeted against a foreign protein or a self-protein that has been altered by a process called post-translational modification. Interestingly, smoking and solvents, exposure to which are both risk factors for developing MS, are two environmental exposures that are known to cause post-translational modifications of proteins.

The following YouTube animation shows you an example of how a TCR (reader) interacts with a specific HLA molecule (signpost) and the peptide (message) in the groove of a specific HLA molecule. By watching this video you may appreciate how specific this interaction really is.

The most important genetic risk factor for deevloping MS is the so-called HLA-DRB1*15:01 molecules. If you have one copy of this gene your risk of getting MS is ~3X greater than someone without this gene. If you have two copies your risk of getting MS is about ~6X greater. In other words from a genetic perspective, you don’t want to have the HLA-DRB1*15:01 signposts.

It turns out that there, not all HLA-DRB1*15:01 molecules are made equal and that if you have the African variety, compared to the European variety, your risk of getting MS is 3x lower. Interestingly, the African and European varieties of the HLA-DRB1*15:01 genes differ in their sequence in a way that would affect the so-called peptide binding groove of the HLA molecule. This would mean that they would bind peptides differently and hence affect the way that T-cells may or may not be activated. How interesting?

The African variety of HLA-DRB1*15:01 is presumably older and the genetic change in HLA-DRB1*15:01 that is now known as the European variant must have been selected for after man left Africa and migrated into Europe. The most likely evolutionary selection pressure for this selection was repeated exposure to an infection, which selected for this variant, with the later consequence of being an increased risk of getting MS.

What is the significance of these findings? It is telling us that MS risk is related to a very specific HLA-DRB1*15:01 variant and this variant, by definition, must be interacting with a specific family of peptides or possibly a single peptide in our environment or body. Wouldn’t it be great if we could find this peptide or family of peptides? It could potentially lead us to the cause of MS.

It is important to realise that the HLA-DRB1*15:01 association with MS, and these new findings in relation to the African and European variants, is telling us that the T-cell must be the central player, or conductor, in the pathogenesis of MS and must be upstream of the B-cell. I have mulled over this for many years and I can’t think of another way of interpreting these results. Do you agree?

Chic et al. Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry. PLoS Genet. 2019 Jan 17;15(1):e1007808. doi: 10.1371/journal.pgen.1007808.

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.