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SUMMARYMultiple sclerosis (MS) is a modern neuro-inflammatory and -degenerative disease, which is most prevalent in Northern Europe. Whilst it is known that inherited risk to MS is located within or within close proximity to immune genes it is unknown when, where and how this genetic risk originated. By using the largest ancient genome dataset from the Stone Age, along with new Medieval and post-Medieval genomes, we show that many of the genetic risk variants for MS rose to higher frequency among pastoralists located on the Pontic Steppe, and were brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the Steppe population, and later in Europe, likely driven by pathogenic challenges coinciding with dietary and lifestyle environmental changes. This study highlights the critical importance of this period as a determinant of modern immune responses and its subsequent impact on the risk of developing MS in a changing environment.

Expression of HLA-C varies widely across individuals in an allele-specific manner. This variation in expression can influence efficacy of the immune response, as shown for infectious and autoimmune diseases. MicroRNA binding partially influences differential HLA-C expression, but the additional contributing factors have remained undetermined. Here we use functional and structural analyses to demonstrate that HLA-C expression is modulated not just at the RNA level, but also at the protein level. Specifically, we show that variation in exons 2 and 3, which encode the α1/α2 domains, drives differential expression of HLA-C allomorphs at the cell surface by influencing the structure of the peptide-binding cleft and the diversity of peptides bound by the HLA-C molecules. Together with a phylogenetic analysis, these results highlight the diversity and long-term balancing selection of regulatory factors that modulate HLA-C expression., HLA-C expression levels correlate with immune responses to pathogens and autoimmunity, and vary in an allele-specific manner across individuals. Here the authors identify factors that drive differential expression of HLA-C allomorphs at the cell surface, and influence the structure of the peptide-binding cleft and diversity of peptides bound by HLA-C molecules.

Patients with Coeliac disease (CD) mount inflammatory T-cell responses to deamidated gluten peptides. Encounter of harmless protein via mucosal surfaces generally induces mucosal tolerance. Using animal models we have shown that oral tolerance to the harmless protein ovalbumin (OVA) depends on differentiation of regulatory T-cells (Treg) in the mucosa draining lymphoid tissue. How this translates to the uptake of gluten is difficult to predict as little is known with respect to localization and presentation of gluten after uptake via the gastrointestinal tract. The aim of this study was to identify the phenotype and localization of the gliadin specific T-cell response In Vivo. Mice transgenically expressing disease predisposing human HLA-DQ2 and human gliadin-specific TCR (CD-TCR) on an MHC-II-/background were used. CD-TCR+CD4+ T-cells from double transgenic mice were isolated and labelled with CFSE. After labelling, the cells were i.v. injected into HLA-DQ2tg x MHC-II-/mice. The acceptor mice received non-deamidated or deamidated chymotrypsin digested gliadin by gavage or deamidated gliadin in the thigh muscle (i.m.). After 72h the response of the gliadin-specific T-cells was analyzed in the gut-draining mesenteric lymph node (MLN), spleen and peripheral lymph nodes (PLN) and compared to the known tolerogenic T-cell response to OVA. At 72h after gavage T-cell response to non-deamidated gliadin was very low suggesting that during homeostasis gliadin is not deamidated by murine tissue transglutaminase. Conversely, a vigorous T-cell response was detected in MLN after gavage of deamidated gliadin. Unlike the response to harmless OVA, deamidated gliadin induced more proliferation in spleen than in MLN implying that the adaptive response to gliadin is not confined to the mucosa draining lymphoid tissue. Proliferating gliadin-specific T-cells in MLN contained minimal numbers of Foxp3+ Treg. By contrast, the cells phenotypically resembled activated T-cells and were comparable to differentiating effector T-cells in the PLN of mice that received deamidated gliadin i.m.. Culture of naive CD4+CD-TCR+ T-cells with HLADQ2+ APC in the presence of deamidated gliadin yielded phenotypically identical effector T-cells. Upon addition of factors that mediate mucosal Treg differentiation, Foxp3+CD4+CD-TCR+ T-cells did differentiate, indicating that the cells do have the intrinsic capacity to develop into adaptive mucosal Treg. Dissecting gliadin-specific T-cell responses in this novel murine system provides important opportunities to study the pathogenesis of CD, investigate efficacy of compounds and treatment strategies but also safety of novel dietary products.