Immunogenetic traits of a heritable CD56+ cell population dysregulated in Multiple sclerosis: clinical utility and implications for pathogenesis

Multiple Sclerosis (MS) is a common neurological disease driven, in part, by an autoimmune response. Genes affecting susceptibility have been identified and indicate many immune cell subsets contribute to pathogenesis. Recent studies have identified that the proportion of some immune cell subsets in peripheral blood is highly heritable, such that environmental factors have limited effect on their relative populations in individuals over time. We recently identified that a population of CD56+ cells are underrepresented in MS from studies of multiple cohorts. In whole blood this dysregulation is tagged by expression of the MS genetic risk factors EOMES and TBX21. From transcriptomic studies a module of genes co-regulated with these two has been identified. This module was confirmed in independent cohorts from Sydney, Perth, and Adelaide in Australia; and Miami in USA; and the correlated gene set is present in controls and people with MS. MS risk factor genes are over-represented in the module genes. The downregulated genes in MS control cytolytic activity and immune cell trafficking. Expression of the module genes is tightly associated with Vitamin D activation, suggesting an interaction of these environmental and genetic risk factors which may be tractable to therapeutic intervention. MS therapies fingolimod and tysabri affect this cell population. The clinical utility of this phenotype is discussed.