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Background and Objectives: HLA-DRB1*15:01 (DR15) and MERTK are 2 risk genes for multiple sclerosis (MS). The variant rs7422195 is an expression quantitative trait locus for MERTK in CD14 + monocytes; cells with phagocytic and immunomodulatory potential. We aimed to understand how drivers of disease risk and pathogenesis vary with HLA and MERTK genotype and disease activity., Methods: We investigated how proportions of monocytes vary with HLA and MERTK genotype and disease activity in MS. CD14 + monocytes were isolated from patients with MS at relapse (n = 40) and 3 months later (n = 23). Healthy controls (HCs) underwent 2 blood collections 3 months apart. Immunophenotypic profiling of monocytes was performed by flow cytometry. Methylation of 35 CpG sites within and near the MERTK gene was assessed in whole blood samples of individuals experiencing their first episode of clinical CNS demyelination (n = 204) and matched HCs (n = 345) using an Illumina EPIC array., Results: DR15-positive patients had lower proportions of CD14 + MERTK+ monocytes than DR15-negative patients, independent of genotype at the MERTK SNP rs7422195. Proportions of CD14 + MERTK+ monocytes were further reduced during relapse in DR15-positive but not DR15-negative patients. Patients homozygous for the major G allele at rs7422195 exhibited higher proportions of CD14 + MERTK+ monocytes at both relapse and remission compared with controls. We observed that increased methylation of the MERTK gene was significantly associated with the presence of DR15., Discussion: DR15 and MERTK genotype independently influence proportions of CD14 + MERTK+ monocytes in MS. We confirmed previous observations that the MERTK risk SNP rs7422195 is associated with altered MERTK expression in monocytes. We identified that expression of MERTK is stratified by disease in people homozygous for the major G allele of rs7422195. The finding that the proportion of CD14 + MERTK+ monocytes is reduced in DR15-positive individuals supports prior data identifying genetic links between these 2 loci in influencing MS risk. DR15 genotype-dependent alterations in methylation of the MERTK gene provides a molecular link between these loci and identifies a potential mechanism by which MERTK expression is influenced by DR15. This links DR15 haplotype to MS susceptibility beyond direct influence on antigen presentation and suggests the need for HLA-based stratification of approaches to MERTK as a therapeutic target.

Myelination within the central nervous system (CNS) is crucial for the conduction of action potentials by neurons. Variation in compact myelin morphology and the structure of the paranode are hypothesised to have significant impact on the speed of action potentials. There are, however, limited experimental data investigating the impact of changes in myelin structure upon conductivity in the central nervous system. We have used a genetic model in which myelin thickness is reduced to investigate the effect of myelin alterations upon action potential velocity. A detailed examination of the myelin ultrastructure of mice in which the receptor tyrosine kinase Tyro3 has been deleted showed that, in addition to thinner myelin, these mice have significantly disrupted paranodes. Despite these alterations to myelin and paranodal structure, we did not identify a reduction in conductivity in either the corpus callosum or the optic nerve. Exploration of these results using a mathematical model of neuronal conductivity predicts that the absence of Tyro3 would lead to reduced conductivity in single fibres, but would not affect the compound action potential of multiple myelinated neurons as seen in neuronal tracts. Our data highlight the importance of experimental assessment of conductivity and suggests that simple assessment of structural changes to myelin is a poor predictor of neural functional outcomes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)