Susceptibility to multiple sclerosis implicates peripheral immune cells and microglia (via genome map studies)

Because these GEITP pages believe that multiple sclerosis (MS) represents a combination of genetic susceptibility and external signals, this falls within the theme of gene-environment interactions. Over the past decade, elements of the genetic architecture (i.e. the underlying genetic basis of a phenotypic trait and all properties that cause its variability in each individual) of MS susceptibility have gradually emerged from genome-wide association studies (GWAS) and targeted studies.

The role of the adaptive arm of the immune system — especially its CD4+ T-cell component — has become clearer, with multiple different T-cell subsets being implicated. Although the T-cell component plays an important role, functional and epigenomic annotation studies have begun to suggest that other elements of the immune system may be involved as well. Authors [see attached article] assembled available genome-wide MS data, in order to perform a meta-analysis (data examination from numerous independent studies of the same topic, and then trying to determine overall trends) — followed by a systematic, comprehensive replication effort in large independent sets of subjects. This effort yielded a detailed genome-wide genetic map that includes the first successful evaluation of the X chromosome in MS and provides a powerful platform for creating a detailed genomic map, outlining the functional consequences of most variants and their assembly into susceptibility networks.

Authors [see attached article] analyzed genetic data from 47,429 MS and 68,374 control (non-MS) subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal (pertaining to all chromosomes other than the X and Y chromosome) susceptibility variants — outside the major histocompatibility complex (MHC; the set of genes that encode cell surface proteins essential for the acquired immune system to recognize foreign molecules in vertebrates; this determines donor-recipient histocompatibility), one chromosome X variant, and 32 variants within the extended MHC region (located on human chromosome 6). Authors used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate (defense mechanisms that are activated within minutes/hours of an antigen’s appearance in the body) and adaptive (also known as ‘acquired immune system’, this is a subsystem of the overall immune system comprised of highly specialized, systemic cells and processes that eliminate pathogens, or prevent their growth) pathways distributed across the cellular components of the immune system.

Using expression profiles from purified human microglia (brain cells derived from mesoderm that function as macrophages (scavengers) in the central nervous system), authors observed enrichment for MS genes in these brain-resident immune cells — suggesting that these MS genes might have a role in targeting a specific autoimmune process to the central nervous system (CNS), although MS is most likely initially triggered by perturbation of peripheral immune responses. ☹



· Science Sept 2019; 365: 1417-1424

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