The multiple sclerosis exposome: environmental determinants, immunological convergence, and the Gulf Region as a natural test case.

Background: The multiple sclerosis (MS) exposome is widely invoked but rarely measured; grouping environmental exposures together obscures large differences in evidence quality. Much of the existing gene-environment evidence originates from genetically and environmentally homogeneous northern European cohorts, leaving open whether it generalizes elsewhere. The Gulf Cooperation Council (GCC) region is a largely untested candidate for such a test: ambient particulate concentrations there routinely exceed international guideline values, the dominant particulate sources and composition differ from those characterized in European studies, and the region's HLA-DRB1 allele distribution diverges substantially from the populations in which most gene-environment interaction evidence has been generated. Approach: This narrative review appraises exposure domains against six pre-specified criteria-design, exposure assessment, temporality, dose-response, confounding control, and gene-environment interaction-and reports effect estimates. Search strategy, selection criteria, and appraisal limitations are stated explicitly. Key findings: Inhalational exposures carry the most coherent signal. Pooled long-term particulate estimates are modest but consistent (PM Working model: Chemically diverse exposures converge toward a limited set of immunological nodes-aryl hydrocarbon receptor activation, short-chain fatty acid depletion, EBNA1/GlialCAM mimicry, and oxidative impairment of regulatory T cells-each conditioned by HLA-restricted susceptibility. Implications: We set out why the Gulf Cooperation Council region may be an informative setting for testing this model, which designs and immunological endpoints would test it, and what would falsify it.