{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:03:55Z","timestamp":1791198235971,"version":"4.1.0"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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\u2013environment 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\u2019s HLA-DRB1 allele distribution diverges substantially from the populations in which most gene\u2013environment interaction evidence has been generated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach<\/jats:title>\n                    <jats:p>This narrative review appraises exposure domains against six pre-specified criteria\u2014design, exposure assessment, temporality, dose\u2013response, confounding control, and gene\u2013environment interaction\u2014and reports effect estimates. Search strategy, selection criteria, and appraisal limitations are stated explicitly.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key findings<\/jats:title>\n                    <jats:p>\n                      Inhalational exposures carry the most coherent signal. Pooled long-term particulate estimates are modest but consistent (PM\n                      <jats:sub>2.5<\/jats:sub>\n                      HR 1.21, 95% CI 1.07\u20131.38); combustion-related NO\n                      <jats:italic>\n                        <jats:sub>x<\/jats:sub>\n                      <\/jats:italic>\n                      shows dose dependence and interaction with HLA-DRB1*15:01; organic solvents and industrial dust show similar HLA-restricted interaction patterns. Two discordances temper this: the two largest prospective cohorts were null, and Mendelian randomization does not support a causal effect of smoking. Much of the interaction evidence derives from related Swedish datasets and is not independently replicated. Heavy metals rest on cross-sectional biomonitoring vulnerable to reverse causation; persistent organic pollutants contribute a mixture-level signal. Contemporary evidence does not support a Gulf-War-attributable increase in MS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Working model<\/jats:title>\n                    <jats:p>Chemically diverse exposures converge toward a limited set of immunological nodes\u2014aryl hydrocarbon receptor activation, short-chain fatty acid depletion, EBNA1\/GlialCAM mimicry, and oxidative impairment of regulatory T cells\u2014each conditioned by HLA-restricted susceptibility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Implications<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  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