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Why these neurons are particularly vulnerable in ALS remains\u00a0unclear, as does why certain MN groups\u00a0remain resistant\u00a0throughout the disease course. We investigated the role\u00a0of the human leukocyte antigens (HLAs) and beta2-microglobulin (\u03b22m) in MN susceptibility to ALS, given their reported involvement in\u00a0both prolonging and shortening disease\u00a0progression. Loss of HLAs in ALS has also been\u00a0shown to increase MNs vulnerability to toxicity exerted by activated astrocytes. RNA\u00a0sequencing of control tissues\u00a0demonstrated that disease-resistant oculomotor neurons (OMNs) and Onuf\u2019s MNs exhibited\n                    <jats:italic>\u03b22m<\/jats:italic>\n                    and\n                    <jats:italic>HLA<\/jats:italic>\n                    mRNA levels comparable\u00a0to those of\u00a0vulnerable spinal MNs, suggesting that\u00a0baseline differences in these transcripts do not explain the differential vulnerabilities\u00a0of\u00a0these MN groups. However, HLA protein levels showed an inverse correlation with spinal MN size, with the large MNs, those lost early in ALS, displaying the\u00a0lowest HLA expression. HLA protein levels were also reduced in spinal MNs from\u00a0end-stage ALS patient\u00a0tissues, while remaining relatively\u00a0unchanged in OMNs. In contrast, spinal MNs uniquely exhibited significant upregulation of\n                    <jats:italic>\u03b22m<\/jats:italic>\n                    and\n                    <jats:italic>HLA-C<\/jats:italic>\n                    transcripts during disease, likely reflecting a protective compensatory response. Together,\u00a0these findings suggest that \u03b22m and HLAs may contribute to spinal MN\u00a0vulnerability in ALS. To assess their functional role, \u03b22m\u00a0knockout mice were crossbred\u00a0with SOD1G93A ALS mice. Loss of \u03b22m\u00a0did not alter life span\u00a0of the ALS mice, but led to\u00a0partial preservation of lumbrical muscle\u00a0innervation that\u00a0was insufficient to maintain motor function. Analysis of GFAP immunoreactivity revealed marked neuroinflammation activation\u00a0in the\u00a0spinal cords of \u03b22m knockout mice. As these mice retain normal MN numbers\u00a0and life-span, this indicates that loss of functional MHC-I, even in the presence of\u00a0astrocyte activation, is insufficient to cause MN disease. Furthermore, \u03b22m knockout significantly increased GFAP activation in SOD1G93A mice, but did not further exacerbate disease progression, suggesting\u00a0that loss of functional MHC-I does not necessarily render MNs more vulnerable to\u00a0astrocyte toxicity. Overall,\u00a0these findings indicate that \u03b22m and HLAs are dynamically regulated in ALS, and may influence MN vulnerability, but they are not major disease\u00a0modifiers in ALS.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03024-3","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T10:06:48Z","timestamp":1780049208000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reevaluating the role of beta2-microglobulin: new insights on selective vulnerability in ALS pathology"],"prefix":"10.1007","volume":"151","author":[{"given":"Melanie","family":"Leboeuf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jik","family":"Nijssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Helen","family":"Comley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio Cesar","family":"Aguila Benitez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"G\u00f3mez Alcalde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram\u00f3n A.","family":"Mu\u00f1oz de Bustillo-Alfaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vlad","family":"Radoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Nichterwitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Schweingruber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abraham","family":"Acevedo Arozena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Hedlund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Staffan","family":"Cullheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"3024_CR1","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1038\/nri3084","volume":"11","author":"J Neefjes","year":"2011","unstructured":"Neefjes J, Jongsma MLM, Paul P, Bakke O (2011) Towards a systems understanding of MHC class I and MHC class II antigen presentation. 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