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ICAM-1 expression has been shown to be elevated in many types of infections and inflammatory diseases. Strategies to block ICAM-1 function, including monoclonal anti-ICAM-1 antibodies, have been successful in treating the effects of chronic respiratory, autoimmune, and cardiovascular diseases. Naturally occurring autoantibodies targeting cytokines, endothelial cells, and other host receptors have been identified, and have been found to play a role in immunoregulation in health and disease. In this study, we determined the presence and levels of ICAM-1 autoantibodies across different age groups and disease states. We found that ICAM-1 autoantibody levels increased with age and were lower in individuals with various inflammatory states, suggesting a dynamic role in immune regulation. Using peptide microarrays, we identified high-resolution epitopes targeted by ICAM-1 autoantibodies that overlap with critical functional ICAM-1 binding sites. Finally, we determined that ICAM-1 autoantibodies were enriched for the IgG2 subclass that is critical for the response to bacterial antigens and chronic inflammation. This could indicate that molecular mimicry of bacterial antigens or underlying immune dysregulation could trigger the generation of anti-ICAM-1 antibodies. Understanding the functional implications of ICAM-1 autoantibodies could provide new insights into their contribution to immune homeostasis and their potential impact on inflammatory and autoimmune conditions.<\/jats:p>","DOI":"10.1093\/immhor\/vlaf025","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T08:49:03Z","timestamp":1750841343000},"source":"Crossref","is-referenced-by-count":2,"title":["ICAM-1 autoantibodies detected in healthy individuals and cross-react with functional epitopes"],"prefix":"10.1093","volume":"9","author":[{"given":"Marc L","family":"Herman","sequence":"first","affiliation":[{"name":"Genomic Medicine Center, Children\u2019s Mercy Research Institute , Kansas City, MO,","place":["United States"]},{"name":"University of Missouri\u2013Kansas City School of Medicine , Kansas City, MO,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric S","family":"Geanes","sequence":"additional","affiliation":[{"name":"Genomic Medicine Center, Children\u2019s Mercy Research Institute , Kansas City, MO,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"McLennan","sequence":"additional","affiliation":[{"name":"Genomic Medicine Center, Children\u2019s Mercy Research Institute , Kansas City, MO,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gage J","family":"Greening","sequence":"additional","affiliation":[{"name":"Genomic Medicine Center, Children\u2019s Mercy Research Institute , Kansas City, MO,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Mwitanti","sequence":"additional","affiliation":[{"name":"Genomic Medicine Center, Children\u2019s Mercy Research Institute , Kansas City, MO,","place":["United States"]},{"name":"College of Osteopathic Medicine, Kansas City 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