Ruiz-Pablos, ManuelPaiva, BrunoZabaleta, Aintzane2026-03-162026-03-162025-12-04Ruiz-Pablos, M., Paiva, B., & Zabaleta, A. (2025). The origin of autoimmune diseases: Is there a role for ancestral HLA-II haplotypes in immune hyperactivity. Frontiers in Immunology, 16, 1710571. https://doi.org/10.3389/fimmu.2025.17105711664-322410.3389/fimmu.2025.1710571https://hdl.handle.net/20.500.14352/134027Funding The author(s) declare financial support was received for the research and/or publication of this article. This research was supported by The Solve ME/CFS Initiative under the RAMSAY GRANT PROGRAM 2019 and through donations for chronic fatigue syndrome research through the Helpify crowdfunding platform. Acknowledgments All Figures were created with BioRender.com.The prevalence of autoimmune diseases in contemporary human populations poses a challenge for both medicine and evolutionary biology. This review explores how the ancestral human leukocyte antigen class II (HLA-II) haplotypes DR2-DQ6, DR4-DQ8 and DR3-DQ2 could play a central role in susceptibility to these diseases. We propose that these haplotypes, selected in historical contexts of high infectious pressure, may have been maintained because of their ability to elicit strong T-cell responses against pathogens; however, that antigenic promiscuity may be associated with an increased tendency toward immune hyperreactivity in modern environments. This hyperreactivity, involving proinflammatory cytokines including interferon-gamma (IFN-γ), could contribute to the breakdown of tolerance and the emergence of autoimmunity and related clinical phenomena (e.g., Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome and post-vaccination syndromes), although the evidence for the latter remains limited. Finally, we discuss how chronic infections, immunotherapies, vaccination, obesity and chronic physical stressors may exacerbate this susceptibility and consider the therapeutic implications of integrating HLA-II profiling into clinical practice.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://doi.org/10.3389/fimmu.2025.1710571open access576.809.7:616-002AutoimmunityHla class IIDrb1Dqb1CytokinesImmune toleranceEvolutionary geneticsPathogen selectionInmunologíaGenética2412 Inmunología2407 Biología Celular2410.07 Genética Humana