REVIEW article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
The origin of autoimmune diseases: is there a role for ancestral HLA-II haplotypes in immune hyperactivity?
Provisionally accepted
- 1Complutense University of Madrid, Madrid, Spain
- 2Clinica Universidad de Navarra Centro de Investigacion Medica Aplicada, Pamplona, Spain
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
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.
Keywords: Autoimmunity, HLA class II, DRB1, DQB1, Cytokines, Immune Tolerance, evolutionary genetics, Pathogen selection
Received: 22 Sep 2025; Accepted: 17 Nov 2025.
Copyright: © 2025 Ruiz-Pablos, Paiva and Zabaleta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Manuel Ruiz-Pablos, manruipa@gmail.com
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.