{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:56:52Z","timestamp":1781585812977,"version":"3.54.5"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"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:p>\n                    The TYK2 P1104A variant has been cast as a textbook example of evolutionary compromise-protecting against autoimmunity whilst increasing susceptibility to tuberculosis (TB). This narrative has been invoked to explain its decline in frequency in European populations since the Bronze Age. However, accumulating evidence suggests that this widely accepted trade-off may be more complex than originally proposed. At the mechanistic level, P1104A reduces TYK2 catalytic activity without abolishing cytokine signalling, owing to compensatory, non-hierarchical JAK activation. Critically, IL-12-dependent interferon-\u03b3 responses, central to antimycobacterial immunity, remain largely preserved. By contrast, IL-23 signalling is selectively impaired, leading to attenuated Th17 responses, and type I interferon signalling is also dampened. Rather than necessarily compromising host defence, this configuration could influence TB outcome by limiting IL-17-driven neutrophilic pathology and by curbing type I IFN-mediated suppression of protective Th1 immunity. Consistent with this model, clinical use of IL-23 and IL-17 inhibitors has not resulted in a meaningful rise in TB reactivation, further challenging the assumption that these pathways are essential for protection against TB in humans. Together, these observations support a more nuanced interpretation than a simple evolutionary trade-off. Instead, TYK2 P1104A may fine-tune immune responses by uncoupling protective Th1 immunity from deleterious inflammation. An additional speculative possibility is that such an immune configuration may also have influenced responses to other pathogens, including pneumonic plague caused by\n                    <jats:italic>Yersinia pestis<\/jats:italic>\n                    . Although speculative, this perspective suggests that multiple infectious pressures -not TB alone- may have shaped the evolutionary trajectory of this variant.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1845279","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:28:02Z","timestamp":1781584082000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Rethinking TYK2 P1104A: a flawed evolutionary trade-off in tuberculosis?"],"prefix":"10.3389","volume":"17","author":[{"given":"Pere-Joan","family":"Cardona","sequence":"first","affiliation":[{"name":"Experimental Tuberculosis Unit (UTE), Institut de Recerca Germans Trias i Pujol (IGTP)","place":["Badalona, Spain"]},{"name":"Microbiology and Genetics Department, Universitat Aut\u00f2noma de Barcelona","place":["Bellaterra, Spain"]},{"name":"Servei de Microbiologia, Laboratori Cl\u00ednic de la Metropolitana Nord (LCMN), Hospital Universitari Germans Trias i Pujol (HUGTiP)","place":["Badalona, Spain"]},{"name":"Centre de Medicina Comparativa i Bioimatge de Catalunya (CMCiB)","place":["Badalona, Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Respiratorias (CIBERES)","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aau8714","article-title":"Tuberculosis and impaired IL-23\u2013dependent IFN-\u03b3 immunity in humans homozygous for a common TYK2 missense variant","volume":"3","author":"Boisson-Dupuis","year":"2018","journal-title":"Sci Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2009.41","article-title":"Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor","volume":"17","author":"Ban","year":"2009","journal-title":"Eur J Hum 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