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Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by aberrant wound healing, immune dysregulation, heterogeneous trajectories, and poor prognosis. Only two antifibrotic agents,\n                      <jats:italic>nintedanib<\/jats:italic>\n                      and\n                      <jats:italic>pirfenidone<\/jats:italic>\n                      , are currently approved to slow disease progression, yet inter-individual variability in treatment benefit remains largely unexplained. In IPF, impaired NK-cell activity within the altered lung microenvironment may hinder removal of stressed or senescent cells, promoting fibrosis. The MHC-class I chain-related gene A (\n                      <jats:italic>MICA<\/jats:italic>\n                      ) encodes a stress-induced ligand of the NKG2D receptor on NK and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, crucial for immune surveillance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed clinical and genetic data from 129 Sardinian IPF patients genotyped for MICA and stratified by antifibrotic therapy (\n                      <jats:italic>nintedanib, pirfenidone<\/jats:italic>\n                      , no therapy, and switchers). Genotypes were assessed in relation to longitudinal lung function, overall survival (OS), and treatment-specific outcomes using multivariate Cox models adjusted for demographic and immunogenetic variables.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>MICA-129<\/jats:italic>\n                      genotype frequencies were comparable across treatment groups. In\n                      <jats:italic>nintedanib<\/jats:italic>\n                      -treated patients, the Val\/Val genotype was associated with significantly reduced 48-month OS versus Met\/Met and Met\/Val (p = 0.005). No statistically significant association was observed among pirfenidone-treated patients. After adjustment, Val\/Val remained an independent predictor of mortality in the\n                      <jats:italic>nintedanib<\/jats:italic>\n                      group (p = 0.01), irrespective of\n                      <jats:italic>HLA<\/jats:italic>\n                      background.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>MICA<\/jats:italic>\n                      -129 Val\/Val genotype may represent a candidate immunogenetic marker associated with poorer outcome in\n                      <jats:italic>nintedanib<\/jats:italic>\n                      -treated patients with IPF, underscoring the influence of immune-genetic context on antifibrotic response. Although subgroup sizes limit precision, the consistency and mechanistic plausibility of the association support integrating\n                      <jats:italic>MICA<\/jats:italic>\n                      genotyping into future randomized trials to refine personalized therapeutic strategies in IPF.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1722213","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T04:21:09Z","timestamp":1784521269000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MICA-129Met\/Val as a therapeutic compass in idiopathic pulmonary fibrosis: prognosis and antifibrotic benefit"],"prefix":"10.3389","volume":"17","author":[{"given":"Stefano","family":"Mocci","sequence":"first","affiliation":[{"name":"Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari","place":["Cagliari, Italy"]},{"name":"Centre for Research University Services (CeSAR, Centro Servizi di Ateneo per la Ricerca), University of Cagliari","place":["Cagliari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Mereu","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari","place":["Cagliari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Littera","sequence":"additional","affiliation":[{"name":"Medical Genetics, R. Binaghi Hospital","place":["Cagliari, Italy"]},{"name":"AART-ODV (Association for the Advancement of Research on Transplantation)","place":["Cagliari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Deidda","sequence":"additional","affiliation":[{"name":"Pneumology Unit, R. Binaghi Hospital","place":["Cagliari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Cannas","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari","place":["Cagliari, Italy"]},{"name":"Centre for Research University Services (CeSAR, Centro Servizi di Ateneo per la Ricerca), University of Cagliari","place":["Cagliari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Lorrai","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari","place":["Cagliari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Zedda","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari","place":["Cagliari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Murgia","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari","place":["Cagliari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste","family":"Sanna","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari","place":["Cagliari, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Giuressi","sequence":"additional","affiliation":[{"name":"Medical Genetics, R. 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