{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:53:52Z","timestamp":1791262432317,"version":"4.1.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"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:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Fabry disease (FD) is an X-linked lysosomal storage disorder in which chronic inflammation contributes to disease progression beyond substrate accumulation. Although nuclear factor kappa B (NF-\u03baB) signaling has been implicated in FD pathogenesis, the contribution of alternative NF-\u03baB splicing to immune-inflammatory remodeling remains unknown. Here, we investigated the recently identified NF-\u03baB p65 iso5 splice variants p65 iso5 \u03946\/7 and p65 iso5 \u039410 in FD and in individuals carrying GLA variants of uncertain significance (GVUS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We characterized p65 iso5 \u03946\/7 and p65 iso5 \u039410 in peripheral blood mononuclear cells from 103 patients with FD, including classic and late-onset phenotypes, 30 GVUS subjects, and 30 healthy controls. Isoform expression was assessed at the mRNA and protein levels, and circulating inflammatory mediators were evaluated in selected groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Both isoforms were constitutively expressed under physiological conditions and were significantly upregulated at the mRNA level in FD, whereas p65 iso5 \u03946\/7 was also increased at the protein level. A similar expression profile was observed in GVUS subjects despite preserved \u03b1-galactosidase A activity and normal Lyso-Gb3 levels. In carriers of the p.Ala143Thr (A143T) variant, increased isoform expression was associated with enhanced expression of pro-inflammatory cytokines and elevated circulating inflammatory mediators.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Together with the previously reported downregulation of p65 iso5, these findings indicate that selective NF-\u03baB splice variant redistribution, rather than uniform pathway activation, characterizes immune-inflammatory remodeling in FD. Altered p65 isoforms expression may contribute to immune dysregulation and clinical heterogeneity in FD and\n                      <jats:italic>GLA<\/jats:italic>\n                      variants of uncertain significance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1922658","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:25:13Z","timestamp":1791260713000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["NF-\u03baB p65 iso5 \u03946\/7 and p65 iso5 \u039410 isoforms drive immune-inflammatory remodeling in Fabry disease and GLA variants of uncertain significance"],"prefix":"10.3389","volume":"17","author":[{"given":"Giuseppa","family":"Biddeci","sequence":"first","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (CNR-IRIB)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Colomba","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (CNR-IRIB)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Spinelli","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (CNR-IRIB)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monia","family":"Anania","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (CNR-IRIB)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Giacalone","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (CNR-IRIB)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Duro","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (CNR-IRIB)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita Stefania","family":"Rodolico","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council (CNR-IRIB), Section of Catania","place":["Catania, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso Silvano","family":"Aronica","sequence":"additional","affiliation":[{"name":"Complex Operative Unit of Clinical Pathology, Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico Di Cristina e Benfratelli Hospitals","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Di Blasi","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Research and Innovation, National Research Council of Italy (CNR-IRIB)","place":["Palermo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.221739","article-title":"Lysosomal storage disorders - challenges, concepts and avenues for therapy: beyond rare diseases","volume":"132","author":"Marques","year":"2019","journal-title":"J Cell Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjms.2020.07.011","article-title":"When and how to diagnose Fabry disease in clinical pratice","volume":"360","author":"Michaud","year":"2020","journal-title":"Am J Med 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