{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T04:05:20Z","timestamp":1793505920977,"version":"4.5.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"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>Background<\/jats:title>\n                    <jats:p>Transient low-dose methotrexate (MTX) induces long-term immune tolerance to enzyme replacement therapy (ERT) in Pompe disease; however, the underlying immunological mechanisms remain unclear. We hypothesized that TLD-MTX would reduce immune activation and induce a regulatory phenotype in patients with Infantile-Onset Pompe Disease (IOPD) and Late-Onset Pompe Disease (LOPD) treated with ERT.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We evaluated immune cell profile changes in patients treated with ERT+MTX using multiparameter flow cytometry on peripheral blood mononuclear cells collected at baseline and six months post-treatment. We analyzed 40 immune parameters in (1) thirteen unpaired samples from ERT+MTX-untreated (n=10) and -treated (n=3) IOPD patients and (2) six paired pre- and post-treatment samples from LOPD (n=6) patients. Linear regression analyses were used to assess correlations between immune parameters and disease activity measured by urinary glucose tetrasaccharide (Glc\n                      <jats:sub>4<\/jats:sub>\n                      ; a breakdown product of glycogen).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In IOPD, ERT+MTX-treated samples (median age: 12.3 months) showed reduced % CD16\n                      <jats:sup>+<\/jats:sup>\n                      monocytes and increased classical CD14\n                      <jats:sup>+<\/jats:sup>\n                      CD16\n                      <jats:sup>\u2212<\/jats:sup>\n                      monocytes, suggesting a shift toward a less activated immune profile. Untreated samples had higher % mature memory B cells and lower % plasmablasts, central memory CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, and TIGIT\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. In contrast, LOPD patients (median age: 51.5 years) exhibited decreased % B cells and increased % TIGIT\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells after treatment. Baseline Glc\n                      <jats:sub>4<\/jats:sub>\n                      levels were higher in IOPD than LOPD (42.5 vs. 7) and decreased in both groups following ERT+MTX. In untreated IOPD patients, Glc\n                      <jats:sub>4<\/jats:sub>\n                      levels positively correlated with CD16\n                      <jats:sup>+<\/jats:sup>\n                      monocytes, mature memory B cells, and terminally differentiated CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells; these associations were not observed after treatment. In LOPD, T follicular regulatory cells correlated with Glc\n                      <jats:sub>4<\/jats:sub>\n                      prior to treatment but not after, and no additional significant correlations were identified.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These findings demonstrate distinct immune profiles before and after ERT+MTX treatment in IOPD and LOPD patients. In IOPD, reduced pro-inflammatory monocytes and memory T cells provide evidence to suggest decreased immune activation. In LOPD, increased TIGIT\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells may reflect a regulatory mechanism contributing to immune tolerance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1843379","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:26:23Z","timestamp":1788495983000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Enzyme replacement therapy (ERT) combined with transient low-dose methotrexate (TLD-MTX) results in age- and disease-dependent immune profile changes in Infantile- vs. late-onset Pompe disease patients"],"prefix":"10.3389","volume":"17","author":[{"given":"Parisa","family":"Amirifar","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University Health System","place":["Durham, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankit K.","family":"Desai","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University Health System","place":["Durham, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Hye","family":"Jung","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University Health System","place":["Durham, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah P.","family":"Young","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University Health System","place":["Durham, NC, United States"]},{"name":"Biochemical Genetics Laboratory, Duke University Health System","place":["Durham, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. Brian","family":"Smith","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Duke University School of Medicine","place":["Durham, NC, United States"]},{"name":"Duke Clinical Research Institute","place":["Durham, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University Health System","place":["Durham, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bijan","family":"Abar","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University Health System","place":["Durham, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya S.","family":"Kishnani","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke 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