{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T06:04:09Z","timestamp":1789365849107,"version":"build-2803163510"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CP22\/00022, CIBERFES; CB16\/10\/00475, PI21\/01069"],"award-info":[{"award-number":["CP22\/00022, CIBERFES; CB16\/10\/00475, PI21\/01069"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006393","name":"Universidad de Granada","doi-asserted-by":"publisher","award":["Programa 20"],"award-info":[{"award-number":["Programa 20"]}],"id":[{"id":"10.13039\/501100006393","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011011","name":"Junta de Andaluc\u00eda","doi-asserted-by":"publisher","award":["EXC-2023-06, C1-0001-2024"],"award-info":[{"award-number":["EXC-2023-06, C1-0001-2024"]}],"id":[{"id":"10.13039\/501100011011","id-type":"DOI","asserted-by":"publisher"}]}],"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>\n                      Hypophosphatasia (HPP) is a rare metabolic disorder caused by mutations in the\n                      <jats:italic>ALPL<\/jats:italic>\n                      gene leading to tissue-nonspecific alkaline phosphatase (TNSALP) deficiency. Although traditionally considered a skeletal disease, emerging evidence suggests an immunomodulatory role for TNSALP in systemic inflammation and immune-mediated inflammatory diseases (IMIDs). This study investigated clinical, biochemical, and immunological features associated with inflammation in HPP.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Forty-seven genetically confirmed HPP patients and 30 healthy controls with a comparable age and sex distribution were evaluated. Analyses included serum alkaline phosphatase (ALP), bone-specific ALP (BALP), C-reactive protein (CRP), fecal calprotectin (FCP), and flow cytometry in a subset of 29 HPP patients and 26 controls to assess leukocyte subpopulations and TNSALP expression, with confirmation by confocal microscopy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HPP patients exhibited reduced TNSALP expression in T cells, B cells, neutrophils, and monocytes, together with lower CD3 and CD8 fluorescence intensity and an increased CD16+\/CD14+ monocyte ratio. IMIDs were frequent in this referral cohort and were associated with lower ALP and higher FCP. Within the flow-cytometry subset, lower proportions of CD8+ cells within the CD3\u2212\/CD19\u2212 NK-enriched population and of TNSALP+ B cells were associated with IMID status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These cross-sectional findings identify an association between TNSALP deficiency and a coordinated immune-inflammatory phenotype in HPP. They support the biological plausibility of an immunomodulatory role for TNSALP but do not establish that TNSALP deficiency causes inflammation or the development of IMIDs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1906557","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:39:05Z","timestamp":1789364345000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tissue-nonspecific alkaline phosphatase deficiency is associated with altered immune cell profiles in hypophosphatasia"],"prefix":"10.3389","volume":"17","author":[{"given":"Luis","family":"Mart\u00ednez-Heredia","sequence":"first","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria de Granada (Ibs. 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