Frontiers in immunology · 2026
Tissue-nonspecific alkaline phosphatase deficiency is associated with altered immune cell profiles in hypophosphatasia.
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Martínez-Heredia Luis, Muñoz-Torres Manuel, González-Cejudo Trinidad, López-Robles María Dolores, Cabeo Mónica, Carazo-Gallego Ángel, García-Recio Enrique, González-Salvatierra Sheila, Contreras-Bolívar Victoria, Andreo-López María Carmen, Iglesias-Baena Iván, Andújar-Vera Francisco, García-Fontana Cristina, García-Fontana Beatriz
Аннотация
BACKGROUND: Hypophosphatasia (HPP) is a rare metabolic disorder caused by mutations in the ALPL 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.
METHODS: 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.
RESULTS: 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-/CD19- NK-enriched population and of TNSALP+ B cells were associated with IMID status.
DISCUSSION: 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.
METHODS: 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.
RESULTS: 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-/CD19- NK-enriched population and of TNSALP+ B cells were associated with IMID status.
DISCUSSION: 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.