Tissue-nonspecific alkaline phosphatase deficiency is associated with altered immune cell profiles in hypophosphatasia

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.