Metabolic alterations associated with immune dysfunction in lysinuric protein intolerance

Lysinuric protein intolerance (LPI) is a rare inherited metabolic disorder characterized by multisystem involvement, including failure to thrive, protein intolerance, hepatosplenomegaly, osteoporosis, pulmonary and renal disease, neurological impairment, and immune-dysregulation. Although immune-abnormalities are increasingly recognized in LPI, the immunological consequences of altered amino acid homeostasis remain incompletely understood. According to this, we aimed to characterize the immunologic-phenotype of patients with LPI. Patients with LPI and age-matched healthy controls were enrolled. Peripheral lymphocyte subsets, intracellular protein and cytokine expression, and lymphocyte-proliferative responses were assessed by flow cytometry. Serum immunoglobulin levels and amino acid profiles were analyzed using high-performance-liquid-chromatography. A total of 10 patients with LPI and 18 healthy-controls were included. Patients exhibited a combined immunological and metabolic phenotype characterized by reduced B-cell and class-switched memory B-cell compartments with IgG deficiency, together with impaired lymphocyte-proliferative responses despite preserved T-cell numbers. Cytokine profiling demonstrated decreased IL-17 and IL-4 responses, whereas IFN-γ production was relatively preserved. In parallel, stimulation-dependent alterations in amino acid profiles and disease-specific correlations between amino acids and immune-parameters suggested a direct link between disrupted amino acid homeostasis and immune dysfunction. Beyond quantitative immune defects, our findings reveal disease-specific metabolic signatures accompanying lymphocyte activation in LPI. Mitogenic stimulation induced coordinated amino acid changes in healthy controls, whereas this response was altered and accompanied by distinct metabolic changes, including increased citrulline levels. Overall, our findings indicate that lysinuric protein intolerance is associated with an immune phenotype characterized by humoral and cellular immune abnormalities accompanied by metabolic alterations. Together with previous studies describing innate immune dysfunction, these findings further support immune dysregulation as an important feature of LPI.