Identification of alterations of immunometabolism associated with Pompe disease

Pompe disease (PD) is a neuromuscular lysosomal storage disorder caused by mutations in the GAA gene, characterized by progressive glycogen accumulation in multiple tissues and autophagy and metabolic abnormalities. While immunological changes have largely been overlooked as part of PD's symptomatology, autophagy and metabolic regulation are crucial in immune cell function. High incidence of immune reactions against therapeutic recombinant GAA (rhGAA) in PD patients suppose an important hindrance to treatment efficacy, yet the impact of GAA deficiency on the immune system remains unclear. Here we explored the T cell phenotype in late-onset PD patient cells and in a PD mouse model, revealing heightened expression of activation markers in effector T cells compared to controls. Additionally, we observed decreased frequencies of regulatory T cells in mice. We also hypothesized that metabolic and autophagy defects in PD extend to immune cells. In fact, Gaa−/− T cells reproduced autophagy and mitophagy defects reported in muscle cells, and upon stimulation, T cells showed impaired mitochondrial function consistent with defective mitophagy. Preliminary findings also suggest that alterations translate to a subset of CD24+CD172− conventional dendritic cells with regulatory function, which could indirectly contribute to higher T cell activation. Our observations indicate that immune homeostasis is altered in PD, offering new insights on immune dysfunction in the context of lysosomal impairment and providing the rationale for investigating its potential role in the pathogenesis of PD.