Chronic autoimmune activation in patients with mucopolysaccharidosis III

Abstract Mucopolysaccharidosis (MPS) III are a group of four lysosomal storage diseases with severe neurological manifestation. While the primary pathology of MPS III is the lysosomal storage of heparan sulfates, detailed mechanisms of neuropathology are unclear. Using a mouse model, we showed that a profound neuroimmune response contributes to the CNS disease progression of MPS IIIB. Immune status in MPS III patients remains unexplored. Here, we tested peripheral blood from 12 patients with MPS III, including MPS IIIA and IIIB, to assess their immune status. White blood cell differential showed higher lymphocyte ratio (48-70%) in majority tested MPS III patients than healthy control children (41-54%). PBWC from all patients exhibited significant increase in 3H-thymidine-incorporation when stimulated ex vivo with an anti-CD3 or anti-CD40 antibody, suggesting the activation of T-cells and B-cells. Complement deposition assays showed increased levels of RBC-C4d and/or reticulocyte-C4d in majority patients, indicating an ongoing activation of the classical complement pathway. In addition, antinuclear antibodies were detected in the serum of 6 patients. No association was seen between immune activation and age/gender/disease forms. This is the first study that has demonstrated a chronic autoimmune status in MPS III patients, which may also contribute to the disease progression and may have potential as therapeutic target in these patients, as demonstrated in MPS IIIB mice.