Immune Dysfunction and Systemic Inflammatory infiltration Exist in Neuronal Intranuclear Inclusion Disease

Abstract

Abstract Neuronal intranuclear inclusion disease (NIID) is primarily recognized as a neurodegenerative disorder due to the production of a neurotoxicity protein, uN2CpolyG. However, evidence suggests its systemic nature, prompting an exploration of the immune and systemic inflammatory aspects of NIID in this study. A cohort of 32 diagnosed NIID patients participated in a comprehensive study involving clinical presentations, and tissue specimen analyses. Peripheral blood monocyte cells (PBMCs) were collected to detect uN2CpolyG expression in NIID patients by immunofluorescence staining and Western blotting. NIID patients showed varied neurological and extra-neurological symptoms alongside systemic inflammatory and autoimmune disorders, including ulcerative colitis, Sjögren's syndrome, Hashimoto's thyroiditis, and IgA nephropathy. 19 previous tissue specimens from these patients displayed evidence of inflammatory cell infiltration. Notably, our observations unveiled the novel presence of eosinophilic inclusions within the nuclei of these infiltrating inflammatory cells, primarily concentrated in mononuclear cells. Additionally, uN2CpolyG aggregates, identified as ubiquitin-positive inclusions, were detected in peripheral blood monocyte cells (PBMCs) from NIID patients for the first time, contrasting with the weak signal observed without inclusions in the control group. The detection of uN2CpolyG as a 30 to 40 kDa protein in the PBMCs from three NIID patients further supports our findings. This study highlights NIID's systemic nature, emphasizing immune dysfunction and systemic inflammatory infiltration. The detection of uN2CpolyG aggregates in the PBMCs of NIID patients suggests that it may have a toxic potential and alter the immune response of these cells.