The MHC class II transactivator affects local and systemic immune responses in an α-synuclein seeded rat model for Parkinson’s disease

Abstract

ABSTRACTParkinson’s disease (PD) is characterized by intraneuronal inclusions of alpha-synuclein (α-Syn), neurodegeneration and a strong neuroinflammatory component. Studies have shown that genetic variants affecting quantity and quality of major histocompatibility complex II (MHCII) have implications in PD susceptibility and that PD patients have α-Syn specific T lymphocytes in circulation. The class II transactivator (CIITA) is the major regulator of MHCII expression and reduced CIITA expression has been shown to significantly increase α-Syn induced neurodegeneration and pathology in an α-Syn overexpression rat model combined with α-Syn pre-formed fibrils (PFF). In this study, we characterized immune profiles associated with the enhanced PD-like pathology observed in congenic rats withCiitaallelic variants causing lower CIITA levels compared to the background strain. Flow cytometry showed that rats with lower CIITA levels had an increased proportion of MHCII+ microglia and circulating myeloid cells, yet lower levels of MHCII on individual cells. Additionally, lower CIITA levels were associated to higher TNF levels in serum, trends of higher CD86 levels in circulating myeloid cells and a lower CD4/CD8 T lymphocyte ratio in blood. Taken together, these results indicate that CIITA regulates susceptibility to PD-like pathology through baseline immune populations and serum TNF levels.