MHC class II transactivator effects on local and systemic immune responses in an α-synuclein seeded rat model for Parkinson's disease

BACKGROUNDParkinsons disease (PD) is characterized by alpha-synuclein (-Syn) pathology, neurodegeneration and neuroinflammation. HLA variants associated with PD and -Syn specific circulating CD4+ T lymphocytes in PD patients highlight the importance of antigen presentation in PD etiology. The class II transactivator (CIITA) is the major regulator of MHCII expression. Reduced Ciita levels significantly increase -Syn pathology, nigrostriatal neurodegeneration and behavioral deficits in -Syn seed-induced rat PD models. OBJECTIVETo characterize immune profiles associated with enhanced PD-like pathology observed in rats expressing lower Ciita levels (DA.VRA4) compared to the background (DA) strain. METHODSTo model PD, we combined rAAV-mediated -Syn overexpression in the substantia nigra with striatal injection of -Syn pre-formed fibrils (PFF). Immune profiles in brain and blood were analyzed by flow cytometry and multiplexed ELISA in naive rats, 4- and 8 weeks post rAAV injection. RESULTSFlow cytometry showed Ciita-dependent regulation of MHCII on microglia, brain macrophages and circulating myeloid cells. The MHCII-dependent microglial response peaked at 4 weeks post rAAV injection, whereas the MHCII levels in circulating myeloid cells peaked at 8 weeks. There was no major infiltration of macrophages or T lymphocytes into the CNS in response to -Syn and only subtle Ciita- and/or -Syn-dependent changes in the T lymphocyte compartment. Lower Ciita levels were consistently associated with higher TNF levels in serum. CONCLUSIONSThese results suggest that Ciita regulates susceptibility to PD-like pathology through minor but detectable changes in resident and peripheral immune cells and TNF levels, and indicate that mild immunomodulatory therapies could have therapeutic effects in PD.