A190 HELICOBACTER PYLORI INDUCES AN AUTO-REACTIVE PHENOTYPE IN PINK1 DEFICIENT MICE THAT CORRELATES WITH MOTOR DYSFUNCTION

Abstract

Abstract Background Parkinson’s disease (PD) is a chronic neurodegenerative disorder. Several genetic predispositions, including the PTEN-induced kinase 1 (PINK1) mutation, have been implicated in early onset family cases. Besides the loss of dopaminergic neurons in the brain, PD patients have a unique immune phenotype that includes increased inflammation, blood serum, brain levels of proinflammatory cytokines, brain infiltration with cytotoxic CD8 T cells, and loss of regulatory T cells (Treg) and their anti-inflammatory phenotype. The role of the gut microbiota and gastrointestinal infections are increasingly recognized as a cofactor in PD. One of pathogens associated with the risk of PD is Helicobacter pylori. The prevalence of this Gram-negative bacteria in PD patients is higher than in the general population and its eradication in PD patients improves motor function. Loss of the PD-associated PINK1 alters induced Treg function in vitro. We previously have shown that in PINK1 knock-out (KO) mice, gut infection with Gram-negative bacteria, Citrobacter rodentium, induces mitochondrial antigen presentation (MitAP) to the CD8 T cells that later infiltrate the brain. In this model, PINK1 KO mice develop a Parkinson-like L-DOPA-responsive motor phenotype after four C. rodentium infections. Aims Here we aimed to scrutinize potential role of the H. pylori infection in the induction of motor dysfunction and disbalanced immune tolerance in PINK1 KO mice. Methods In addition to standard behavioural testing, at 2- and 6-months post-infection we performed a multiplex cytokine analysis of gastric homogenates and spectral flow cytometry of gastric lamina propria, mesenteric lymph nodes, blood, spleen, and brain infiltrating immunocytes. As well as in vitro immunocytes response and function assays to H.pylori exposure in PINK1 KO and wild-type (WT) littermate controls. Results We show that infection with H. pylori causes a long-lasting inflammation in the stomach; and local and systemic immune phenotype that remains 6 months post-infection. This phenotype, though present in some WT infected mice, is higher in PINK1 KOs and similarly to PD patients includes a decrease in Treg proportion, FoxP3 downregulation in regulatory T cells, Gata3+ CD4 T cell loss, as well as increase of circulating mitochondrial antigen-specific CD8 T cells. Moreover, the immune phenotype in the H. pylori infected PINK1 KO mice correlates with motor dysfunction and CD8 T cell brain infiltration with no such association seen in the WT mice. Conclusions These results provide insight to the gut-immunity-brain axis in the pathogenesis of Parkinson’s disease, and further investigate the role of Gram-negative bacteria in the establishment of immune tolerance-autoreactivity balance. Funding Agencies ASAP