Gut bacteria-specific IgG regulates CNS neuroinflammation 2309610

Abstract

Abstract Introduction The gut microbiota is an emerging regulator of neuroinflammatory diseases like Multiple Sclerosis (MS), but the mechanisms underlying microbiota-immune crosstalk are not fully understood. We previously showed that commensal bacteria-specific IgG antibodies shape the gut microbiota and restrain intestinal inflammation by facilitating the clearance of pathogenic gut bacteria. However, the role of bacteria-specific IgG in regulating neuroinflammation via the gut-brain-immune axis remains undefined. Methods Flow cytometry was used to profile immune cells in the intestinal lamina propria and brain parenchyma of IgG-deficient (IgG KO) and WT mice. Mice were immunized with MOG35-55 to induce Experimental Autoimmune Encephalomyelitis (EAE). To study the role of B cells, we treated mice with B cell-depleting αCD20 or adoptively transferred naïve splenic B cells from WT and IgG KO mice into B cell-deficient μMT recipients. To assess how IgG-targeted bacteria affect neuroinflammation, we transplanted IgG-coated bacteria isolated from human stool into germ-free (GF) mice. Results At steady state, IgG KO mice have increased inflammatory T cells in the CNS and elevated systemic levels of CNS-reactive autoantibodies. Consistently, IgG KO mice exhibit increased EAE susceptibility and disease severity. B cell depletion rescues EAE severity in IgG KO mice and adoptive transfer of IgG KO, but not WT, B cells promotes more severe EAE, suggesting a pathogenic role for B cells in driving neuroinflammation in the absence of IgG. Finally, GF mice given human IgG-coated gut bacteria recapitulate immune activation in the CNS and EAE severity, suggesting that IgG controls neuroinflammation through the microbiota. Conclusion Together, our findings demonstrate a critical role for IgG-mediated control of the gut microbiota and adaptive immune responses in the regulation of CNS neuroinflammation. This work will inform the development of novel gut microbiome-targeting therapies to treat neuroinflammatory diseases like MS. Funding Source n/a Topic Categories Neuroimmunology (NEUR)