Gut-microbiota specific IgA B cells traffic to the CNS in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) of unknown etiology. In addition to genetic factors and other environmental variables, changes in gut microbiota composition have been recently implicated in MS pathogenesis. Immunoglobulin A (IgA) is the predominant antibody isotype produced at mucosal surfaces, and mounting evidence suggests that IgA-producing cells specific for gut microbiota participate in systemic immune responses. However, whether and how gut microbiota shape IgA responses and what role IgA B cells have in neuroinflammation are still unknown. Recently, we reported that intestinal IgA-producing cells migrate from the gut to the brain in experimental autoimmune encephalomyelitis. Here we show that gut microbiota-specific IgA-producing cells traffic to the inflamed CNS in MS patients. Specifically, we observed an increased frequency of IgA-bound taxa in fecal samples from MS patients. Furthermore, we found significant elevation of IgA in the cerebrospinal fluid during MS relapses, which correlated with an enrichment of IgA-producing cells in the meninges and active demyelinating lesions in MS brains. Single-cell B cell receptor sequencing and cloning of CSF-derived antibodies revealed evidence for trafficking of microbiota-specific IgA-producing cells across the blood brain barrier during acute inflammation. Our findings establish the importance of intestine-derived, gut microbiota-specific IgA-producing cells in MS autoimmune neuroinflammation. We anticipate our study to be the starting point for future investigations assessing the role of IgA in immune-mediated diseases and its potential as a biomarker for inflammation.