Distinct systemic and gut IgA responses to bacteria of the human upper gastrointestinal tract

The mucosa lining the gastrointestinal tract harbors the body's largest population of plasma cells, most of which produce dimeric immunoglobulin A (IgA) for release into the lumen. In addition, there is systemic production of monomeric IgA circulating in the blood. Little is known about the connection between systemic and mucosal IgA. To address this relationship and to explore antibody responses against the microbiota, we isolated bacteria from duodenal biopsies and assessed antibody reactivity. Systemic IgA shows reactivity to bacteria of the upper gastrointestinal tract with a preference for binding Neisseria species, while duodenal IgA has broader reactivity. Single-cell RNA sequencing of gut and bone marrow plasma cells demonstrates limited clonal overlap between the two compartments. Yet, a few shared clones specific to bacterial antigens are identified. Overall, gut and bone marrow plasma cells have distinct V(D)J repertoires and IgA subclass distributions, and they likely depend on B cell activation at discrete anatomical sites.