Studies of human gut plasma cells: implications for vaccination and treatment of chronic inflammation

Morbidity and mortality caused by infections in the gastrointe¬stinal tract is a major health problem worldwide. Gut infections are responsible for approxi¬mately 10 million deaths annually of children younger than 5 years of age. For the majority of these diseases, there are no available effective vaccines. The gut is the habitat for trillions of commensal microbes (microbiota) that are beneficial for the host. However, disruption to the normal balance between the gut microbiota and the host (termed dysbiosis) has been associated with inflammatory bowel disease, obesity, allergy and asthma, autoimmune diseases and neurological disorders. The microbiota has thus become a very attractive target for therapeutic interventions. Plasma cells (PCs) are one of the most prominent immune cell-types in the gastrointestinal tract. They produce secretory antibodies (mainly immunoglobulin A (IgA)) that are actively transported into the gut lumen where they protect against invading enteropathogens. Moreover, we and others have shown that secretory antibodies reinforce homeostasis in the gut by regulating the composition of the microbiota.
The prevailing scientific dogma states that PCs of the gut have short half-lives. However, we have provided conclusive evidence that intestinal PCs per¬sist for decades in humans. This finding fundamentally changes the concept of gut humoral immunity with implications both for vaccine development and for therapeutic strategies to target the microbiota. This project directly builds on this paradigm-shifting discovery and our main objectives are to: 1) Identify molecular mechanisms underlying the selection of long-lived intestinal PCs; 2) Identify and characterize members of the microbiota that are targeted by long-lived PCs.
We believe results from this project will have far-reaching clinical implications: 1) Understanding the molecular mechanisms that drive the selection of long-lived PCs is of great importance for the design of vaccines with long-lasting protective effects. 2) There is good reason to believe that commensals that induce persistent IgA responses are particularly important for gut homeostasis and that they therefore would be very attractive targets for therapeutic interventions in diseases associated with dysbiosis.

Distribution of plasma cells (CD38, red) and CD45+ cells (green) in the small intestine

Age of plasma cell subsets (CD19+, CD45+, CD45-) derived from small intestine of 5 individuals based on carbon-14 concentrations in genomic DNA (upper). Percentage of plasma cell subsets changes with age (lower). For details see Landsverk et al. J Exp Med, 2017.

(A) The frequency of IGHV gene segments used by plasma cells. (B) The level of somatic hypermutation among plasma cells. (C) Morisita-Horn indices for clonal similarity between PC subsets. (D) Clonally related sequences assigned between plasma cell subsets illustrated in a Circos plot.