The Wanderings of Gut-Derived IgA Plasma Cells: Impact on Systemic Immune Responses

Abstract

Humoral immunity is mainly mediated by a B cell population highly specialized to synthesize and secrete large quantities of antibodies - the antibody-secreting cells (ASC). In the gastrointestinal environment, a mixture of foreign antigens from the diet, commensal microbiota as well as occasional harmful pathogens lead to a constant differentiation of B cells into ASC. Due to this permanent immune response, more than 80% of mammalian ASC reside in the gut, of which most express immunoglobulin A (IgA). IgA antibodies contribute to intestinal homeostasis and can mediate protective immunity. Recent evidence points at a role for gut-derived ASC in modulating immune responses also outside of mucosal tissues. We here summarize recent evidence for wandering ASC, their antibodies and their involvement in systemic immune responses.

Keywords: IgA antibodies; autoimmunity; gut-associated lymphoid tissues (GALT); inflammation; mucosal immunity; plasma cell (PC).

Figure 1

B cells differentiate into IgA ASC in the GALT due to the constant stimulation of the immune system by commensal bacteria, invading pathogens as well as food antigens. From there, gut-derived IgA ASC potentially travel through the blood to the PC niches in the BM. There, survival and function of PC can be supported by the secretion of exemplarily indicated survival factors. IgA ASC in the BM are thought to release monomeric IgA antibodies into the bloodstream directed against a variety of pathogens to counter sepsis in case of a microbial breach in the gut. Furthermore, IgA antibodies can be the cause for pathogenic immunoglobulin deposits in kidney glomeruli during autoinflammatory diseases. It is currently unknown, whether or not the infiltration of IgA ASC into the inflamed kidney further boosts disease through local antibody production. Finally, in the CNS, IgA PC protect the blood-brain barrier at the meninges from invading pathogens. Furthermore, gut-derived IgA PC can enter the CNS in inflammatory conditions like MS lesions, where they attenuate neuroinflammation in an IL-10 dependent manner. The brain might also provide factors needed for PC survival and hence constitute a novel PC niche. As more and more evidence points at the possibility of a systemic migration of gut-derived IgA ASC, further survival niches for those cells need to be considered. ASC, antibody secreting cell; GALT, gut associated lymphoid tissue; CNS, central nervous system; BM, bone marrow; PC, plasma cell; SLE, systemic lupus erythematosus; IgAN, IgA nephropathy; IL-10, interleukin-10.