Functional flexibility of intestinal IgA - broadening the fine line

Abstract

Intestinal bacteria outnumber our own human cells in conditions of both health and disease. It has long been recognized that secretory antibody, particularly IgA, is produced in response to these microbes and hypothesized that this must play an important role in defining the relationship between a host and its intestinal microbes. However, the exact role of IgA and the mechanisms by which IgA can act are only beginning to be understood. In this review we attempt to unravel the complex interaction between so-called "natural," "primitive" (T-cell-independent), and "classical" IgA responses, the nature of the intestinal microbiota/intestinal pathogens and the highly flexible dynamic homeostasis of the mucosal immune system. Such an analysis reveals that low-affinity IgA is sufficient to protect the host from excess mucosal immune activation induced by harmless commensal microbes. However, affinity-maturation of "classical" IgA is essential to provide protection from more invasive commensal species such as segmented filamentous bacteria and from true pathogens such as Salmonellatyphimurium. Thus a correlation is revealed between "sophistication" of the IgA response and aggressiveness of the challenge. A second emerging theme is that more-invasive species take advantage of host inflammatory mechanisms to more successfully compete with the resident microbiota. In many cases, the function of IgA may be to limit such inflammatory responses, either directly by coagulating or inhibiting virulence of bacteria before they can interact with the host or by modulating immune signaling induced by host recognition. Therefore IgA appears to provide an added layer of robustness in the intestinal ecosystem, promoting "commensal-like" behavior of its residents.

Keywords: IgA; adaptive immunity; innate immunity; microbiota; mucosal immunology; mucosal infection; natural antibody.

Figure 1

Schematic of the composite nature of the mucosal IgA system, consisting of “natural” (microbiota-independent), “primitive” (microbobially induced, T-cell independent), and “classical” (microbe/pathogen-induced, helper T-cell-dependent) IgA responses. Whether there is a specific immunogen inducing “natural” IgA is unknown. “Natural” IgA can be sufficient for controlling benign commensal bacteria. Commensal microbes induce “primitive” T-cell independent IgA with is sufficient for the management of commensal bacteria (Green), mainly by exclusion from the mucus layer and the resulting “buffering” of mucosal responses. The more invasive pathobionts (orange) and infection with pathogenic microbes (red) further induce “classical” T-cell-dependent IgA of high-affinity that is important for the control of these types of microorganisms via efficient mucosal exclusion and neutralization. SHM, somatic hypermutation.