Polymeric immunoglobulin receptor in regulation of intestinal inflammation

See article in J. Gastroenterol. Hepatol. 2006; 21: 1372–1380. Antibodies present in the external secretions of mucosal surfaces play an important role in the immunological defenses against the environment.1 Secretory antibodies of the immunoglobulin (Ig) A class represent the first line of antigen-specific immune protection against inhaled, ingested and sexually transmitted pathogens and antigens at mucosal surfaces.2 Polymeric immunoglobulins of the A, G, and M classes are transported across mucosal and glandular epithelia by the polymeric immunoglobulin receptor (pIgR).3 The magnitude of pIgR-mediated transport of IgA in the human intestine is impressive, as it has been estimated that 3 g of IgA are transported daily in the average adult. Proteolytic cleavage of pIgR at the apical surface leads to the release of a complex of antibody bound to the soluble external domain of pIgR, known as the secretory component (SC).4,5 At the apical surface, the SC is cleaved and released in free form or as a component of secretory IgA. SC has innate antimicrobial properties and protects secretory IgA from proteolytic degradation. Expression of pIgR is regulated by microbial products through Toll-like receptor signaling6 and by host factors such as cytokines and hormones. Polymeric IgA neutralizes pathogens and antigens within intracellular vesicular compartments during transcytosis. The level of pIgR expression controls the rate of epithelial transcytosis of secretory IgA and IgM. pIgR knockout mice have significantly reduced IgA in external secretions and corresponding elevations in serum IgA and accumulation of IgA in the intestinal lamina propria.7 Accumulation of intestinal intraepithelial lymphocytes is observed in association with lack of pIgR. These mice have a deterioration of their epithelial barrier function; consequently, secretory IgA contributes to the maintenance of mucosal homeostasis. In humans, IgA deficiency has been associated with celiac disease and inflammatory bowel diseases. However, the precise role of IgA in the pathogenesis of these disorders is yet to be fully understood. In their article in this Journal, Murthy et al.8 examined the role of IgA and pIgR during the course of dextran sulfate sodium (DSS) induced model of chronic colitis using mice with a targeted disruption in IgA gene expression (IgA-/- mice) resulting in complete absence of IgA, and animals that lack the polymeric immunoglobulin receptor (pIgR-/- mice), resulting in serum but not secretory IgA. They showed that DSS-treated pIgR-/- mice displayed greater loss of body weight and severe clinical illness compared to similarly treated IgA-/- mice and wild type animals. In addition, colonic tissues from the pIgR-/- mice exhibited progressively and significantly greater inflammation compared to similarly treated IgA-/- mice and wild type animals. These results suggest that pIgR and SC may play an important underappreciated role in modulating inflammatory responses in the mucosa during active colitis. Consequently, secretory immunoglobulins contribute to the protection of the colonic mucosa against DSS, although the isotype of the secretory immunoglobulin (IgA or IgM) may not be a decisive factor in such protection. Thus, pIgR and/or SC are important for the maintenance of epithelial integrity and mucosal homeostasis in the colonic epithelium. This study contributes to the importance of secretory antibodies in the external secretions in physiological as well as pathological conditions and underlines the role of the immune response in inflammatory processes.