Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems

Abstract

Mucosal IgA or secretory IgA (SIgA) are structurally equipped to resist chemical degradation in the harsh environment of mucosal surfaces and enzymes of host or microbial origin. Production of SIgA is finely regulated, and distinct T-independent and T-dependent mechanisms orchestrate Ig α class switching and SIgA responses against commensal and pathogenic microbes. Most infectious pathogens enter the host via mucosal surfaces. To provide a first line of protection at these entry ports, vaccines are being developed to induce pathogen-specific SIgA in addition to systemic immunity achieved by injected vaccines. Mucosal or epicutaneous delivery of vaccines helps target the inductive sites for SIgA responses. The efficacy of such vaccines relies on the identification and/or engineering of vaccine adjuvants capable of supporting the development of SIgA alongside systemic immunity and delivery systems that improve vaccine delivery to the targeted anatomic sites and immune cells.

Figure 1. Mechanisms of induction of mucosal IgA and their protection role at mucosal surfaces

(A) Polymeric IgA (pIgA) and secretory IgA (SIgA). Polymeric IgA Abs are made of two monomers of IgA linked by a junction chain (J-chain) and bind to the polymeric immunoglobulin receptor (pIgR) at the basolateral membrane of epithelial cells. After transepithelial transport, they are released into the lumen as SIgA containing the secretory components (SC), a portion of the pIgR, which confers resistance to proteolysis. (B) Induction of IgA class switching and acquisition of mucosal homing capabilities. IgA class switching and production of mucosal IgA can occur in a T-independent or T-dependent fashion. In response to luminal stimulation by microbes, vaccines or allergen, epithelial cells and conventional antigen presenting cells in the Peyer’s patches (PP), cryptopatches, isolated lymph follicles or lamina propria will produce cytokines (IL-1β, IL-10, TGF-β), nitric oxid (NO), and the B cell stimulating factors BAFF and APRIL. IgA class switching and production of IgA facilitated through the help of cytokines derived from Th cells and NKT cells (T-dependent) will yield high-affinity IgA. On the other hand, cytokine help from innate lymphoid cells (ILCs) and other innate cells such as plasmacytoid dendritic cells (pDC) (T-independent) will result in low-affinity IgA. The presence of retinoic acid (RA) imprints IgA-producing cells with homing receptors and chemokine receptors for homing to the gastrointestinal (GI) tract. (C) Mechanisms of protection by SIgA in mucosal surfaces.