Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis

Abstract

Transcytosis of polymeric IgA and IgM from the basolateral surface to the apical side of the epithelium and subsequent secretion into mucosal fluids are mediated by the polymeric immunoglobulin receptor (pIgR). Secreted IgA and IgM have vital roles in mucosal immunity in response to pathogenic infections. Binding and recognition of polymeric IgA and IgM by pIgR require the joining chain (J chain), a small protein essential in the formation and stabilization of polymeric Ig structures. Recent studies have identified marginal zone B and B1 cell-specific protein (MZB1) as a novel regulator of polymeric IgA and IgM formation. MZB1 might facilitate IgA and IgM transcytosis by promoting the binding of J chain to Ig. In this review, we discuss the roles of pIgR in transcytosis of IgA and IgM, the roles of J chain in the formation of polymeric IgA and IgM and recognition by pIgR, and focus particularly on recent progress in understanding the roles of MZB1, a molecular chaperone protein.

Keywords: antibody secretion; immunoglobulin A (IgA); immunoglobulin M (IgM); immunoglobulin transcytosis; joining chain (J chain); marginal zone B and B1 cell-specific protein (MZB1); mucosal immunity; polymeric immunoglobulin receptor (pIgR).

Figure 1

Structure of polymeric immunoglobulin receptor (pIgR). The pIgR contains an intracellular portion, a transmembrane portion and an extracellular portion. The extracellular portion has six domains. Extracellular domains 1 to 5 (D1–D5) are five tandem immunoglobulin-like domains that are involved in binding to Ig polymers. The extracellular domain 6 (D6) contains a site for proteolytic cleavage.

Figure 2

A proposed scheme for transcytosis of polymerized IgA (immunoglobulin A) and IgM (immunoglobulin M). (1) Formation of the IgM pentamer is mediated by marginal zone B and B-1 cell specific protein (MZB1) and J chain. MZB1 assists the assembly of IgM as a co-chaperone of the glucose-regulated protein 94 (GRP94)-binding immunoglobulin protein (BiP) complex. J chain aids formation of the IgM pentamer. J chain-containing IgM pentamers are secreted from IgM-positive plasma cells. (2) Formation of the IgA dimer is mediated sequentially by BiP, MZB1 and J chain. BiP binds and stabilizes the α heavy chain. MZB1 binds to the α heavy chain and stabilizes the light chain-heavy chain complex. J chain joins two IgA monomers. J chain-containing IgA dimers are secreted from IgA-positive plasma cells. (3) Polymeric immunoglobulin receptor (PIgR) mediates transcytosis of IgA dimers and IgM pentamers. IgA dimers and IgM pentamers, via the J chain, bind to the pIgR on the basolateral membrane of the epithelial cells. The Ig-pIgR complex undergoes clathrin-mediated endocytosis and is conveyed through the endosomal sorting pathway. PIgR is cleaved and its extracellular portion, the secretory component (SC), remains bound to the immunoglobulin (Ig) polymers. The SC-Ig polymer complex is released from the apical membrane of epithelial cells and secreted into the mucus. Note that the molecules and cells in this figure are not to scale.