Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis (1)

Only IgA and IgM can polymerize. The formation of IgA dimers and IgM pentamers is mediated by the joining chain (J chain), while IgM hexamers can be formed in the absence of J chain.　Polymerized IgA, and to a lesser extent IgM, protect the mucosal surfaces from infection。Daily production of IgA in humans reaches 40 to 60 mg per kg of bodyweight, which is higher than that of all of the other immunoglobulin isotypes combined.

Delivery of antibodies to the mucosal surfaces and secretion in milk requires transport across epithelial layers. The polymeric immunoglobulin receptor (pIgR) recognizes the J chain region of polymerized IgA and IgM and transports the antibodies across the epithelial cell.

Human pIgR is a type I membrane protein that has high glycosylation levels and is molecular weight of about 83 kDa. The structure of pIgR can be categorized into three portions: an extracellular portion (620 amino acids, a.a.), a transmembrane portion (23 a.a.), and a cytoplasmic portion (103 a.a.). The extracellular portion of pIgR contains six domains [10]. Domains 1 to 5 are five tandem immunoglobulin-like domains that are involved in binding to IgA dimers or IgM pentamers.

PIgR is expressed on epithelial cells of the gastrointestinal tract, respiratory tract and the skin, as well as on the glandular epithelial cells of the breast and liver. In order to move across the epithelial barrier, large solutes such as immunoglobulins must undergo transcytosis or the transcellular endosomal pathway. The major function of pIgR is to bind polymeric immunoglobulins, thereby facilitating their transport across the epithelium.

Secretory component (SC) increases the stability of dimerized IgA, possibly by masking proteolytic cleavage sites within the IgA molecule, delaying the degradation of IgA by the host and bacterial enzymes in the mucus. Even in the absence of Ig polymers, SC itself may bind and neutralize bacteria and toxins via its glycan moieties. Functions of SC may be especially important for immunity in breast-fed infants, as the abundance of SC in both its free and Ig-bound forms has long been recorded in maternal milk.

In humans, there are two subtypes of IgA, IgA1 and IgA2, whereas in mice there is only one type of IgA, which more closely resembles to human IgA2. IgA1 and IgA2 differ mainly in their hinge region and the number of glycosylation sites. IgA1 is the predominant subtype in serum, while IgA1 and IgA2 are more evenly distributed in mucosal tissues, and relative proportions vary according to the specific site. Structurally, J chain is an acidic polypeptide with a molecular mass of about 15 kDa and a length of 137 a.a. residues. It includes eight cysteine residues, six of which form three intramolecular disulfide bonds (C13–C101, C72–C92, C109–C134), and the remaining two (C15 and C69) are involved in forming disulfide bonds with cysteine residues at the conserved 18-residue tailpieces of IgA and IgM heavy chains. The C-terminal domain (25 a.a.) of J chain is involved in binding to the extracellular portion of pIgR. IgA remains bound to SC, which is cleaved off from pIgR, after Ig polymers are secreted into the mucus.

There are two distinct versions of IgM, namely the natural IgM and the adaptive IgM. The natural IgM is the predominant subtype, while the adaptive IgM accounts for 10–20% of all IgM antibodies in the serum in humans and mice.

Co-immunoprecipitation (Co-IP) experiments showed that Marginal Zone B and B-1 Cell-Specific Protein (MZB1) , an 18 kDa ER-localized protein, binds to the heavy chain of IgM, via both disulfide bridges and non-covalent interactions. MZB1 may function as a molecular chaperone in dimerization of J chain-containing IgA, which is a prerequisite for the recognition of IgA by pIgR. MZB1 was required for efficient secretion of IgA, but not IgG, both in vivo and in vitro. Both the heavy chain and the light chain of IgA were more rapidly degraded in the absence of MZB1.

Anti-MZB1 treatment may not address the etiology or pathogenesis, yet it could be useful to measure the expression of MZB1 for prognosis and diagnosis of cancer.

1. H. Wei, J.-Y. Wang, Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis. Int. J. Mol. Sci. 22 (2021), doi:10.3390/ijms22052284.