IgA: Structure, Function, and Developability

Abstract

Immunoglobulin A (IgA) plays a key role in defending mucosal surfaces against attack by infectious microorganisms. Such sites present a major site of susceptibility due to their vast surface area and their constant exposure to ingested and inhaled material. The importance of IgA to effective immune defence is signalled by the fact that more IgA is produced than all the other immunoglobulin classes combined. Indeed, IgA is not just the most prevalent antibody class at mucosal sites, but is also present at significant concentrations in serum. The unique structural features of the IgA heavy chain allow IgA to polymerise, resulting in mainly dimeric forms, along with some higher polymers, in secretions. Both serum IgA, which is principally monomeric, and secretory forms of IgA are capable of neutralising and removing pathogens through a range of mechanisms, including triggering the IgA Fc receptor known as FcαRI or CD89 on phagocytes. The effectiveness of these elimination processes is highlighted by the fact that various pathogens have evolved mechanisms to thwart such IgA-mediated clearance. As the structure-function relationships governing the varied capabilities of this immunoglobulin class come into increasingly clear focus, and means to circumvent any inherent limitations are developed, IgA-based monoclonal antibodies are set to emerge as new and potent options in the therapeutic arena.

Keywords: CD89; FcαRI; IgA; immune evasion; immunoglobulin A; structure; therapeutic antibodies.

Figure 1

Hinge sequences of IgAs from different species. Numbers following the species name indicate the IgA subclass, and allotype where appropriate. Amino acid numbering above human IgA1 is according to the commonly adopted scheme used for IgA1 Bur [8].

Figure 2

Schematic diagram of IgA structures—monomeric, dimeric, and secretory IgA. In IgA1, the heavy chain domains are in blue, and those of the light chains in yellow. In IgA2, the heavy chain domains are in red, and the light chain domains in yellow. The tailpieces are shown as extensions to the C-termini of the Cα3 domains in the monomeric forms. Dimeric and secretory forms of IgA2 are not depicted. J chain, which is present in both dimeric and secretory IgA, is shown in cyan. The domains of secretory component, derived from the extracellular region of pIgR, are present in secretory IgA and are shown in orange.

Figure 3

Schematic structures of IgA (A) N-linked and (B) O-linked glycan side chains. Structure (A) occurs in both IgA1 and IgA2, while structure (B) is present only attached to the hinge region of IgA1. NeuNAc, N-acetyl neuraminic (sialic) acid; Gal, galactose; GlcNAc, N-acetyl glucosamine; Man, mannose; Fuc, fucose; GalNAc, N-acetyl galactosamine. ±Gal, ±NeuNAc, or ±Fuc indicate that some chains terminate at the preceding sugar.

Figure 4

X-ray crystal structure of human IgA1 Fc generated from PDB accession code 1OW0 using only the IgA coordinates. One heavy chain is shown in blue, the other in gold. Residues critical for binding to FcαRI are shown in red on the middle image, and those implicated in the interaction with pIgR are shown in purple on the right hand image.

Figure 5

Molecular models of human IgA1 and IgA2(m)1 using coordinates from PDB accession codes 1IGA and 1R70, respectively, seen face on (upper image in each case) and from above (lower image in each case). In IgA1, heavy chains (HCs) are shown in blue and light chains (LCs) in yellow, while in IgA2m(1), HCs are shown in red and LCs in yellow.

Figure 6

Schematic diagram illustrating the role of pIgR in transporting IgA across the mucosal epithelium. Gut epithelium is shown as an example. (1) Dimeric IgA (shown in red) produced locally at the mucosal surface binds pIgR (cyan) at the basolateral surface of the epithelial cell layer. (2) The complex is internalised and undergoes vesicular transport across the cell. (3) pIgR is cleaved to release secretory component (SC), which becomes disulphide-bonded to the dimeric IgA. (4) At the apical surface, SIgA is released. (5) SIgA binds to and neutralises bacterial and viral pathogens (shown in purple and dark blue). (6) Some pathogens (shown in bright pink) may gain access to the lamina propria underlying the epithelium. (7) Such pathogens can be bound by dimeric IgA. (8) The dimeric IgA–pathogen complex binds to pIgR. (9) The pathogen is carried out across the epithelium and released back out into the lumen. (10) Some pathogens (shown in lime green) can be intersected by dimeric IgA during transit across the epithelial cells. (11) The pathogen is ejected upon release of SIgA at the mucosal surface. (12) Dimeric IgA can mediate clearance mechanisms against pathogens (in salmon pink) through engaging phagocytes.

Figure 7

Crystal structure of the extracellular domains of human pIgR (using coordinates from PBD accession code 5D4K). Each of the five domains (D1–D5) has been coloured differently.

Figure 8

Amino acid sequence in the hinge region of human IgA1 and the cleavage sites of various IgA1 proteases. The IgA1 hinge contains a duplicated octapeptide sequence that is missing in IgA2. O-linked glycans are represented by yellow circles.