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.

IgA binds to the AD‐2 epitope of glycoprotein B and neutralizes human cytomegalovirus

“…Abs to these viral components are known to block infection of fibroblasts, epithelial cells, endothelial cells, macrophages and dendritic cells 12,13 . Most mAbs studied are of the IgG isotype despite increasing evidence of the importance of IgA, particularly at mucosal surfaces 14 . Humans have two subclasses of IgA, with serum consisting of 90% of IgA1 and 10% IgA2, whereas in mucosal samples such as saliva and breastmilk, the ratio is closer to 40:60 14 .…”

Human IgA Monoclonal Antibodies That Neutralize Poliovirus, Produced by Hybridomas and Recombinant Expression

“…IgA antibodies are important for overcoming intestinal infections, shaping the microbiome, and preventing autoimmunity, but the therapeutic potential of IgA mAbs is relatively unexplored, in part due to technical challenges [45,46]. In PV infection, an anti-PV mucosal IgA response correlates with resolution of PV shedding from the gastrointestinal tract, and orally administered colostrum was able to transiently reduce PV shedding in a chronically infected individual [9,10].…”

IgA and FcαRI: Versatile Players in Homeostasis, Infection, and Autoimmunity

“…41,42 IgA Binding to FcαRI Humans express two closely related IgA subclasses, ie, IgA1 and IgA2, whereas most mammals, except for rabbits and certain primates, express only a single IgA subclass that resembles IgA2. [43][44][45] In serum, IgA1 is the predominant subclass with an IgA1:IgA2 ratio of 9:1, while IgA2 is mainly found in the colon. In other mucosal tissues, IgA1 and IgA2 are more evenly distributed.…”