Immune regulation via IgA
IgA is the predominant antibody isotype in the mucosal
immunity91. IgA can be found in two forms: mucosal IgA
and serum IgA. Mucosal IgA has a polymeric structure and is concentrated
in the outer layer of mucus. Mucosal IgA is produced by plasma cells
within the germinal centers of the Peyer’s patches and binds to
microbial antigens with a very high affinity92,93.
Secretory IgA, cleaved from the mucosal polymeric IgA, interacts with
many antigens in the lumen of the intestine94. IgA has
numerous roles in the gut homeostasis, which include entrapping antigens
in the mucus, reducing invasive properties of bacteria, excreting
antigens from the lamina propria into the intestinal lumen, and reducing
bacterial motility92. IgA’s pro- and anti-inflammatory
effects are mediated by its binding to the FcαRI. While the FcαRI
binding of soluble IgA mediates the anti-inflammatory responses, binding
of the aggregated form mediates the pro-inflammatory
responses95. IgA helps maintain gut immune regulation
in a non-specific fashion via a process called immune
exclusion96. This process is dependent on IgA’s
ability to prevent microbial access to the epithelial layer with a chain
of events called agglutination (bacterial clump formation), entrapment,
and clearance (Fig. 1C, Fig. 2C)97.
IgA is heavily glycosylated, and variations in its glycosylation have
been associated with colorectal cancer (as well as breast and ovarian
cancer)95. Alterations in the terminal glycan motifs
such as high fucosylation and sialylation, are accompanied by malignant
transformation98. IgA antibodies distinctly recognize
tumor-associated cancer antigens (TACAs) (i.e., T, Tn, and sialyl-Tn
antigens), and glycosylation alterations in IgA antibodies that bind to
TACAs are observed in CRC patients95,99.