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.