Transcytosis of polymeric IgA and IgM from the basolateral surface to the apical side of the epithelium and subsequent secretion into mucosal fluids are mediated by the pIgR. Secreted IgA and IgM have vital roles in mucosal immunity in response to pathogenic infections.
Overview of Polymeric pIgR
pIgR is expressed on the basolateral surface of mucous epithelium and ducts of excretory glands. The highest level of pIgR expression is observed in small and large intestines. pIgR is also present in the kidneys, pancreas, lungs, and endometrium. pIgR belongs to the Ig protein superfamily. The pIgR molecule is highly glycosylated, the carbohydrates being up to 22% of its weight. The creation of a series of mutant IgM revealed that the pentameric form of the molecule, the presence of the Cμ4 domain, and the J chain are crucial for binding to pIgR. Biochemical and molecular studies revealed that the ligand-binding region of pIgR is located in D1, most distant from the membrane. D1 is a necessary and sufficient element for IgM binding, though there are also other domains taking part in this process in some animal species.
Fig.1 Structure of pIgR. (Klimovich, 2011)
Interaction of IgM with pIgR
The pIgR belongs to the super-Ig family, binds IgM and IgA. After pIgR binds to its ligand, IgM or IgA, the complex is transported across the cell and exposed on the apical cell surface, where it is cleaved by endopeptidases and released as a “secreted” complex of IgM and a still attached fragment of pIgR, which fragment is denoted as the secretory component. In mammals, the pIgR is responsible for the transfer of IgM and IgA antibodies from body fluids into secretions including tears, saliva, breast milk as well as into the intestinal lumen by the mucus epithelium and ducts of excretory glands. The antibodies bind at the basolateral side of the epithelial cells and the antibody receptor complexes are then transported, by transcytosis, to the apical side of the cells in vesicles. Studies on the binding properties of pIgRs in different species show that the first domain, domain 1, is essential and sufficient for the binding of IgA and IgM. However, this binding affinity increases 20-fold by adding additional domains. The pIgR Ig domains are of the V type and three complementarity determining regions (CDRs) can also, similar to Ig V regions, be identified in the pIgR domain 1, which are important for the interactions between the pIgR and IgA and IgM.
Fig.2 Transport of immunoglobulins to mucosal surfaces. (Horton, 2013)
pIgR: Frenemy of Inflammation, EMT, and HCC Progression
Scientists identify the pIgR-a key inflammatory mediator-as a prognostic biomarker for hepatocellular carcinoma (HCC) and a molecular player in hepatitis B infection, chronic liver inflammation, the induction of the epithelial-mesenchymal transition (EMT), HCC recurrence, and metastatic progression. Whereas pIgR aberrant expression has long been associated with HCC, its relevance to malignancy has remained unclear. To date, the only known function of pIgR is in mediating transcytosis of polymeric immunoglobulins from the basolateral to the apical surface of epithelia, ultimately facilitating the secretion of IgA and IgM, which comprise the first line of defense against infection.
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References
- Klimovich, V.B. IgM and its receptors: structural and functional aspects. Biochemistry (Moscow). 2011, 76(5): 534-549.
- Horton, R.; Vidarsson, G. Antibodies and their receptors: different potential roles in mucosal defense. Frontiers in immunology. 2013, 4: 200.
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