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Fc Receptors
Published in Maurizio Zanetti, J. Donald Capra, The Antibodies, 1999
Like other FcR, FcRn and pIgR signal cells upon aggregation. FcRn and pIgR, however, do not need antigen. FcRn are monomeric in the absence of IgG. A single IgG, however, binds to two FcRn that it dimerizes [168]. This delivers an endocytic signal of a not yet clear nature [92]. The binding of polymeric immunoglobulin is sufficient to aggregate pIgR. This initiates endocytosis. FcRn and pIgR ensure opposite functions. FcRn are expressed at the apical pole of cells whereas pIgR are expressed at the basolateral pole. Transcytosis mediated by the two receptors go in opposite directions [202]. Thus, FcRn contributes primarily to absorption, pIgR to secretion. The localization of pIgR is determined by a 17-aminoacid basolateral-sorting sequence at the amino-terminal end of the intracytoplasmic domain, in which three critical residues flank a characteristic β turn. If this sequence is deleted, pIgR are immediately routed to the apical pole. This sequence controls not only the biosynthetic pathway, but also the endocytic pathway [203].
Secretory immunoglobulins and their transport
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Charlotte S. Kaetzel, Jiri Mestecky, Jenny M. Woof
The transport of polymeric immunoglobulins (pIgA and pIgM) across mucosal epithelial cells is mediated by a transmembrane glycoprotein called the polymeric immunoglobulin receptor (pIgR; Figure 11.3). The pIgR binds to the Fc region of polymeric antibodies and can thus be classified as a type of Fc receptor. The single gene encoding pIgR, which is located on chromosome 1 in humans and mice, first emerged in bony fishes and is present in all higher vertebrates. The requirement for pIgR for epithelial transcytosis of SIgA was demonstrated by the finding that pIgR-deficient mice have markedly reduced IgA in external secretions and elevated levels of serum IgA. The magnitude of pIgR-mediated antibody transport is greatest in the gut, resulting in delivery of approximately 3 g per day of SIgA into the intestinal fluids of the average adult. Lesser amounts of SIgM are transported into gut secretions due to the far greater abundance of IgA-producing plasma cells, although SIgM can partially compensate for loss of SIgA in IgA-deficient humans. The pIgR is synthesized as an integral membrane protein in the rough endoplasmic reticulum and is further modified in the Golgi apparatus, including extensive N-linked glycosylation. In the trans-Golgi network, pIgR is sorted into vesicles that deliver it to the basolateral surface of the epithelial cell, where it binds pIgA and pIgM secreted by plasma cells in the lamina propria underlying the epithelium. With or without bound pIg, pIgR is endocytosed and delivered through a series of sorting vesicles to the apical (luminal) membrane of the epithelial cell. During transcytosis, a disulfide bond forms between pIgR and one of the two subunits of dimeric IgA, resulting in a permanent association between the receptor and antibody. Once the pIg–pIgR complex reaches the apical plasma membrane, the extracellular domain of pIgR is proteolytically cleaved to form soluble secretory component. Cleavage of unoccupied pIgR results in release of free secretory component, while cleavage of pIgR bound to pIgA or pIgM results in release of SIgA or SIgM. Many external secretions such as colostrum contain significant amounts of free secretory component, which contributes to mucosal homeostasis by inhibiting the binding of certain microbes and modulating the activity of pro-inflammatory factors. The seven N-glycan chains of human secretory component have a unique structure that is heavily fucosylated and sialylated, similar to those of the antibacterial milk protein lactoferrin. These N-glycans bind a variety of host-, pathogen-, and environment-derived substances with lectin-like activity. Carbohydrate-mediated binding of secretory component to intestinal mucins anchors free secretory component, SIgA, and SIgM to the mucus layer overlying the epithelium, thereby creating an immunologic barrier against infection. Secretory component also stabilizes SIgA by inhibiting the access of microbial proteases to the vulnerable IgA hinge region (see later).
Discovery and characterization of single-domain antibodies for polymeric Ig receptor-mediated mucosal delivery of biologics
Published in mAbs, 2020
Bharathikumar Vellalore Maruthachalam, Adam Zwolak, Xiefan Lin-Schmidt, Edward Keough, Ninkka Tamot, Sathya Venkataramani, Brian Geist, Sanjaya Singh, Rajkumar Ganesan
Human pIgR (hpIgR) is an 82 kDa, single-pass transmembrane receptor containing a 620-residue extracellular domain (ECD), a 23-residue transmembrane domain and a 103-residue intracellular domain.7 hpIgR ECD consists of five Ig domains (domain-1 to domain-5, residues 1–545) that take on a compact, globular structure in the absence of bound IgA (Figure S1A). In this compact form, domain-1 is situated between domain-2 and domain-5 such that residues that are important for interaction with dIgA are involved in these intramolecular interactions.8 Solution x-ray scattering studies suggest that upon interaction with dIgA, pIgR adopts an extended conformation, with domain-1 interacting with the Cα2 domain of one Fcα subunit and domain-5 binding the Cα2 subunit on the same side of the opposite Fcα subunit (Figure S1B).9 This asymmetric binding of pIgR across both subunits of Fcα explains its inability to effectively bind to monomeric IgA, and its interactions with the joining chain support the 1:2 stoichiometry of binding.
Production, characterization, and in vivo half-life extension of polymeric IgA molecules in mice
Published in mAbs, 2019
T. Noelle Lombana, Sharmila Rajan, Julie A. Zorn, Danielle Mandikian, Eugene C. Chen, Alberto Estevez, Victor Yip, Daniel D. Bravo, Wilson Phung, Farzam Farahi, Sharon Viajar, Sophia Lee, Avinash Gill, Wendy Sandoval, Jianyong Wang, Claudio Ciferri, C. Andrew Boswell, Marissa L. Matsumoto, Christoph Spiess
IgA in serum is constituted predominantly of IgA1 monomer secreted from bone marrow cells, while polymeric IgA2 is secreted from plasma cells in the lamina propria at the location of transcytosis.1 The high affinity between polymeric IgA and pIgR may naturally lead to fast scavenging of polymeric IgA from circulation, providing effective clearance of harmful antigens from the circulation as IgA-antigen complexes.52 In a therapeutic setting, this may be exploited to restrict drug activity to a defined tissue, something that may be of particular benefit when agonizing cytokine receptors. The fast clearance of polymeric IgA via pIgR from serum in mice is further supported by the approximately 20-fold increased IgA concentrations in the serum of pIgR-deficient non-obese diabetic (NOD) mice.53 As only polymeric IgA, but not IgA monomer, binds pIgR for transcytosis, this increased concentration of IgA in serum must be reflective of increased polymeric IgA concentrations. Future biodistribution studies will show if removing clearance through glycan receptors contributes to more selective binding to pIgR. Regardless, characterization of an aglycosylated IgA therapeutic molecule is easier compared to a highly glycosylated counterpart. In addition, finding a balance between serum exposure and transcytosis is essential to be able to efficiently deliver a therapeutic molecule to the mucosa. The combination of an aglycosylated IgA molecule that binds FcRn may provide a promising path forward for an IgA therapeutic.
Blood and sputum protein biomarkers for chronic obstructive pulmonary disease (COPD)
Published in Expert Review of Proteomics, 2018
Ji-Yong Moon, Fernando Sergio Leitao Filho, Kimeya Shahangian, Hiroto Takiguchi, Don D. Sin
Polymeric immunoglobulin receptor (PIGR) participates in the regulation of IgA by promoting epithelial transcytosis of polymeric IgA [118]. After binding to dimeric-IgA on the epithelial membrane, PIGR suffers endoproteolytic cleavage, causing the release of free extracellular immunoglobulin-like domains of PIGR (secretory component – SC) and secretory IgA complexes (sIgA) [119]. Using cysteine-specific two-dimensional difference gel electrophoresis (2D-DIGE) coupled with MS, Ohlmeier et al., demonstrated that the sputum proteome contains PIGR. Importantly, authors observed that the PIGR spots on MS were characterized as SC forms and that COPD subjects (stage II – according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [1]) presented with higher PIGR levels compared to non-smokers and healthy smokers [120]. These findings are in contrast with the results from a previous study, which showed lower PIGR expression in lung tissues of COPD patients (GOLD stages III-IV) [121]. Together, it is possible that IgA/PIGR expression in lungs decreases with increasing COPD severity, providing further explanation as to why more severe COPD patients (in GOLD stages III and IV) demonstrate a higher susceptibility to infectious AECOPD. Prospective studies are still needed to investigate the role of sputum PIGR as a predictor of AECOPD.