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Immunoglobulin A: Molecular Mechanisms of Function and Role in Immune Defence

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Molecular and Cellular Mechanisms of Antibody Activity

Abstract

Our immune system produces more immunoglobulin A (IgA) than all of the other antibody classes combined. Much of this synthesis is directed towards protection of the mucosal surfaces which form a vast and vulnerable interface with the environment. As the predominant immunoglobulin class at these surfaces, IgA is an important first line of defence. In addition, IgA is also a major serum immunoglobulin. Both monomeric IgA in serum and polymeric secretory forms of IgA mediate a wide range of protective functions through interaction with numerous receptors and other mediators. It is telling that in order to gain better opportunities for invasion, certain pathogens have evolved mechanisms to thwart IgA function. An improved understanding of this multifaceted immunoglobulin is likely to inform strategies for improved treatments for infections and other diseases.

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References

  • Atkin JD, Pleass RJ, Owens RJ, Woof JM (1996) Mutagenesis of the human IgA1 heavy chain tailpiece that prevents dimer assembly. J Immunol 157:156–159

    PubMed  CAS  Google Scholar 

  • Bakema JE, van Egmond M (2011a) The human immunoglobulin A Fc receptor FcαRI: a multifaceted regulator of mucosal immunity. Mucosal Immunol 4:612–624

    PubMed  CAS  Google Scholar 

  • Bakema JE, van Egmond M (2011b) Immunoglobulin A: a next generation of therapeutic antibodies? MAbs 3:352–361

    PubMed  Google Scholar 

  • Bakema JE, Ganzevles SH, Fluitsma DM, Schilham MW, Beelen RH, Valerius T, Lohse S, Glennie MJ, Medema JP, van Egmond M (2011) Targeting FcαRI on polymorphonuclear cells induces tumor cell killing through autophagy. J Immunol 187:726–732

    PubMed  CAS  Google Scholar 

  • Bakos MA, Kurosky A, Cwerwinski EW, Goldblum RM (1993) A conserved binding site on the receptor for polymeric Ig is homologous to CDR1 of Ig V kappa domains. J Immunol 151:1346–1352

    PubMed  CAS  Google Scholar 

  • Balu S, Reljic R, Lewis MJ, Pleass RJ, McIntosh R, van Kooten C, van Egmond M, Challacombe S, Woof JM, Ivanyi J (2011) A novel human IgA monoclonal antibody protects against tuberculosis. J Immunol 186:3113–3119

    PubMed  CAS  Google Scholar 

  • Bastian A, Kratzin H, Eckart K, Hilschmann N (1992) Intra- and inter-chain disulphide bridges of the human J chain in secretory immunoglobulin A. Biol Chem Hoppe Seyler 373:1255–1263

    PubMed  CAS  Google Scholar 

  • Batten MR, Senior BW, Kilian M, Woof JM (2003) Amino acid sequence requirements in the hinge of human immunoglobulin A1 (IgA1) for cleavage by streptococcal IgA1 proteases. Infect Immun 71:1462–1469

    PubMed  CAS  Google Scholar 

  • Biesbrock AR, Reddy MS, Levine MJ (1991) Interaction of a salivary mucin-secretory immunoglobulin A complex with mucosal pathogens. Infect Immun 59:3492–3497

    PubMed  CAS  Google Scholar 

  • Blank U, Launay P, Benhamou M, Monteiro RC (2009) Inhibitory ITAMs as novel regulators of immunity. Immunol Rev 232:59–71

    PubMed  CAS  Google Scholar 

  • Bomsel M, Heyman M, Hocini H, Lagaye S, Belec L, Dupont C, Desgranges C (1998) Intracellular neutralization of HIV transcytosis across tight epithelial barriers by anti-HIV envelope protein dIgA or IgM. Immunity 9:277–287

    PubMed  CAS  Google Scholar 

  • Braathen R, Sorensen V, Brandtzaeg P, Sandlie I, Johansen FE (2002) The carboxyl-terminal domains of IgA and IgM direct isotype-specific polymerization and interaction with the polymeric immunoglobulin receptor. J Biol Chem 277:42755–42762

    PubMed  CAS  Google Scholar 

  • Brandtzaeg P, Johansen FE (2005) Mucosal B cells: phenotypic characteristics, transcriptional regulation, and homing properties. Immunol Rev 206:32–63

    PubMed  CAS  Google Scholar 

  • Brandtzaeg P, Farstad IN, Johansen FE, Morton HC, Norderhaug IN, Yamanaka T (1999) The B-cell system of human mucosae and exocrine glands. Immunol Rev 171:45–87

    PubMed  CAS  Google Scholar 

  • Burnett RC, Hanly WC, Zhai SK, Knight KL (1989) The IgA heavy-chain gene family in rabbit: cloning and sequence analysis of 13 Cα genes. EMBO J 8:4041–4047

    PubMed  CAS  Google Scholar 

  • Burns JW, Siadat-Pajouh M, Krishnaney AA, Greenberg HB (1996) Protective effect of rotavirus VP6-specific IgA monoclonal antibodies that lack neutralizing activity. Science 272:104–107

    PubMed  CAS  Google Scholar 

  • Cann GM, Zaritsky A, Koshland ME (1982) Primary structure of the immunoglobulin J chain from the mouse. Proc Natl Acad Sci USA 79:6656–6660

    PubMed  CAS  Google Scholar 

  • Carayannopoulos L, Hexham JM, Capra JD (1996) Localization of the binding site for the monocyte immunoglobulin (Ig) A-Fc receptor (CD89) to the domain boundary between Cα2 and Cα3 in human IgA1. J Exp Med 183:1579–1586

    PubMed  CAS  Google Scholar 

  • Cerutti A (2008) The regulation of IgA class switching. Nat Rev Immunol 8:421–434

    PubMed  CAS  Google Scholar 

  • Childers NK, Bruce MG, McGhee JR (1989) Molecular mechanisms of immunoglobulin A defense. Annu Rev Immunol 43:503–536

    CAS  Google Scholar 

  • Chintalacharuvu KR, Raines M, Morrison SL (1994) Divergence of human alpha-chain constant region gene sequences. A novel recombinant alpha2 gene. J Immunol 152:5299–5304

    PubMed  CAS  Google Scholar 

  • Chintalacharuvu KR, Chuang PD, Dragoman A, Fernandez CZ, Qiu J, Plaut AG, Trinh KR, Gala FA, Morrison SL (2003) Cleavage of the human immunoglobulin A1 (IgA1) hinge region by IgA1 proteases requires structures in the Fc region of IgA. Infect Immun 71:2563–2570

    PubMed  CAS  Google Scholar 

  • Coffman RL, Lebman DA, Shrader B (1989) Transforming growth factor beta specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J Exp Med 170:1039–1044

    PubMed  CAS  Google Scholar 

  • Conley ME, Delacroix DL (1987) Intravascular and mucosal immunoglobulin A: two separate but related systems of immune defense? Ann Intern Med 106:892–899

    PubMed  CAS  Google Scholar 

  • Corthésy B (2003) Recombinant secretory immunoglobulin A in passive immunotherapy: linking immunology and biotechnology. Curr Pharm Biotechnol 4:51–67

    PubMed  Google Scholar 

  • Corthésy B, Benureau Y, Perrier C, Fourgeux C, Parez N, Greenberg H, Schwartz-Cornil I (2006) Rotavirus anti-VP6 secretory immunoglobulin A contributes to protection via intracellular neutralization but not via immune exclusion. J Virol 80:10692–10699

    PubMed  Google Scholar 

  • Coyne RS, Siebrecht M, Peitsch MC, Casanova JE (1994) Mutational analysis of polymeric immunoglobulin receptor/ligand interactions. Evidence for the involvement of multiple complementarity determining region (CDR)-like loops in receptor domain I. J Biol Chem 269:31620–31625

    PubMed  CAS  Google Scholar 

  • Dallas SD, Rolfe RD (1998) Binding of Clostridium difficile toxin A to human milk secretory component. J Med Microbiol 47:879–888

    PubMed  CAS  Google Scholar 

  • Dechant M, Valerius T (2001) IgA antibodies for cancer therapy. Crit Rev Oncol Hematol 39:69–77

    PubMed  CAS  Google Scholar 

  • Dechant M, Vidarsson G, Stockmeyer B, Repp R, Glennie MJ, Gramatzki M, van de Winkel JGJ, Valerius T (2002) Chimeric IgA antibodies against HLA class II effectively trigger lymphoma cell killing. Blood 100:4574–4580

    PubMed  CAS  Google Scholar 

  • Du CC, Mashoof SM, Criscitiello MF (2012) Oral immunization of the African clawed frog (Xenopus laevis) upregulates the mucosal immunoglobulin IgX. Vet Immunol Immunopathol 145:493–498

    PubMed  CAS  Google Scholar 

  • Elm C, Braathen R, Bergmann S, Frank R, Vaerman J-P, Kaetzel CS, Chhatwal GS, Johansen F-E, Hammerschmidt S (2004) Ectodomains 3 and 4 of human polymeric immunoglobulin receptor (hpIgR) mediate invasion of Streptococcus pneumoniae into the epithelium. J Biol Chem 279:6296–6304

    PubMed  CAS  Google Scholar 

  • Fallgren-Gebauer E, Gebauer W, Bastian A, Kratzin H, Eiffert H, Zimmerman B, Karas M, Hilschmann N (1995) The covalent linkage of the secretory component to IgA. Adv Exp Med Biol 371A:625–628

    PubMed  CAS  Google Scholar 

  • Feng N, Lawton JA, Gilbert J, Kuklin N, Vo P, Prasad BV, Greenberg HB (2002) Inhibition of rotavirus replication by a non-neutralizing, rotavirus VP6-specific IgA mAb. J Clin Invest 109:1203–1213

    PubMed  CAS  Google Scholar 

  • Fernandez MI, Pedron T, Tournebize R, Olivo-Marin JC, Sansonetti PJ, Phalipon A (2003) Anti-inflammatory role for intracellular dimeric immunoglobulin A by neutralization of lipopolysaccharide in epithelial cells. Immunity 18:739–749

    PubMed  CAS  Google Scholar 

  • Field MC, Amatayakul-Chantler S, Rademacher TW, Rudd PM, Dwek RA (1994) Structural analysis of the N-glycans from human immunoglobulin A1: comparison of normal human serum immunoglobulin A1 from that isolated from patients with rheumatoid arthritis. Biochem J 299:261–275

    PubMed  CAS  Google Scholar 

  • Frithz E, Héden L-O, Lindahl G (1989) Extensive sequence homology between IgA receptor and M proteins in Streptococcus pyogenes. Mol Microbiol 3:1111–1119

    PubMed  CAS  Google Scholar 

  • Frutiger S, Hughes GJ, Paquet N, Luthy R, Jaton JC (1992) Disulfide bond assignment in human J chain and its covalent pairing with immunoglobulin M. Biochemistry 31:12643–12647

    PubMed  CAS  Google Scholar 

  • Ghumra A, Shi J, Mcintosh RS, Rasmussen IB, Braathen R, Johansen FE, Sandlie I, Mongini PK, Areschoug T, Lindahl G, Lewis MJ, Woof JM, Pleass RJ (2009) Structural requirements for the interaction of human IgM and IgA with the human Fcα/μ receptor. Eur J Immunol 39:1147–1156

    PubMed  CAS  Google Scholar 

  • Hamburger AE, West AP, Bjorkman PJ (2004) Crystal structure of a polymeric immunoglobulin binding fragment of the human polymeric immunoglobulin receptor. Structure 12:1925–1935

    PubMed  CAS  Google Scholar 

  • Hammerschmidt S, Tillig MP, Wolff S, Vaerman J-P, Chhatwal GS (2000) Species-specific binding of human secretory component to SpsA protein of Streptococcus pneumoniae via a hexapeptide motif. Mol Microbiol 36:726–736

    PubMed  CAS  Google Scholar 

  • Hanson LA, Korotkova M (2002) The role of breastfeeding in prevention of neonatal infection. Semin Neonatol 7:275–281

    PubMed  Google Scholar 

  • He B, Xu W, Santini PA, Polydorides AD, Chiu A, Estrella J, Shan M, Chadburn A, Villanacci V, Plebani A, Knowles DM, Rescigno M, Cerutti A (2007) Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26:812–826

    PubMed  CAS  Google Scholar 

  • Héden L-O, Frithz E, Lindahl G (1991) Molecular characterization of an IgA receptor from group B streptococci: sequence of the gene, identification of a proline-rich region with unique structure and isolation of N-terminal fragments with IgA-binding capacity. Eur J Immunol 21:1481–1490

    PubMed  Google Scholar 

  • Hellwig SMM, van Spriel AB, Schellekens JFP, Mooi FR, van de Winkel JGJ (2001) Immunoglobulin A-mediated protection against Bordetella pertussis infection. Infect Immun 69:4846–4850

    PubMed  CAS  Google Scholar 

  • Herr AB, Ballister ER, Bjorkman PJ (2003) Insights into IgA-mediated immune responses from the crystal structures of human FcαRI and its complex with IgA1-Fc. Nature 423:614–620

    PubMed  CAS  Google Scholar 

  • Hexham JM, White KD, Carayannopoulos LN, Mandecki W, Brisette R, Yang YS, Capra JD (1999) A human immunoglobulin (Ig)A Cα3 domain motif directs polymeric Ig receptor-mediated secretion. J Exp Med 189:747–752

    PubMed  CAS  Google Scholar 

  • Huang YT, Wright A, Gao X, Kulick L, Yan H, Lamm ME (2005) Intraepithelial cell neutralization of HIV-1 replication by IgA. J Immunol 174:4828–4835

    PubMed  CAS  Google Scholar 

  • Johansen FE, Kaetzel CS (2011) Regulation of the polymeric immunoglobulin receptor and IgA transport: new advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity. Mucosal Immunol 4:598–602

    PubMed  CAS  Google Scholar 

  • Johansen FE, Braathen R, Brandtzaeg P (2001) The J chain is essential for polymeric Ig receptor-mediated epithelial transport of IgA. J Immunol 167:5185–5192

    PubMed  CAS  Google Scholar 

  • Johnson TA, Qiu J, Plaut AG, Holyoak T (2009) Active-site gating regulates substrate selectivity in a chymotrypsin-like serine protease the structure of Haemophilus influenzae immunoglobulin A1 protease. J Mol Biol 389:559–574

    PubMed  CAS  Google Scholar 

  • Kaetzel CS (2005) The polymeric immunoglobulin receptor: bridging innate and adaptive immune responses at mucosal surfaces. Immunol Rev 206:83–99

    PubMed  CAS  Google Scholar 

  • Kaetzel CS, Robinson JK, Chintalacharuvu KR, Vaerman JP, Lamm ME (1991) The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA. Proc Natl Acad Sci USA 88:8796–8800

    PubMed  CAS  Google Scholar 

  • Kawamura S, Ueda S (1992) Immunoglobulin CH gene family in hominoids and its evolutionary history. Genomics 13:194–200

    PubMed  CAS  Google Scholar 

  • Kawamura S, Saitou N, Ueda S (1992) Concerted evolution of the primate immunoglobulin α-gene through gene conversion. J Biol Chem 267:7359–7367

    PubMed  CAS  Google Scholar 

  • Kikuno K, Kang DW, Tahara K, Torii I, Kubagawa HM, Ho KJ, Baudino L, Nishizaki N, Shibuya A, Kubagawa H (2007) Unusual biochemical features and follicular dendritic cell expression of human Fcα/μ receptor. Eur J Immunol 37:3540–3550

    PubMed  CAS  Google Scholar 

  • Kilian M, Reinholdt J, Lomholt H, Poulsen K, Frandsen EV (1996) Biological significance of IgA1 proteases in bacterial colonization and pathogenesis: critical evaluation of experimental evidence. APMIS 104:321–338

    PubMed  CAS  Google Scholar 

  • Koshland ME (1985) The coming of age of the immunoglobulin J chain. Annu Rev Immunol 3:425–453

    PubMed  CAS  Google Scholar 

  • Krugmann S, Pleass RJ, Atkin JD, Woof JM (1997) Structural requirements for assembly of dimeric IgA probed by site-directed mutagenesis of J chain and a cysteine residue of the α chain CH2 domain. J Immunol 159:244–249

    PubMed  CAS  Google Scholar 

  • Lamkhioued B, Gounni AS, Gruart V, Pierce A, Capron A, Capron M (1995) Human eosinophils express a receptor for secretory component. Role in secretory IgA-dependent activation. Eur J Immunol 25:117–125

    PubMed  CAS  Google Scholar 

  • Lang ML, Shen L, Wade WF (1999) Gamma-chain dependent recruitment of tyrosine kinases to membrane rafts by the human IgA receptor FcαR. J Immunol 163:5391–5398

    PubMed  CAS  Google Scholar 

  • Lang ML, Shen L, Gao H, Cusack WF, Lang GA, Wade WF (2001) Fcα receptor cross-linking causes translocation of phosphatidylinositol-dependent protein kinase 1 and protein kinase Bα to MHC class II peptide-loading-like compartments. J Immunol 166:5585–5593

    PubMed  CAS  Google Scholar 

  • Launay P, Patry C, Lehuen A, Pasquier B, Blank U, Monteiro RC (1999) Alternative endocytic pathway for immunoglobulin A Fc receptors (CD89) depends on the lack of FcRγ association and protects against degradation of bound ligand. J Biol Chem 274:7216–7225

    PubMed  CAS  Google Scholar 

  • Lewis MJ, Pleass RJ, Batten MR, Atkin JD, Woof JM (2005) Structural requirements for the interaction of human IgA with the human polymeric Ig receptor. J Immunol 175:6694–6701

    PubMed  CAS  Google Scholar 

  • Lewis MJ, Meehan M, Owen P, Woof JM (2008) A common theme in interaction of bacterial immunoglobulin-binding proteins with immunoglobulins illustrated in the equine system. J Biol Chem 283:17615–17623

    PubMed  CAS  Google Scholar 

  • Lohse S, Derer S, Beyer T, Klausz K, Peipp M, Leusen JH, van de Winkel JG, Dechant M, Valerius T (2011) Recombinant dimeric IgA antibodies against the epidermal growth factor receptor mediate effective tumor cell killing. J Immunol 186:3770–3778

    PubMed  CAS  Google Scholar 

  • Lu L, Lamm ME, Li H, Corthésy B, Zhang JR (2003) The human polymeric immunoglobulin receptor binds to Streptococcus pneumoniae via domains 3 and 4. J Biol Chem 278:48178–48187

    PubMed  CAS  Google Scholar 

  • Ma JK, Hikmat BY, Wycoff K, Vine ND, Chargelegue D, Yu L, Hein MB, Lehner T (1998) Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat Med 4:601–606

    PubMed  CAS  Google Scholar 

  • Macpherson AJ, Uhr T (2004) Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 328:1705–1709

    Google Scholar 

  • Macpherson AJ, Geuking MB, McCoy KD (2012) Homeland security: IgA immunity at the frontiers of the body. Trends Immunol 33:160–167

    PubMed  CAS  Google Scholar 

  • Mansikka A (1992) Chicken IgA H chains. Implications concerning the evolution of H chain genes. J Immunol 149:855–861

    PubMed  CAS  Google Scholar 

  • Mantis NJ, Cheung MC, Chintalacharuvu KR, Rey J, Corthésy B, Neutra MR (2002) Selective adherence of IgA to murine Peyer’s patch M cells: evidence for a novel IgA receptor. J Immunol 169:1844–1851

    PubMed  CAS  Google Scholar 

  • Mantis NJ, Rol N, Corthesy B (2011) Secretory IgA’s roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol 4:603–611

    PubMed  CAS  Google Scholar 

  • Mattu TS, Pleass RP, Willis AC, Kilian M, Wormald MR, Lellouch AC, Rudd PM, Woof JM, Dwek RA (1998) The glycosylation and structure of human serum IgA1, Fab and Fc regions and the role of N-glycosylation on Fcα receptor interactions. J Biol Chem 273:2260–2272

    PubMed  CAS  Google Scholar 

  • Mazanec MB, Kaetzel CS, Lamm ME, Fletcher D, Nedrud JG (1992) Intracellular neutralization of virus by immunoglobulin A antibodies. Proc Natl Acad Sci USA 89:6901–6905

    PubMed  CAS  Google Scholar 

  • Mazanec MB, Coudret CL, Fletcher DR (1995) Intracellular neutralization of influenza virus by immunoglobulin A anti-hemagglutinin monoclonal antibodies. J Virol 69:1339–1343

    PubMed  CAS  Google Scholar 

  • Mestecky J, Russell MW, Jackson S, Brown TA (1986) The human IgA system: a reassessment. Clin Immunol Immunopathol 40:105–114

    PubMed  CAS  Google Scholar 

  • Mestecky J, Lue C, Russell MW (1991) Selective transport of IgA: cellular and molecular aspects. Gastroenterol Clin North Am 20:441–471

    PubMed  CAS  Google Scholar 

  • Mestecky J, Bienenstock J, McGhee JR, Lamm ME, Strober W, Cebra JJ, Mayer L, Ogra PL (2005) Historical aspects of mucosal immunology. In: Mestecky JR, Bienenstock J, Lamm ME, Mayer L, McGhee JR, Strober W (eds) Mucosal immunology, 3rd edn. Elsevier Academic, London

    Google Scholar 

  • Mostov KE, Kraehenbuhl JP, Blobel G (1980) Receptor-mediated transcellular transport of immunoglobulin: synthesis of secretory component as multiple and larger molecular forms. Proc Natl Acad Sci USA 77:7257–7261

    PubMed  CAS  Google Scholar 

  • Moura IC, Centelles MN, Arcos-Fajardo M, Malheiros DM, Collawn JF, Cooper MD, Monteiro RC (2001) Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy. J Exp Med 194:417–426

    PubMed  CAS  Google Scholar 

  • Narimatsu Y, Kubota T, Furukawa S, Morii H, Narimatsu H, Yamasaki K (2010) Effect of glycosylation on the cis/trans isomerization of prolines in IgA1-hinge peptide. J Am Chem Soc 132:5548–5549

    PubMed  CAS  Google Scholar 

  • Natvig IB, Johansen FE, Nordeng TW, Haraldsen G, Brandtzaeg P (1997) Mechanism for enhanced external transfer of dimeric IgA over pentameric IgM: studies of diffusion, binding to the human polymeric Ig receptor, and epithelial transcytosis. J Immunol 159:4330–4340

    PubMed  CAS  Google Scholar 

  • Navarro P, Christenson RK, Ekhardt G, Bosworth B, Lunney JK, Rothschild M, Lemke J, Butler JE (2000) Genetic differences in the frequency of the hinge variants of porcine IgA is breed dependent. Vet Immunol Immunopathol 73:287–295

    PubMed  CAS  Google Scholar 

  • Norderhaug IN, Johansen FE, Krajci P, Brandtzaeg P (1999) Domain deletions in the human polymeric Ig receptor disclose differences between its dimeric and pentameric IgM interaction. Eur J Immunol 29:3401–3409

    PubMed  CAS  Google Scholar 

  • Otten MA, Rudolph E, Dechant M, Tuk CW, Reijmers RM, Beelen RH, van de Winkel JGJ, van Egmond M (2005) Immature neutrophils mediate tumor cell killing via IgA but not IgG Fc receptors. J Immunol 174:5472–5480

    PubMed  CAS  Google Scholar 

  • Pasquier B, Launay P, Kanamaru Y, Moura IC, Pfirsch S, Ruffié C, Hénin D, Benhamou M, Pretolani M, Blank U, Monteiro RC (2005) Identification of FcαRI as an inhibitory receptor that controls inflammation: dual role of FcR γ ITAM. Immunity 22:31–42

    PubMed  CAS  Google Scholar 

  • Phillips-Quagliata JM (2002) Mouse IgA allotypes have major differences in their hinge regions. Immunogenetics 53:1033–1038

    PubMed  CAS  Google Scholar 

  • Pleass RJ, Dunlop JI, Anderson CM, Woof JM (1999) Identification of residues in the CH2/CH3 domain interface of IgA essential for interaction with the human Fcα receptor (FcαR) CD89. J Biol Chem 274:23508–23514

    PubMed  CAS  Google Scholar 

  • Pleass RJ, Areschoug T, Lindahl G, Woof JM (2001) Streptococcal IgA-binding proteins bind in the Cα2-Cα3 interdomain region and inhibit binding of IgA to human CD89. J Biol Chem 276:8197–8204

    PubMed  CAS  Google Scholar 

  • Polissi A, Pontiggia A, Feger G, Altieri M, Mottl H, Ferrari L, Simon D (1998) Large-scale identification of virulence genes from Streptococcus pneumoniae. Infect Immun 66:5620–5629

    PubMed  CAS  Google Scholar 

  • Ramsland PA, Willoughby N, Trist HM, Farrugia W, Hogarth PM, Fraser JD, Wines BD (2007) Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1. Proc Natl Acad Sci USA 104:15051–15056

    PubMed  CAS  Google Scholar 

  • Robinson JK, Blanchard TG, Levine AD, Emancipator SN, Lamm ME (2001) A mucosal IgA-mediated excretory immune system in vivo. J Immunol 166:3688–3692

    PubMed  CAS  Google Scholar 

  • Rogers KA, Jayashankar L, Scinicariello F, Attanasio R (2008) Nonhuman primate IgA: genetic heterogeneity and interaction with CD89. J Immunol 180:4816–4824

    PubMed  CAS  Google Scholar 

  • Roos A, Bouwman LH, van Gijlswijk-Janssen DJ, Faber-Krol MC, Stahl GL, Daha MR (2001) Human IgA activates the complement system via the mannan-binding lectin pathway. J Immunol 167:2861–2868

    PubMed  CAS  Google Scholar 

  • Royle L, Roos A, Harvey DJ, Wormald MR, van Gijlswijk-Jannsen D, Redwan E-RM, Wilson IA, Daha MR, Dwek RA, Rudd PM (2003) Secretory IgA N- and O-linked glycans provide a link between the innate and adaptive immune systems. J Biol Chem 278:20140–20153

    PubMed  CAS  Google Scholar 

  • Ruhl S, Sandberg AL, Cole MF, Cisar JO (1996) Recognition of immunoglobulin A1 by oral actinomyces and streptococcal lectins. Infect Immun 64:5421–5424

    PubMed  CAS  Google Scholar 

  • Russell MW, Kilian M (2005) Biological activities of IgA. In: Mestecky JR, Bienenstock J, Lamm ME, Mayer L, McGhee JR, Strober W (eds) Mucosal immunology, 3rd edn. Elsevier Academic, Amsterdam

    Google Scholar 

  • Schwartz-Cornil I, Benureau Y, Greenberg H, Hendrickson BA, Cohen J (2002) Heterologous protection induced by the inner capsid proteins of rotavirus requires transcytosis of mucosal immunoglobulins. J Virol 76:8110–8117

    PubMed  CAS  Google Scholar 

  • Scinicariello F, Engleman CN, Jayashankar L, McClure HM, Attanasio R (2004) Rhesus macaque antibody molecules: sequences and heterogeneity of alpha and gamma constant regions. Immunology 111:66–74

    PubMed  CAS  Google Scholar 

  • Scinicariello F, Masseoud F, Jayashankar L, Attanasio R (2006) Sooty mangabey (Cercocebus torquatus atys) IGHG and IGHA genes. Immunogenetics 58:955–965

    PubMed  CAS  Google Scholar 

  • Senior BW, Woof JM (2005a) Effect of mutations in the human immunoglobulin A1 (IgA1) hinge on its susceptibility to cleavage by diverse bacterial IgA1 proteases. Infect Immun 73:1515–1522

    PubMed  CAS  Google Scholar 

  • Senior BW, Woof JM (2005b) The influences of hinge length and composition on the susceptibility of human IgA to cleavage by diverse bacterial IgA1 proteases. J Immunol 174:7792–7799

    PubMed  CAS  Google Scholar 

  • Senior BW, Woof JM (2006) Sites in the CH3 domain of human IgA1 that influence sensitivity to bacterial IgA1 proteases. J Immunol 177:3913–3919

    PubMed  CAS  Google Scholar 

  • Senior BW, Dunlop JI, Batten MR, Kilian M, Woof JM (2000) Cleavage of a recombinant human immunoglobulin A2 (IgA2)-IgA1 hybrid antibody by certain bacterial IgA1 proteases. Infect Immun 68:463–469

    PubMed  CAS  Google Scholar 

  • Shibuya A, Honda SI (2006) Molecular and functional characteristics of the Fcα/μR, a novel Fc receptor for IgM and IgA. Springer Semin Immunopathol 28:377–382

    PubMed  CAS  Google Scholar 

  • Slack E, Balmer ML, Fritz JH, Hapfelmeier S (2012) Functional flexibility of intestinal IgA – broadening the fine line. Front Immunol 3(article 100):1–10

    Google Scholar 

  • Snoeck V, Peters IR, Cox E (2006) The IgA system: a comparison of structure and function in different species. Vet Res 37:455–467

    PubMed  CAS  Google Scholar 

  • Spencer J, Klavinskis LS, Fraser LD (2012) The human intestinal IgA response: burning questions. Front Immunol 3(article 108):1–10

    Google Scholar 

  • Spieker-Polet H, Yam PC, Knight KL (1993) Differential expression of 13 IgA-heavy chain genes in rabbit lymphoid tissues. J Immunol 61:5457–5465

    Google Scholar 

  • Stenberg L, O’Toole PW, Mestecky J, Lindahl G (1994) Molecular characterization of protein Sir, a streptococcal cell surface protein that binds both immunoglobulin A and immunoglobulin G. J Biol Chem 269:13458–13464

    PubMed  CAS  Google Scholar 

  • Stephens S, Dolby JM, Montreuil J, Spik G (1980) Differences in inhibition of the growth of commensal and enteropathogenic strains of Escherichia coli by lactotransferrin and secretory immunoglobulin A isolated from human milk. Immunology 41:597–603

    PubMed  CAS  Google Scholar 

  • Stewart WW, Kerr MA (1990) The specificity of the human neutrophil IgA receptor (FcαR) determined by measurement of chemiluminescence induced by serum or secretory IgA1 or IgA2. Immunology 71:328–334

    PubMed  CAS  Google Scholar 

  • Stockert RJ, Kressner MS, Collins JC, Sternlieb I, Morell AG (1982) IgA interaction with the asialoglycoprotein receptor. Proc Natl Acad Sci USA 79:6229–6231

    PubMed  CAS  Google Scholar 

  • Stockmeyer B, Dechant M, van Egmond M, Tutt AL, Sundarapandiyan K, Graziano RF, Repp R, Kalden JR, Gramatzki M, Glennie MJ, van de Winkel JGJ, Valerius T (2000) Triggering Fcα-receptor I (CD89) recruits neutrophils as effector cells for CD20-directed antibody therapy. J Immunol 165:5954–5961

    PubMed  CAS  Google Scholar 

  • Tarelli E, Smith AC, Hendry BM, Challacombe SJ, Pouria S (2004) Human serum IgA1 is substituted with up to six O-glycans as shown by matrix assisted laser desorption ionisation time-of-flight mass spectrometry. Carbohydr Res 339:2329–2335

    PubMed  CAS  Google Scholar 

  • Tenovuo J, Moldoveanu Z, Mestecky J, Pruitt KM, Rahemtulla BM (1982) Interaction of specific and innate factors of immunity: IgA enhances the antimicrobial effect of the lactoperoxidase system against Streptococcus mutans. J Immunol 128:726–731

    PubMed  CAS  Google Scholar 

  • Tomana M, Niedermeier W, Mestecky J, Skvaril F (1976) The differences in carbohydrate composition between the subclasses of IgA immunoglobulins. Immunochemistry 13:325–328

    PubMed  CAS  Google Scholar 

  • Underdown BJ, DeRose J, Plaut A (1977) Disulfide bonding of secretory component to a single monomer subunit in human secretory IgA. J Immunol 118:1816–1821

    PubMed  CAS  Google Scholar 

  • Vaerman JP, Heremans JF, van Kerckhoven G (1969) Identification of IgA in several mammalian species. J Immunol 103:1421–1423

    PubMed  CAS  Google Scholar 

  • van der Pol W, Vidarsson G, Vile HA, van de Winkel JG, Rodriguez ME (2000) Pneumococcal capsular polysaccharide-specific IgA triggers efficient neutrophil effector functions via FcαRI (CD89). J Infect Dis 182:1139–1145

    PubMed  Google Scholar 

  • van Egmond M, van Garderen E, van Spriel AB, Damen CA, van Amersfoort ES, van Zandbergen G, van Hattum J, Kuiper J, van de Winkel JG (2000) FcαRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity. Nat Med 6:680–685

    PubMed  Google Scholar 

  • van Egmond M, van Spriel AB, Vermeulen H, Huls G, Van Garderen E, van de Winkel JGJ (2001) Enhancement of polymorphonuclear cell-mediated tumor cell killing on simultaneous engagement of FcγRI (CD64) and FcαRI (CD89). Cancer Res 61:4055–4060

    PubMed  Google Scholar 

  • van Spriel AB, Leusen JH, Vilé H, van de Winkel JG (2002) Mac-1 (CD11b/CD18) as accessory molecule for FcαR (CD89) binding of IgA. J Immunol 169:3831–3836

    PubMed  Google Scholar 

  • Vidarsson G, van der Pol WL, van den Elsen JM, Vilé H, Jansen M, Duijs J, Morton HC, Boel E, Daha MR, Corthésy B, van de Winkel JG (2001) Activity of human IgG and IgA subclasses in immune defense against Neisseria meningitidis serogroup B. J Immunol 166:6250–6256

    PubMed  CAS  Google Scholar 

  • Wang R, Fu Y, Zhao Q, Pan L, Zhang W (2009) Human Fcα/μR and pIgR distribute differently in intestinal tissues. Biochem Biophys Res Commun 381:148–152

    PubMed  CAS  Google Scholar 

  • Watanabe T, Nagura H, Watanabe K, Brown WR (1984) The binding of human milk lactoferrin to immunoglobulin A. FEBS Lett 168:203–207

    PubMed  CAS  Google Scholar 

  • White KD, Capra JD (2002) Targeting mucosal sites by polymeric immunoglobulin receptor-directed peptides. J Exp Med 196:551–555

    PubMed  CAS  Google Scholar 

  • Wines BD, Hulett MD, Jamieson GP, Trist HM, Spratt JM, Hogarth PM (1999) Identification of residues in the first domain of human Fcα receptor essential for interaction with IgA. J Immunol 162:2146–2153

    PubMed  CAS  Google Scholar 

  • Wines BD, Sardjono CT, Trist HH, Lay CS, Hogarth PM (2001) The interaction of FcαRI with IgA and its implications for ligand binding by immunoreceptors of the leukocyte receptor cluster. J Immunol 166:1781–1789

    PubMed  CAS  Google Scholar 

  • Wines BD, Willoughby N, Fraser JD, Hogarth PM (2006) A competitive mechanism for staphylococcal toxin SSL7 inhibiting the leukocyte IgA receptor, FcαRI, is revealed by SSL7 binding at the Cα2/Cα3 interface of IgA. J Biol Chem 281:1389–1393

    PubMed  CAS  Google Scholar 

  • Wines BD, Trist HM, Farrugia W, Ngo C, Trowsdale J, Areschoug T, Lindahl G, Fraser JD, Ramsland PA (2012) A conserved host and pathogen recognition site on immunoglobulins: structural and functional aspects. Adv Exp Med Biol 946:87–112

    PubMed  CAS  Google Scholar 

  • Wold A, Mestecky J, Tomana M, Kobata A, Ohbayashi H, Endo T, Edén CS (1990) Secretory immunoglobulin A carries oligosaccharide receptors for Escherichia coli type 1 fimbrial lectin. Infect Immun 58:3073–3077

    PubMed  CAS  Google Scholar 

  • Woof JM, Burton DR (2004) Human antibody-Fc receptor interactions illuminated by crystal structures. Nat Rev Immunol 4:89–99

    PubMed  CAS  Google Scholar 

  • Woof JM, Russell MW (2011) Structure and function relationships in IgA. Mucosal Immunol 4:590–597

    PubMed  CAS  Google Scholar 

  • Wright A, Yan H, Lamm ME, Huang YT (2006) Immunoglobulin A antibodies against internal HIV-1 proteins neutralize HIV-1 replication inside epithelial cells. Virology 356:165–170

    PubMed  CAS  Google Scholar 

  • Yan H, Lamm ME, Björling E, Huang YT (2002) Multiple functions of immunoglobulin A in mucosal defense against viruses: an in vitro measles virus model. J Virol 76:10972–10979

    PubMed  CAS  Google Scholar 

  • Yoo EM, Coloma MJ, Trinh KR, Nguyen TQ, Vuong LU, Morrison SL, Chintalacharuvu KR (1999) Structural requirements for polymeric immunoglobulin assembly and association with J chain. J Biol Chem 274:33771–33777

    PubMed  CAS  Google Scholar 

  • Yoo EM, Trinh KR, Lim H, Wims LA, Morrison SL (2011) Characterization of IgA and IgM binding and internalization by surface-expressed human Fcα/μ receptor. Mol Immunol 48:1818–1826

    PubMed  CAS  Google Scholar 

  • Zhang JR, Mostov KE, Lamm ME, Nanno M, Shimida S, Ohwaki M, Tuomanen E (2000) The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells. Cell 102:827–837

    PubMed  CAS  Google Scholar 

  • Zhang YA, Salinas I, Li J, Parra D, Bjork S, Xu Z, LaPatra SE, Bartholomew J, Sunyer JO (2010) IgT, a primitive immunoglobulin class specialized in mucosal immunity. Nat Immunol 11:827–835

    PubMed  CAS  Google Scholar 

  • Zhao J, Kuroki M, Shibaguchi H, Wang L, Huo Q, Takami N, Tanaka T, Kinugasa T, Kuroki M (2008) Recombinant human monoclonal IgA antibody against CEA to recruit neutrophils to CEA-expressing cells. Oncol Res 17:217–222

    PubMed  Google Scholar 

  • Zikan J, Novotny J, Trapane TL, Koshland ME, Urry DW, Bennett JC, Mestecky J (1985) Secondary structure of the immunoglobulin J chain. Proc Natl Acad Sci USA 82:5905–5909

    PubMed  CAS  Google Scholar 

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Correspondence to Jenny M. Woof B.Sc. Ph.D .

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Woof, J.M. (2013). Immunoglobulin A: Molecular Mechanisms of Function and Role in Immune Defence. In: Nimmerjahn, F. (eds) Molecular and Cellular Mechanisms of Antibody Activity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7107-3_2

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