Skip to main content
SpringerLink
Log in

Intracellular Antibody Immunity

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Antibodies allow the immune system to target pathogens despite their tremendous diversity and rapid evolution. Once bound to a pathogen, antibodies induce a broad range of effector mechanisms, including phagocytosis and complement. However, these mechanisms are all initiated in the extracellular space, meaning that pathogens like viruses evade them upon infection of their target cells. Recently, it has been shown that, in addition to mediating extracellular immune responses, antibodies also activate immunity inside infected cells. Antibodies that are bound to the surface of non-enveloped viruses or bacteria are carried into the cell during pathogen entry. Once inside the cell, these pathogen-attached antibodies are recognised by a highly conserved, high affinity cytosolic antibody receptor called TRIM21. TRIM21 initiates both sensor and effector responses that reduce viral replication and induce an antiviral state. These responses are an important part of antiviral immunity and the removal of TRIM21 results in uncontrolled viraemia and death in a mouse model of infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Burns JW, Siadat-Pajouh M, Krishnaney AA, Greenberg HB. Protective effect of rotavirus VP6-specific IgA monoclonal antibodies that lack neutralizing activity. Science. 1996;272(5258):104–7.

    Article  CAS  PubMed  Google Scholar 

  2. Feng N, Lawton JA, Gilbert J, Kuklin N, Vo P, Prasad BV. Inhibition of rotavirus replication by a non-neutralizing, rotavirus VP6-specific IgA mAb. J Clin Invest. 2002;109(9):1203–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Fujioka H, Emancipator SN, Aikawa M, Huang DS, Blatnik F, Karban T, et al. Immunocytochemical colocalization of specific immunoglobulin A with sendai virus protein in infected polarized epithelium. J Exp Med. 1998;188(7):1223–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Mazanec MB, Kaetzel CS, Lamm ME, Fletcher D, Nedrud JG. Intracellular neutralization of virus by immunoglobulin A antibodies. Proc Natl Acad Sci U S A. 1992;89(15):6901–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Mazanec MB, Coudret CL, Fletcher DR. Intracellular neutralization of influenza virus by immunoglobulin A anti-hemagglutinin monoclonal antibodies. J Virol. 1995;69(2):1339–43.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Bomsel M, Heyman M, Hocini H, Lagaye S, Belec L, Dupont C, et al. Intracellular neutralization of HIV transcytosis across tight epithelial barriers by anti-HIV envelope protein dIgA or IgM. Immunity. 1998;9(2):277–87.

    Article  CAS  PubMed  Google Scholar 

  7. Bai Y, Ye L, Tesar DB, Song H, Zhao D, Bjorkman PJ, et al. Intracellular neutralization of viral infection in polarized epithelial cells by neonatal Fc receptor (FcRn)-mediated IgG transport. Proc Natl Acad Sci U S A. 2011;108(45):18406–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Mallery DL, McEwan WA, Bidgood SR, Towers GJ, Johnson CM, James LC. Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proc Natl Acad Sci U S A. 2010;107(46):19985–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Yang Y, Eversole T, Lee DJ, Sontheimer RD, Capra JD. Protein–protein interactions between native Ro52 and immunoglobulin G heavy chain. Scand J Immunol. 1999;49(6):620–8.

    Article  CAS  PubMed  Google Scholar 

  10. McEwan WA, Hauler F, Williams CR, Bidgood SR, Mallery DL, Crowther RA, et al. Regulation of virus neutralization and the persistent fraction by TRIM21. J Virol. 2012;86(16):8482–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. McEwan WA, Mallery DL, Rhodes DA, Trowsdale J, James LC. Intracellular antibody-mediated immunity and the role of TRIM21. Bioessays News Rev Mol Cell Dev Biol. 2011;33(11):803–9.

    Article  CAS  Google Scholar 

  12. Auf der Maur A, Escher D, Barberis A. Antigen-independent selection of stable intracellular single-chain antibodies. FEBS Lett. 2001;508(3):407–12.

    Article  CAS  PubMed  Google Scholar 

  13. Rhodes DA, Ihrke G, Reinicke AT, Malcherek G, Towey M, Isenberg DA, et al. The 52 000 MW Ro/SS-A autoantigen in Sjogren’s syndrome/systemic lupus erythematosus (Ro52) is an interferon-gamma inducible tripartite motif protein associated with membrane proximal structures. Immunology. 2002;106(2):246–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. James LC, Keeble AH, Khan Z, Rhodes DA, Trowsdale J. Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. Proc Natl Acad Sci U S A. 2007;104(15):6200–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Keeble AH, Khan Z, Forster A, James LC. TRIM21 is an IgG receptor that is structurally, thermodynamically, and kinetically conserved. Proc Natl Acad Sci U S A. 2008;105(16):6045–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Hauler F, Mallery DL, McEwan WA, Bidgood SR, James LC. AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization. Proc Natl Acad Sci U S A. 2012;109(48):19733–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Beskow A, Grimberg KB, Bott LC, Salomons FA, Dantuma NP, Young P. A conserved unfoldase activity for the p97 AAA-ATPase in proteasomal degradation. J Mol Biol. 2009;394(4):732–46.

    Article  CAS  PubMed  Google Scholar 

  18. McEwan WA, Tam JC, Watkinson RE, Bidgood SR, Mallery DL, James LC. Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. Nat Immunol. 2013;14(4):327–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Vaysburd M, Watkinson RE, Cooper H, Reed M, O’Connell K, Smith J, et al. Intracellular antibody receptor TRIM21 prevents fatal viral infection. Proc Natl Acad Sci U S A. 2013;110(30):12397–401.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK

    Ruth E. Watkinson, William A. McEwan & Leo C. James

Authors
  1. Ruth E. Watkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William A. McEwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leo C. James
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leo C. James.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watkinson, R.E., McEwan, W.A. & James, L.C. Intracellular Antibody Immunity. J Clin Immunol 34 (Suppl 1), 30–34 (2014). https://doi.org/10.1007/s10875-014-0017-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-014-0017-4

Keywords

Search

Navigation