Clinical and Experimental Medicine

, Volume 11, Issue 1, pp 1–10 | Cite as

Advances in the understanding of the Fc gamma receptors-mediated autoantibodies uptake

  • Sabrina Lisi
  • Margherita Sisto
  • Dario Domenico Lofrumento
  • Simona D’Amore
  • Massimo D’Amore
Review Article


Receptors for the Fc fragment of immunoglobulin G (FcγRs) are important molecules not only to mediate and control the effectors’ functions of IgG antibodies, but they also control the autoimmunity-tolerance balance in the periphery. In humans, three different types of FcγRs, belonging to the Ig gene superfamily, have been identified; FcγRI (cluster of differentiation (CD64), FcγRII (CD32) and FcγRIII (CD16). A wide range of inflammatory and autoimmune diseases, such as vasculitis, glomerulonephritis, and autoimmune hemolytic anemia, seems to be mediated, in part, by FcγRs. Recent findings supposed that, under certain conditions, FcγRs are involved in the penetration of antibodies into cells and FcγRs constitute one of the main effector mechanisms through which autoantibodies exert their action. In this review, we concentrate on the role of human FcγRs in autoantibodies penetration and summarize the current knowledge on the structure, ligand binding capacity and their role in autoimmunity and pathogenic effect of autoantibodies.


Autoantibodies Fcγ Receptors IgG Adalimumab Salivary gland 



We are grateful to M.V.C. Pragnell, B.A., for critical reading of the manuscript.

Conflict of interest



  1. 1.
    Arbuckle MR, Mc Clain MT, Rubertone MV et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349:1526–1533CrossRefPubMedGoogle Scholar
  2. 2.
    Shoenfeld Y, Blank M, Abu-Shakra M et al (2008) The mosaic of autoimmunity: prediction, autoantibodies, and therapy in autoimmune diseases-2008. Isr Med Assoc J 10:13–19PubMedGoogle Scholar
  3. 3.
    Bizzaro N (2007) Autoantibodies as predictors of disease: the clinical and experimental evidence. Autoimmun Rev 6:325–333CrossRefPubMedGoogle Scholar
  4. 4.
    Alarcon-Segovia D, Ruiz-Arguelles A, Llorente L (1979) Antibody penetration into living cells. II. Anti-ribonucleoprotein IgG penetrates into T gamma lymphocytes causing their deletion and the abrogation of suppressor function. J Immunol 122:1562–1855Google Scholar
  5. 5.
    Kramers K, van Bruggen MCJ, Rijke-Schilder TPM et al (1996) In vivo ANA is a fixation artifact: nucleosome-complexed antinucleosome autoantibodies bind to cell surface and are internalized. J Am Soc Nephrol 7:946–954PubMedGoogle Scholar
  6. 6.
    Ruiz-Arguelles A, Perez-Romano B, Llorente L et al (1998) Antibody penetration of anti-DNA antibodies into immature live cells. J Autoimmun 11:547–556CrossRefPubMedGoogle Scholar
  7. 7.
    Madaio MP, Yanase K (1998) Cellular penetration and nuclear localization of anti-DNA antibodies: mechanisms, consequences, implications and applications. J Autoimmun 11:535–538CrossRefPubMedGoogle Scholar
  8. 8.
    Reichlin M (1998) Cellular dysfunction induced by penetration of autoantibodies into living cells: cellular damage and dysfunction mediated by antibodies to dsDNA and ribosomal P proteins. J Autoimmun 11:557–561CrossRefPubMedGoogle Scholar
  9. 9.
    Adamus G, Machniki M, Elerding H et al (1998) Antibodies to recoverin induce apoptosis of photoreceptor and bipolar cells in vivo. J Autoimmun 11:523–533CrossRefPubMedGoogle Scholar
  10. 10.
    Wesibart RH, Baldwin R, Huh B et al (2000) Novel protein transfection of primary rat cortical neurons using an antibody that penetrates living cells. J Immunol 164:6020–6026Google Scholar
  11. 11.
    Tezel G, Wax MB (2000) The mechanism of hsp antibody-mediated apoptosis in retinal neuronal cells. J Neurosci 20:3552–3562PubMedGoogle Scholar
  12. 12.
    Ritz MF, Erne B, Ferracin F et al (1999) Anti-MAG IgM penetration into myelinated fibers correlates with the extent of myelin widening. Muscle Nerve 22:1030–1037CrossRefPubMedGoogle Scholar
  13. 13.
    El-Fawal HA, Waterman SJ, DeFeo A et al (1999) Neuroimmunotoxicology: humoral assessment of neurotoxicity and autoimmune mechanisms. Environ Health Perspect 107:767–775CrossRefPubMedGoogle Scholar
  14. 14.
    Schulze K, Becker BF, Schultheiss HP (1989) Antibodies to the ADP/ATP carrier, an autoantigen in myocarditis and dilated cardiomyopathy, penetrate into myocardial cells and disturb energy metabolism in vivo. Circ Res 64:179–192PubMedGoogle Scholar
  15. 15.
    Abedi-Valugerdi M, Hu H, Moller G (1999) Mercury-induced anti-nucleolar autoantibodies can transgress the membrane of living cells in vivo and in vitro. Int Immunol 11:605–615CrossRefPubMedGoogle Scholar
  16. 16.
    Schmidt-Acevedo S, Perez-Romano B, Ruiz-Arguelles A (2000) ‘LE Cells’ result from phagocytosis of apoptotic bodies induced by antinuclear antibodies. J Autoimmun 15:15–20CrossRefPubMedGoogle Scholar
  17. 17.
    Tse E, Rabbitts TH (2000) Intracellular antibody-caspase-mediated cell killing: an approach for application in cancer therapy. Proc Nat Acad Sci USA 97:12266–12271CrossRefPubMedGoogle Scholar
  18. 18.
    Brucato A, Cimaz R, Stramba-Badiale M (2002) Neonatal lupus. Clin Rev Allergy Immunol 23:279–299CrossRefPubMedGoogle Scholar
  19. 19.
    Lisi S, Sisto M, Soleti R et al (2007) Fcgamma receptors mediate internalization of anti-Ro and anti-La autoantibodies from Sjögren’s syndrome and apoptosis in human salivary gland cell line A-253. J Oral Pathol Med 36:511–523CrossRefPubMedGoogle Scholar
  20. 20.
    Lisi S, D’Amore M, Lofrumento D et al (2008) Modulation of the Fcgamma receptors induced by anti-Ro and anti-La autoantibodies: observations in salivary gland cells. Rheumatol Int 28:943–948CrossRefPubMedGoogle Scholar
  21. 21.
    Goldtsein JL, Anderson RGW, Brown MS (1979) Coated pits, coated vesicles and receptor mediated endocytosis. Nature 279:679–685CrossRefGoogle Scholar
  22. 22.
    Golan TD, Grushko G, Shemuel Z et al (1998) Anti-La+ and anti-Ro+ autoimmune sera favor intranuclear IgG import in cultured epidermal cells. Lupus 7:121Google Scholar
  23. 23.
    Cauza K, Grassauer A, Hinterhuber G et al (2002) FcgammaRIII expression on cultured human keratinocytes and upregulation by interferon-gamma. J Invest Dermatol 119:1074–1079CrossRefPubMedGoogle Scholar
  24. 24.
    Stavnezer J (1996) Immunoglobulin class switching. Curr Opin Immunol 8:199–205CrossRefPubMedGoogle Scholar
  25. 25.
    Hulett MD, Hogarth PM (1994) Molecular basis of Fc receptor function. Adv Immunol 57:1–127CrossRefPubMedGoogle Scholar
  26. 26.
    Ravetch JV, Anderson CL (1990) Fc receptors and the action of antibodies. In: Metzger H (ed) ASM, Washington, D.C., pp 211–235Google Scholar
  27. 27.
    Maxwell KF, Powell MS, Hulett MD (1999) Crystal structure of the human leukocyte Fc receptor, FcgRlla. Nat Struct Biol 6:437–442CrossRefPubMedGoogle Scholar
  28. 28.
    Takai T (2005) Fc receptors and their role in immune regulation and autoimmunity. J Clin Immunol 25:1–18CrossRefPubMedGoogle Scholar
  29. 29.
    Kato K, Sautes-Fridman C, Yamada W et al (2000) Structural basis of the interaction between IgG and FcγR. J Mol Biol 295:213–224CrossRefPubMedGoogle Scholar
  30. 30.
    Sondermann P, Huber R, Oosthuizen V et al (2000) The 3.2-A crystal structure of the human IgG1 Fc fragment-FcγRIII complex. Nature 406:267–273CrossRefPubMedGoogle Scholar
  31. 31.
    Cowan FM, Broomfield CA, Smith WJ (1998) Sulfur mustard exposure enhances Fc receptor expression on human epidermal keratinocytes in cell culture: implications for toxicity and medical countermeasures. Cell Biol Toxicol 14:261–266CrossRefPubMedGoogle Scholar
  32. 32.
    Nitta T, Yagita H, Okumura K et al (1990) Analysis of receptor expression on astrocytic cells. No To Shinkei 42:945–950PubMedGoogle Scholar
  33. 33.
    Dobre MA, Ghetie V (1979) Binding of cytophilic rabbit IgG to homologous hepatocytes. Experientia 35:763–765CrossRefPubMedGoogle Scholar
  34. 34.
    Andoh T, Kuraishi Y (2004) Direct action of immunoglobulin G on primary sensory neurons through Fc gamma receptor I. FASEB J 18:182–184PubMedGoogle Scholar
  35. 35.
    Lyden TW, Robinson JM, Tridandapani S et al (2001) The Fc receptor for IgG expressed in the villus endothelium of human placenta is Fc gamma RIIb2. J Immunol 166:3882–3889PubMedGoogle Scholar
  36. 36.
    Antonsson A, Johansson PJ (2001) Binding of human and animal immunoglobulins to the IgG Fc receptor induced by human cytomegalovirus. J Gen Virol 82:1137–1145PubMedGoogle Scholar
  37. 37.
    Ober RJ, Martinez C, Lai X et al (2004) Exocytosis of IgG as mediated by the receptor, FcRn: an analysis at the single molecule level. Proc Natl Acad Sci USA 101:11076–11081CrossRefPubMedGoogle Scholar
  38. 38.
    Takai T, Li M, Sylvestre D et al (1994) FcR γ chain deletion results in pleiotrophic effector cell defects. Cell 76:519–529CrossRefPubMedGoogle Scholar
  39. 39.
    Torsteinsdottir I, Arvidson NG, Hallgren R et al (1999) Monocyte activation in rheumatoid arthritis (RA): increased integrin, Fc gamma and complement receptor expression and the effect of glucocorticoids. Clin and Exp Immunol 115:554–560CrossRefGoogle Scholar
  40. 40.
    Broker BM, Edwards JC, Fanger MW et al (1990) The prevalence and distribution of macrophages bearing Fc gamma R I, Fc gamma R II, and Fc gamma R III in synovium. Scand J Rheumatol 19:123–135CrossRefPubMedGoogle Scholar
  41. 41.
    Wijngaarden S, van de Winkel JG, Bijlsma JW et al (2008) Treatment of rheumatoid arthritis patients with anti-TNF-alpha monoclonal antibody is accompanied by down-regulation of the activating Fcgamma receptor I on monocytes. Clin Exp Rheum 26:89–95Google Scholar
  42. 42.
    Wijngaarden S, van Roon JA, van de Winkel JG et al (2005) Down-regulation of activating Fcgamma receptors on monocytes of patients with rheumatoid arthritis upon methotrexate treatment. Rheumatology (Oxford) 44:729–734CrossRefGoogle Scholar
  43. 43.
    Ravetch JV, Perussia B (1989) Alternative membrane forms of Fc gamma RIII (CD16) on human natural killer cells and neutrophils. Cell type-specific expression of two genes that differ in single nucleotide substitutions. J Exp Med 170:481–497CrossRefPubMedGoogle Scholar
  44. 44.
    Hartnell A, Kay AB, Wardlaw AJ (1992) IFN-gamma induces expression of Fc gamma RIII (CD16) on human eosinophils. J Immunol 148:1471–1478PubMedGoogle Scholar
  45. 45.
    Shen H, Zhang M, Kaita K et al (2005) Expression of Fc fragment receptors of immunoglobulin G (Fc gammaRs) in rat hepatic stellate cells. Dig Dis Sci 50:181–187CrossRefPubMedGoogle Scholar
  46. 46.
    Magnusson SE, Engström M, Jacob U et al (2007) High synovial expression of the inhibitory FcgammaRIIb in rheumatoid arthritis. Arthritis Res Ther 9:R51CrossRefPubMedGoogle Scholar
  47. 47.
    Reimold AM (2002) TNF alpha as therapeutic target: new drugs, more applications. Curr Drug Targets Inflamm Allergy 1:377–392CrossRefPubMedGoogle Scholar
  48. 48.
    Salfeld J, Kaymakçalan Z, Tracey D et al (1998) Generation of fully human anti-TNF antibody D2E7. Arthritis Rheum 41:S57Google Scholar
  49. 49.
    Cassard L, Cohen-Solal JF, Galinha A et al (2002) Modulation of tumor growth by inhibitory Fcγ receptor expressed by human melanoma cells. J Clin Invest 110:1549–1557PubMedGoogle Scholar
  50. 50.
    Nakamura A, Akiyama K, Takai T (2005) Fc receptor targeting in the treatment of allergy, autoimmune diseases and cancer. Expert Opin Ther Targets 9:169–190CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Sabrina Lisi
    • 1
  • Margherita Sisto
    • 1
  • Dario Domenico Lofrumento
    • 2
  • Simona D’Amore
    • 3
  • Massimo D’Amore
    • 3
  1. 1.Department of Human Anatomy and Histology, Section of Cell BiologyUniversity of Bari Medical SchoolBariItaly
  2. 2.Department of Biological and Environmental Sciences and TechnologiesUniversity of SalentoLecceItaly
  3. 3.Department of Internal Medicine and Public Medicine, Section of RheumatologyUniversity of Bari Medical SchoolBariItaly

Personalised recommendations