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Functional regulation of human neutrophil Fc γ receptors

  • Immunology at Emory University
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Abstract

Interaction between Fc receptors expressed on phagocytic cells and antibodies play a critical role in innate immune response. Interestingly, immune cells such as neutrophils, monocytes, and dendritic cells (DCs) express multiple Fc receptors for IgG (FγR) with overlapping ligand specificity. These receptors compete for the same ligand on the target and are known to transduce positive and negative signals to the same cell, depending on presence of type of signaling motif in their cytoplasmic domain. Neutrophils, the first line of defense against bacterial infection and the major phagocytic cell in the blood, express two types of FcγRs depending on the species. In humans, the neutrophils co-express immunoreceptor tyrosine-based activation motif (ITAM) containing CD32A and glycosylphosphatidyl inositol (GPI)-anchored CD16B, which is in contrast to co-expression of ITAM containing CD16A and ITIM containing CD32B in mouse neutrophils. Recent studies in gene knockout mice have demonstrated that the negative signaling by CD32B plays a critical role in preventing immune complex (IC)-mediated autoimmune diseases by regulating the activation signal delivered by CD16A. However, it is not known how the function of ITAM signaling CD32A is regulated in human neutrophils. Recent observations from our laboratory suggest that in human neutrophils, the CD32A receptor is regulated at the ligand-binding stage. Using a CD16B-deficient donor, we found that the CD32A expressed on resting neutrophils is unable to bind ligand; however, once neutrophils are activated with fMLP, a bacterial chemotactic peptide, the CD32A is functionally active in binding ligand. We also observed that this regulation is neutrophil-specific phenomenon. These observations suggest that FcγR can be regulated by distinct mechanisms and factors such as membrane-anchoring, cell-specific signaling, and avidity modulation that may be coordinately involved in regulating the function of human FγR. Because neutrophils may be activated during infectious and inflammatory diseases, the knowledge of functional regulation of Fc γR will be useful in designing therapies for many autoimmune diseases.

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References

  1. Kimberly RP, Wu J, Gibson AW, et al.: Diversity and duplicity: human Fc gamma receptors in host defense and autoimmunity. Immunol Res 2002;26:177–189.

    Article  PubMed  CAS  Google Scholar 

  2. Pritchard NR: B cell inhibitory receptors and autoimmunity. Immunology 2003;108:263–273.

    Article  PubMed  CAS  Google Scholar 

  3. Hogarth PM: Fc receptors are major mediators of antibody based inflammation in autoimmunity. Curr Opin Immunol 2002;14:798–802.

    Article  PubMed  CAS  Google Scholar 

  4. Salmon JE, Pricop L: Human receptors for immunoglobulin G: key elements in the pathogenesis of rheumatic disease. Arthritis Rheum 2001;44:739–750.

    Article  PubMed  CAS  Google Scholar 

  5. Ravetch JV, Bolland S: IgG Fc Receptors. Annu Rev Immunol 2001;19:275–290.

    Article  PubMed  CAS  Google Scholar 

  6. Raghavan M, Bjorkman PJ: Fc receptors and their interactions with immunoglobulins. Annu Rev Cell Biol 1996;12:181–220.

    Article  CAS  Google Scholar 

  7. Unkeless JC, Scigliano E, Freedman VH: Structure and function of human and murine receptors for IgG. Annu Rev Immunol 1988;6:251–281.

    Article  PubMed  CAS  Google Scholar 

  8. Anderson CL, Looney RJ: Human leukocyte IgG Fc receptors. Immunol Today 1986;7:264–266.

    Article  CAS  Google Scholar 

  9. Fanger MW, Shen L, Graziano RF, Guyre PM: Cytotoxicity mediated by human Fc receptors for IgG. Immunol Today 1989;10:92–99.

    Article  PubMed  CAS  Google Scholar 

  10. Malavasi F, Tetta C, Funaro A, et al.: Fc receptor triggering induces expression of surface activation antigens and release of platele-activating factor in large granular lymphocytes. Proc Natl Acad Sci USA 1986;83:2443–2447.

    Article  PubMed  CAS  Google Scholar 

  11. Cassatella MA, Anegon I, Cuturi MC, Griskey P, Trinchieri G, Perussia B: Fc gamma R (CD16) interaction with ligand induces Ca2+ mobilization and phosphoinositide turnover in human natural killer cells. J Exp Med 1989;169:549–567.

    Article  PubMed  CAS  Google Scholar 

  12. Frank MM, Hamburger MI, Lawley T, Kimberly RP, Plotz PH: Defective reticuloendothelial system Fc-receptor function in systemic lupus erythematosus. N Engl J Med 1979;300:518–523.

    Article  PubMed  CAS  Google Scholar 

  13. Clark MR, Liu L, Clarkson SB, Ory PA, Goldstein IM: An abnormality of the gene that encodes neutrophil Fc receptor III in a patient with systemic lupus erythematosus. J Clin Invest 1990;86:341–346.

    PubMed  CAS  Google Scholar 

  14. Frank MM, Lawley TJ, Hamburger MI, Brown EJ: Immunoglobulin G Fc receptor-mediated clearence in autoimmune diseases. Ann Intern Med 1983;98:206–218.

    PubMed  CAS  Google Scholar 

  15. Lawley TJ, Hall RP, Fauci AS, Katz SI, Hamburger MI, Frank MM: Defective Fc-receptor functions associated with the HLA-B8/DRw3 haplotype. Studies in patients with dermatitis herpetiformis and normal subjects. N Engl J Med 1981;304:185–192.

    Article  PubMed  CAS  Google Scholar 

  16. Takai T, Li M, Sylverstre D, Clynes R, Ravetch JV: FcR gamma chain deletion results in pleiotrophic effector cell defects. Cell 1994;76:519–529.

    Article  PubMed  CAS  Google Scholar 

  17. Ravetch JV, Clynes RA: Divergent roles for Fc receptors and complement in vivo. Annu Rev Immunol 1998; 16:421–432.

    Article  PubMed  CAS  Google Scholar 

  18. Hazenbos WL, Gessner JE, Hofhuis FM, et al.: Impaired IgG-dependent anaphylaxis and Arthus reaction in FcγRIII (CD16) deficient mice. Immunity 1996;5: 181–188.

    Article  PubMed  CAS  Google Scholar 

  19. Ravetch JV, Kinet J-P: Fc Receptors. Annu Rev Immunol 1991;9:457–492.

    PubMed  CAS  Google Scholar 

  20. Nag B, Wada HG, Passmore D, Clark BR, Sharma SD, McConnell HM: Purified beta-chain of MHC class II binds to CD4 molecules on transfected HeLa cells. J Immunol 1993;150:1358–1364.

    PubMed  CAS  Google Scholar 

  21. Hulett MD, Hogarth PM: Molecular basis of Fc receptor function. Adv Immunol 1994;57:1–127.

    PubMed  CAS  Google Scholar 

  22. Unkeless JC, Shen Z, Lin C, DeBeus E: Function of human FcγRIIA and Fc γRIIIB. Sem Immunol 1995; 7:37–44.

    Article  CAS  Google Scholar 

  23. Indik ZK, Park JG, Hunter S, Schreiber AD: Structure/function relationships of Fc gamma receptors in phagocytosis. Sem Immunol 1995;7:45–54.

    Article  CAS  Google Scholar 

  24. Brooks DG, Qui WQ, Luster AD, Ravetch JV: Structure and expression of human IgG FcRII(CD32). Functional heterogeneity is encoded by the alternatively spliced products of multiple genes. J Exp Med 1989;170: 1369–1385.

    Article  PubMed  CAS  Google Scholar 

  25. Werner G, Von dem Borne AEG, Bos MJE, et al.: Localization of NA1 alloantigen on neutrophil Fcg receptors. In Leukocyte Typing II. (Reinherz EL, Haynes BF, Nadler LM, Bernstein ID, eds.). Springer-Verlag, New York, 1986, pp. 109–121.

    Google Scholar 

  26. Selvaraj P, Rosse WF, Silber R, Springer TA: The major Fc receptor in blood has a phosphatidylinositol anchor and is deficient in paroxysmal nocturnal hemoglobinuria. Nature 1988;333:565–567.

    Article  PubMed  CAS  Google Scholar 

  27. Selvaraj P, Carpen O, Hibbs ML, Springer TA: Natural Killer cell and granulocyte Fc γRIII (CD 16) differ in membrane anchor and signal transduction. J Immunol 1989;143:3283–3288.

    PubMed  CAS  Google Scholar 

  28. Lanier LL, Phillips JH, Testi R: Membrane anchoring and spontaneous release of CD 16 (FcγR III) by natural killer cells and granulocytes. Eur J Immunol 1989; 19:775–778.

    Article  PubMed  CAS  Google Scholar 

  29. Ravetch JV, Perussia B: Alternative membrane forms of Fc gamma RIII (CD16) on human NK cells and neutrophils: Cell-type specific expression of two genes which differ in single nucleotide substitutions. J Exp Med 1989;170:481–497.

    Article  PubMed  CAS  Google Scholar 

  30. Scallon BJ, Scigliano E, Freedman VH, et al.: A human immunoglobulin G receptor exists in both polypeptide-anchored and phosphatidylinositol-glycananchored forms. Proc Natl Acad Sci USA 1989;86: 5079–5083.

    Article  PubMed  CAS  Google Scholar 

  31. Edberg JC, Redecha PB, Salmon JC, Kimberly RP: Human FcγRIII (CD 16): isoforms with distinct allelic expression, extracellular domains, and membrane linkages on polymorphonuclear and natural killer cells. J immunol 1989;143:1642–1649.

    PubMed  CAS  Google Scholar 

  32. Ueda E, Kinoshita T, Nojima J, Inoue K, Kitani T: Different membrane anchors of Fc gamma RIII (CD16) on K/NK-lymphocytes and neutrophils proteins-vs lipid-anchor. J Immunol 1989;143:1274–1277.

    PubMed  CAS  Google Scholar 

  33. Simmons D, Seed B: The Fc gamma receptor of natural killer cells is a phospholipid-linked membrane protein. Nature 1988;333:568–570.

    Article  PubMed  CAS  Google Scholar 

  34. Nagarajan S, Chesla SE, Cobern L, Anderson P, Zhu C, Selvaraj P: Ligand binding and phagocytosis by CD16 (Fc gamma receptor III) isoforms. J Biol Chem 1995;270:25762–25770.

    Article  PubMed  CAS  Google Scholar 

  35. Lanier LL, Rutenberg JJ, Phillips JH: Functional and biochemical analysis of CD16 antigen on natural killer cells and granulocytes. J Immunol 1988;141:3478–3485.

    PubMed  CAS  Google Scholar 

  36. Kimberly RP, Ahlstrom JW, Click ME, Edberg JC: The glycosyl phosphatidy linositol-linked Fc γRIII PMN mediates transmembrane signaling events distinct from FcγRII. J Exp Med 1990;171:1239–1255.

    Article  PubMed  CAS  Google Scholar 

  37. Huizinga TWJ, Dolman KM, Van Der Linden NJM, et al.: Phosphatidylinositol-linked FcγRIII mediates exocytosis of neutrophil granule proteins, but does not mediate initiation of the respiratory burst. J Immunol 1990;144:1432–1437.

    PubMed  CAS  Google Scholar 

  38. Hibbs ML, Selvaraj P, Carpen O, et al.: Mechanism regulating expression of membrane isoforms of Fc γRIII (CD16). Science 1989;246:1608–1611.

    Article  PubMed  CAS  Google Scholar 

  39. Anderson P, Caligiuri M, O'Brien C, Manley T, Ritz J, Schlossman SF: Fc γ Receptor type III (CD16) is included in the zeta NK receptor complex expressed by human natural killer cells. Proc Natl Acad Sci USA 1990;87:2274–2278.

    Article  PubMed  CAS  Google Scholar 

  40. Lanier LL, Yu G, Phillips JH: Co-association of CD3 zeta with a receptor (CD16) for IgG Fc on human natural killer cells. Nature 1989;342:803–805.

    Article  PubMed  CAS  Google Scholar 

  41. Yuasa T, Kubo S, Yoshino T, et al.: Deletion of Fcgamma receptor IIB renders H-2(b) mice susceptible to collagen-induced arthritis. J Exp Med 1999;189:187–194.

    Article  PubMed  CAS  Google Scholar 

  42. Clynes R, Maizes JS, Guinamard R, Ono M, Takai T, Ravetch JV: Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors. J Exp Med 1999;189:179–185.

    Article  PubMed  CAS  Google Scholar 

  43. Bolland S, Ravetch JV: Inhibitory pathways triggered by ITIM-containing receptors. Adv Immunol 1999;72: 149–177.

    PubMed  CAS  Google Scholar 

  44. Anderson CL, Shen L, Eicher DM, Wewers MD, Gill JK: Phagocytosis mediated by three distinct Fc γ receptor classes on human leukocytes. J Exp Med 1990; 171:1333–1345.

    Article  PubMed  CAS  Google Scholar 

  45. Edberg JC, Kimberly RP: Modulation of Fcγ and complement receptor function by the glycosyl-phosphatidylinositol-anchored form of FcγRIII. J Immunol 1994;152:5826–5835.

    PubMed  CAS  Google Scholar 

  46. Nagarajan S, Venkiteswaran K, Anderson M, Sayed U, Zhu C, Selvaraj P: Cell specific, activation dependent regulation of neutrophil CD32A ligand binding function. Blood 2000;95:1069–1077.

    PubMed  CAS  Google Scholar 

  47. Springer TA: Adhesion receptors of the immune system. Nature 1990;346:425–434.

    Article  PubMed  CAS  Google Scholar 

  48. Hynes RO: Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 1992;69:11–25.

    Article  PubMed  CAS  Google Scholar 

  49. Dustin ML, Springer TA: T cell receptor cross-linking transiently stimulates adhesiveness through LFA-1. Nature 1989;341:619–624.

    Article  PubMed  CAS  Google Scholar 

  50. Kishmoto TK, Larson RS, Corbi AL, Dutstin ML, Stauton DE, Springer TA: The leukocyte integrins. Adv Immunol 1990;46:149–182.

    Google Scholar 

  51. Miller KL, Duchemin A, Anderson CL: A novel role for the Fc receptor γ subunit: enhancement of FcγR ligand affinity. J Exp Med 1996;183:2227–2233.

    Article  PubMed  CAS  Google Scholar 

  52. Koenderman L, Hermans SWG, Capel JA, Van de Winkel JGJ: Granulocyte-macrophage colony-stimulating factor induces sequential activation and deactivation of binding via a low-affinity IgG Fc receptor, hFcγRII, on human eosinophils. Blood 1993;81:2413–2419.

    PubMed  CAS  Google Scholar 

  53. Chuang FY, Sassaroli M, Unkeless JC: Convergence of Fc gamma receptor IIA and Fc gamma receptor IIIB signaling. J Immunol 2000;164:350–360.

    PubMed  CAS  Google Scholar 

  54. Salmon JE, Millard SS, Brogle NL, Kimberly RP: Fcγ receptor IIIb enhances Fc γ receptor IIa function in an oxidant-dependent and allele-sensitive manner. J Clin Invest 1995;95:2877–2885.

    PubMed  CAS  Google Scholar 

  55. Salmon JE, Brogle NL, Edberg JC, Kimberly RP: Fc γ receptor III induces actin polymerization in human neutrophils and primes phagocytosis mediated by Fcγ receptor II. J Immunol 1991;146:997–1004.

    PubMed  CAS  Google Scholar 

  56. Anderson CL, Spence JM, Edwards TS, Nusbacher J: Characterization of a polyvalent antibody directed against the IgG Fc receptor of human mononuclear phagocytes. J Immunol 1985;134:465–470.

    PubMed  CAS  Google Scholar 

  57. Huizinga TWJ, Dolman KM, van Der Linden NMJ, et al.: Phosphatidylinositol-linked FcγRIII mediates exocytosis of neutrophil granule proteins, but does not mediate initiation of the respiratory burst. J Immunol 1990;144:1432–1437.

    PubMed  CAS  Google Scholar 

  58. Tax WJM, Van de Winkel JGJ: Human Fcγ receptor II: a standby receptor activated by proteolysis? Immunol Today 1990;11:308–310.

    Article  PubMed  CAS  Google Scholar 

  59. Trevani AS, Andonegui GA, Istruriz MA, Schatner M, Serebrinsky G, Gefner JR: Effect of proteolytic enzymes on neutrophil Fc γRII activity. Immunology 1994;82: 632–637.

    PubMed  CAS  Google Scholar 

  60. Kallenberg CG, Heeringa P: Pathogenesis of vasculitis. Lupus 1998;7:280–284.

    Article  PubMed  CAS  Google Scholar 

  61. Salmon JE, Millard S, Schachter LA, et al.: Fc γRIIA alleles are heritable risk factors for Lupus nephritis in African americans. J Clin Invest 1996;97:1348–1354.

    Article  PubMed  CAS  Google Scholar 

  62. Lassmann H, Bruck W, Lucchinetti C: Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 2001;7:115–121.

    Article  PubMed  CAS  Google Scholar 

  63. Bredius RGM, Fijen CAP, DeHaas M, et al.: Role of neutrophil Fc-gamma RIIa (CD32) and Fc-gammaR IIIb (CD16) polymorphic in phagocytosis of human IgG1- and IgG3-opsonized bacteria and erythrocytes. Immunology 1994;83:624–630.

    PubMed  CAS  Google Scholar 

  64. Fijen CAP, Bredius RGM, Kuijper EJ: Polymorphism of IgG Fc receptors in meningococcal disease. Ann Intern Med 1993;119:636.

    PubMed  CAS  Google Scholar 

  65. Sanders LAM, van de Winkel JGL, Rukers GT, et al.: Fc gamma receptor IIa (CD32) heterogeneity in patients with recurrent bacterial respiratory tract infections. J Infect Dis 1994;170:854–861.

    PubMed  CAS  Google Scholar 

  66. Yee AMF, Phan HM, Zuniga R, Salmon JE, Musher DM: Association between Fc γRIIa-R131 allotype and bacteremic pneumococcal pneumonia. Clin Infect Dis 2000;30:25–28.

    Article  PubMed  CAS  Google Scholar 

  67. Rascu A, Repp R, Westerdaal NAC, Kalden JR, Van de Winkel JGJ: Clinical relevance of Fc γ receptor polymorphisms. Ann NY Acad Sci 1997;815:282–295.

    Article  PubMed  CAS  Google Scholar 

  68. Chang DJ: Differential regulation of Fcgamma receptor isoforms: implications for therapeutic interventions. Am J Ther 1995;2:777–781.

    Article  PubMed  Google Scholar 

  69. Johnson P: The mechanisms of action of rituximab in the elimination of tumor cells. Semin Oncol 2003;30:3–8.

    Article  PubMed  CAS  Google Scholar 

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  1. Periasamy Selvaraj Ph.D.

    Present address: Department of Pathology and Laboratory Medicine, Emory, University School of Medicine, Rm 7309, Woodruff Memorial Research Building, 1639 Pierce Drive, 30322, Atlanta, GA

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory, University School of Medicine, Rm 7309, Woodruff Memorial Research Building, 1639 Pierce Drive, 30322, Atlanta, GA

    Nimita Fifadara, Shanmugam Nagarajan, Ashley Cimino & Guixian Wang

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  1. Periasamy Selvaraj Ph.D.
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Selvaraj, P., Fifadara, N., Nagarajan, S. et al. Functional regulation of human neutrophil Fc γ receptors. Immunol Res 29, 219–229 (2004). https://doi.org/10.1385/IR:29:1-3:219

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