Targeting the Fc receptor in autoimmune disease

Expert Opinion on Therapeutic Targets

Volumn 18, Issue 3, 2014, Pages 335-350

  Li, Xinrui ^a   Kimberly, Robert P ^b  

^a UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

^b University of Alabama at Birmingham   (United States)

Author keywords

Antibody therapy; Antibody dependent cellular cytotoxicity; Autoimmunity; Fc receptor

Indexed keywords

ANIMALS; AUTOIMMUNE DISEASES; HUMANS; RECEPTORS, FC;

EID: 84894204713     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2014.877891     Document Type: Review

References (175)

1. Marmont AM. Defining criteria for autoimmune diseases. Immunol Today 1994;15(8): 388
2. Nimmerjahn F, Ravetch JV. Fc-receptors as regulators of immunity. Adv Immunol 2007;96: 179-204 • A comprehensive review on types of FcRs, their signaling and functions.
3. Ernst LK, van de Winkel JG, Chiu IM, et al. Three genes for the human high affinity Fc receptor for IgG (Fc gamma RI) encode four distinct transcription products. J Biol Chem 1992;267(22): 15692-700
4. Hoffmeyer F, Witte K, Schmidt RE. The high-affinity Fc gamma RI on PMN: regulation of expression and signal transduction. Immunology 1997;92(4): 544-52
5. Capel PJ, van de Winkel JG, van den Herik-Oudijk IE, et al. Heterogeneity of human IgG Fc receptors. Immunomethods 1994;4(1): 25-34
6. Ernst LK, Metes D, Herberman RB, et al. Allelic polymorphisms in the FcgammaRIIC gene can influence its function on normal human natural killer cells. J Mol Med 2002;80(4): 248-57
7. Breunis WB, van Mirre E, Bruin M, et al. Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura. Blood 2008;111(3): 1029-38
8. Simmons D, Seed B. The Fc gamma receptor of natural killer cells is a phospholipid-linked membrane protein. Nature 1988;333(6173): 568-70
9. Kinet JP. The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. Annu Rev Immunol 1999;17: 931-72 • A comprehensive review on FceRI.
10. Turner H, Kinet JP. Signalling through the high-affinity IgE receptor Fc epsilonRI. Nature 1999;402(6760 Suppl):B24-30
11. Fiebiger E, Maurer D, Holub H, et al. Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients? J Clin Invest 1995;96(6): 2606-12
12. Hide M, Francis DM, Grattan CE, et al. Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med 1993;328(22): 1599-604
13. Tong LJ, Balakrishnan G, Kochan JP, et al. Assessment of autoimmunity in patients with chronic urticaria. J Allergy Clin Immunol 1997;99(4): 461-5
14. Yokota A, Kikutani H, Tanaka T, et al. Two species of human Fc epsilon receptor II (Fc epsilon RII/CD23): tissue-specific and IL-4-specific regulation of gene expression. Cell 1988;55(4): 611-18
15. Barrow AD, Trowsdale J. You say ITAM and I say ITIM, let's call the whole thing off: the ambiguity of immunoreceptor signalling. Eur J Immunol 2006;36(7): 1646-53
16. Monteiro RC, Van De Winkel JG. IgA Fc receptors. Annu Rev Immunol 2003;21: 177-204 • A comprehensive review on FcaRI.
17. Kubagawa H, Oka S, Kubagawa Y, et al. Identity of the elusive IgM Fc receptor (FcmuR) in humans. J Exp Med 2009;206(12): 2779-93
18. Shima H, Takatsu H, Fukuda S, et al. Identification of TOSO/FAIM3 as an Fc receptor for IgM. Int Immunol 2010;22(3): 149-56
19. Lang KS, Lang PA, Meryk A, et al. Involvement of Toso in activation of monocytes, macrophages, and granulocytes. Proc Natl Acad Sci USA 2013;110(7): 2593-8
20. Honjo K, Kubagawa Y, Kubagawa H. Is Toso/IgM Fc receptor (FcmuR) expressed by innate immune cells? Proc Natl Acad Sci USA 2013;110(28):E2540-1
21. Lang KS, Lang PA, Meryk A, et al. Reply to Honjo et al.: functional relevant expression of Toso on granulocytes. Proc Natl Acad Sci USA 2013;110(28):E2542-3
22. Story CM, Mikulska JE, Simister NE. A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus. J Exp Med 1994;180(6): 2377-81
23. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007;7(9): 715-25 • A comprehensive review on FcRn.
24. Wang AV, Scholl PR, Geha RS. Physical and functional association of the high affinity immunoglobulin G receptor (Fc gamma RI) with the kinases Hck and Lyn. J Exp Med 1994;180(3): 1165-70
25. Ghazizadeh S, Bolen JB, Fleit HB. Physical and functional association of Src-related protein tyrosine kinases with Fc gamma RII in monocytic THP-1 cells. J Biol Chem 1994;269(12): 8878-84
26. Ono M, Okada H, Bolland S, et al. Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell 1997;90(2): 293-301
27. Bolland S, Pearse RN, Kurosaki T, et al. SHIP modulates immune receptor responses by regulating membrane association of Btk. Immunity 1998;8(4): 509-16
28. Ravetch JV, Bolland S. IgG Fc receptors. Annu Rev Immunol 2001;19: 275-90
29. Tan Sardjono C, Mottram PL, van de Velde NC, et al. Development of spontaneous multisystem autoimmune disease and hypersensitivity to antibodyinduced inflammation in Fcgamma receptor IIa-transgenic mice. Arthritis Rheum 2005;52(10): 3220-9
30. Tsuboi N, Asano K, Lauterbach M, et al. Human neutrophil Fcgamma receptors initiate and play specialized nonredundant roles in antibody-mediated inflammatory diseases. Immunity 2008;28(6): 833-46
31. Mullazehi M, Mathsson L, Lampa J, et al. Surface-bound anti-type II collagen-containing immune complexes induce production of tumor necrosis factor alpha, interleukin-1beta, and interleukin-8 from peripheral blood monocytes via Fc gamma receptor IIA: a potential pathophysiologic mechanism for humoral anti-type II collagen immunity in arthritis. Arthritis Rheum 2006;54(6): 1759-71
32. Belostocki K, Park MS, Redecha PB, et al. FcgammaRIIa is a target for modulation by TNFalpha in human neutrophils. Clin Immunol 2005;117(1): 78-86
33. Clarkson SB, Kimberly RP, Valinsky JE, et al. Blockade of clearance of immune complexes by an anti-Fc gamma receptor monoclonal antibody. J Exp Med 1986;164(2): 474-89
34. Clarkson SB, Bussel JB, Kimberly RP, et al. Treatment of refractory immune thrombocytopenic purpura with an anti- Fc gamma-receptor antibody. N Engl J Med 1986;314(19): 1236-9
35. Marino M, Ruvo M, De Falco S, et al. Prevention of systemic lupus erythematosus in MRL/lpr mice by administration of an immunoglobulinbinding peptide. Nat Biotechnol 2000;18(7): 735-9 • An important paper on targeting activating FcgR with small molecule antagonist in treating SLE.
36. Pietersz GA, Mottram PL, van de Velde NC, et al. Inhibition of destructive autoimmune arthritis in FcgammaRIIa transgenic mice by small chemical entities. Immunol Cell Biol 2009;87(1): 3-12
37. de Haas M, Kleijer M, Minchinton RM, et al. Soluble Fc gamma RIIIa is present in plasma and is derived from natural killer cells. J Immunol 1994;152(2): 900-7
38. Rappaport EF, Cassel DL, Walterhouse DO, et al. A soluble form of the human Fc receptor Fc gamma RIIA: cloning, transcript analysis and detection. Exp Hematol 1993;21(5): 689-96
39. Huizinga TW, Ioan-Facsinay A. Soluble FcgammaRIIIa as a marker for rheumatoid arthritis: the use of genetics in selected populations to study pathogenetic pathways. J Rheumatol 2003;30(9): 1904-6
40. Werwitzke S, Trick D, Sondermann P, et al. Treatment of lupus-prone NZB/NZW F1 mice with recombinant soluble Fc gamma receptor II (CD32). Ann Rheum Dis 2008;67(2): 154-61
41. Ellsworth JL, Hamacher N, Harder B, et al. Recombinant soluble human FcgammaR1A (CD64A) reduces inflammation in murine collagen-induced arthritis. J Immunol 2009;182(11): 7272-9
42. Ellsworth JL, Maurer M, Harder B, et al. Targeting immune complex-mediated hypersensitivity with recombinant soluble human FcgammaRIA (CD64A). J Immunol 2008;180(1): 580-9
43. Magnusson SE, Andren M, Nilsson KE, et al. Amelioration of collagen-induced arthritis by human recombinant soluble FcgammaRIIb. Clin Immunol 2008;127(2): 225-33
44. Galon J, Paulet P, Galinha A, et al. Soluble Fc gamma receptors: interaction with ligands and biological consequences. Int Rev Immunol 1997;16(1-2): 87-111
45. de la Salle H, Galon J, Bausinger H, et al. Soluble CD16/Fc gamma RIII induces maturation of dendritic cells and production of several cytokines including IL-12. Adv Exp Med Biol 1997;417: 345-52
46. Bolland S, Ravetch JV. Spontaneous autoimmune disease in Fc(gamma)RIIBdeficient mice results from strain-specific epistasis. Immunity 2000;13(2): 277-85
47. Yajima K, Nakamura A, Sugahara A, et al. FcgammaRIIB deficiency with Fas mutation is sufficient for the development of systemic autoimmune disease. Eur J Immunol 2003;33(4): 1020-9
48. McGaha TL, Sorrentino B, Ravetch JV. Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 2005;307(5709): 590-3 • An important paper on the inhibitory effect of FcgRIIb.
49. Li X, Wu J, Carter RH, et al. A novel polymorphism in the Fcgamma receptor IIB (CD32B) transmembrane region alters receptor signaling. Arthritis Rheum 2003;48(11): 3242-52
50. Floto RA, Clatworthy MR, Heilbronn KR, et al. Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts. Nat Med 2005;11(10): 1056-8
51. Su K, Li X, Edberg JC, et al. A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. II. Differential binding of GATA4 and Yin-Yang1 transcription factors and correlated receptor expression and function. J Immunol 2004;172(11): 7192-9
52. Su K, Wu J, Edberg JC, et al. A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus. J Immunol 2004;172(11): 7186-91
53. van Mirre E, van Royen A, Hack CE. IVIg-mediated amelioration of murine ITP via FcgammaRIIb is not necessarily independent of SHIP-1 and SHP-1 activity. Blood 2004;103(5): 1973; author reply 1974
54. Mackay M, Stanevsky A, Wang T, et al. Selective dysregulation of the FcgammaIIB receptor on memory B cells in SLE. J Exp Med 2006;203(9): 2157-64
55. Veri MC, Gorlatov S, Li H, et al. Monoclonal antibodies capable of discriminating the human inhibitory Fcgamma-receptor IIB (CD32B) from the activating Fcgamma-receptor IIA (CD32A): biochemical, biological and functional characterization. Immunology 2007;121(3): 392-404
56. Su K, Yang H, Li X, et al. Expression profile of FcgammaRIIb on leukocytes and its dysregulation in systemic lupus erythematosus. J Immunol 2007;178(5): 3272-80
57. Rankin CT, Veri MC, Gorlatov S, et al. CD32B, the human inhibitory Fcgamma receptor IIB, as a target for monoclonal antibody therapy of B-cell lymphoma. Blood 2006;108(7): 2384-91
58. Xiang Z, Cutler AJ, Brownlie RJ, et al. FcgammaRIIb controls bone marrow plasma cell persistence and apoptosis. Nat Immunol 2007;8(4): 419-29
59. Veri MC, Burke S, Huang L, et al. Therapeutic control of B cell activation via recruitment of Fcgamma receptor IIb (CD32B) inhibitory function with a novel bispecific antibody scaffold. Arthritis Rheum 2010;62(7): 1933-43
60. Horton HM, Chu SY, Ortiz EC, et al. Antibody-mediated coengagement of FcgammaRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus. J Immunol 2011;186(7): 4223-33 • An important paper on targeting FcgRIIb with engineered bispecific antibodies.
61. Zhu D, Kepley CL, Zhang M, et al. A novel human immunoglobulin Fc gamma Fc epsilon bifunctional fusion protein inhibits Fc epsilon RI-mediated degranulation. Nat Med 2002;8(5): 518-21
62. Tam SW, Demissie S, Thomas D, et al. A bispecific antibody against human IgE and human FcgammaRII that inhibits antigen-induced histamine release by human mast cells and basophils. Allergy 2004;59(7): 772-80
63. Mertsching E, Bafetti L, Hess H, et al. A mouse Fcgamma-Fcepsilon protein that inhibits mast cells through activation of FcgammaRIIB, SH2 domaincontaining inositol phosphatase 1, and SH2 domain-containing protein tyrosine phosphatases. J Allergy Clin Immunol 2008;121(2): 441-7; e5
64. Van Scott MR, Mertsching E, Negrou E, et al. Systemic administration of an Fcgamma-Fc(epsilon)-fusion protein in house dust mite sensitive nonhuman primates. Clin Immunol 2008;128(3): 340-8
65. Pescovitz MD. Rituximab, an anti-cd20 monoclonal antibody: history and mechanism of action. Am J Transplant 2006;6(5 Pt 1): 859-66
66. Gurcan HM, Keskin DB, Stern JN, et al. A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 2009;9(1): 10-25 • A comprehensive review on anti-CD20 mAb therapy in autoimmune diseases.
67. Chakravarty SD, Yee AF, Paget SA. Rituximab successfully treats refractory chronic autoimmune urticaria caused by IgE receptor autoantibodies. J Allergy Clin Immunol 2011;128(6): 1354-5
68. de Haij S, Jansen JH, Boross P, et al. In vivo cytotoxicity of type I CD20 antibodies critically depends on Fc receptor ITAM signaling. Cancer Res 2010;70(8): 3209-17
69. Weng W.K, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003;21(21): 3940-7
70. Anolik JH, Campbell D, Felgar RE, et al. The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum 2003;48(2): 455-9
71. Lim SH, Vaughan AT, M, et al. Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy. Blood 2011;118(9): 2530-40
72. Gea-Banacloche JC. Rituximab-associated infections. Semin Hematol 2010;47(2): 187-98
73. Radaev S, Motyka S, Fridman WH, et al. The structure of a human type III Fcgamma receptor in complex with Fc. J Biol Chem 2001;276(19): 16469-77
74. Jefferis R, Lefranc MP. Human immunoglobulin allotypes: possible implications for immunogenicity. MAbs 2009;1(4): 332-8
75. Albert H, Collin M, Dudziak D, et al. In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner. Proc Natl Acad Sci USA 2008;105(39): 15005-9
76. Umana P, Jean-Mairet J, Moudry R, et al. Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat Biotechnol 1999;17(2): 176-80 • An important paper on manipulating antibody affinity for FcgR through modifying glycosylation.
77. Shields RL, Lai J, Keck R, et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibodydependent cellular toxicity. J Biol Chem 2002;277(30): 26733-40
78. Yamane-Ohnuki N, Kinoshita S, Inoue-Urakubo M, et al. Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibodydependent cellular cytotoxicity. Biotechnol Bioeng 2004;87(5): 614-22
79. Mori K, Kuni-Kamochi R, Yamane-Ohnuki N, et al. Engineering Chinese hamster ovary cells to maximize effector function of produced antibodies using FUT8 siRNA. Biotechnol Bioeng 2004;88(7): 901-8
80. Kanda Y, Yamane-Ohnuki N, Sakai N, et al. Comparison of cell lines for stable production of fucose-negative antibodies with enhanced ADCC. Biotechnol Bioeng 2006;94(4): 680-8
81. Kanda Y, Imai-Nishiya H, Kuni-Kamochi R, et al. Establishment of a GDP-mannose 4,6-dehydratase (GMD) knockout host cell line: a new strategy for generating completely non-fucosylated recombinant therapeutics. J Biotechnol 2007;130(3): 300-10
82. Imai-Nishiya H, Mori K, Inoue M, et al. Double knockdown of alpha1,6- fucosyltransferase (FUT8) and GDPmannose 4,6-dehydratase (GMD) in antibody-producing cells: a new strategy for generating fully non-fucosylated therapeutic antibodies with enhanced ADCC. BMC Biotechnol 2007;7: 84
83. Cox KM, Sterling JD, Regan JT, et al. Glycan optimization of a human monoclonal antibody in the aquatic plant Lemna minor. Nat Biotechnol 2006;24(12): 1591-7
84. Ferrara C, Brunker P, Suter T, et al. Modulation of therapeutic antibody effector functions by glycosylation engineering: influence of Golgi enzyme localization domain and co-expression of heterologous beta1, 4-N-acetylglucosaminyltransferase III and Golgi alpha-mannosidase II. Biotechnol Bioeng 2006;93(5): 851-61
85. Ferrara C, Stuart F, Sondermann P, et al. The carbohydrate at FcgammaRIIIa Asn-162. An element required for high affinity binding to non-fucosylated IgG glycoforms. J Biol Chem 2006;281(8): 5032-6
86. Ercan A, Cui J, Chatterton DE, et al. Aberrant IgG galactosylation precedes disease onset, correlates with disease activity, and is prevalent in autoantibodies in rheumatoid arthritis. Arthritis Rheum 2010;62(8): 2239-48
87. Pasek M, Duk M, Podbielska M, et al. Galactosylation of IgG from rheumatoid arthritis (RA) patients-changes during therapy. Glycoconj J 2006;23(7-8): 463-71
88. van de Geijn FE, Wuhrer M, Selman MH, et al. Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study. Arthritis Res Ther 2009;11(6):R193
89. Jefferis R. Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. Trends Pharmacol Sci 2009;30(7): 356-62
90. Jefferis R. Glycosylation as a strategy to improve antibody-based therapeutics. Nat Rev Drug Discov 2009;8(3): 226-34
91. Karsten CM, Pandey MK, Figge J, et al. Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcgammaRIIB and dectin-1. Nat Med 2012;18(9): 1401-6
92. Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 2006;313(5787): 670-3
93. Andersen JT, Justesen S, Berntzen G, et al. A strategy for bacterial production of a soluble functional human neonatal Fc receptor. J Immunol Methods 2008;331(1-2): 39-49
94. Feng Y, Gong R, Dimitrov DS. Design, expression and characterization of a soluble single-chain functional human neonatal Fc receptor. Protein Expr Purif 2011;79(1): 66-71
95. Vaccaro C, Zhou J, Ward ES, Ober RJ. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol 2005;23(10): 1283-8
96. Petkova SB, Akilesh S, Sproule TJ, et al. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol 2006;18(12): 1759-69
97. Vaccaro C, Bawdon R, Wanjie S, et al. Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies. Proc Natl Acad Sci USA 2006;103(49): 18709-14
98. Liu L, Garcia AM, Santoro H, et al. Amelioration of experimental autoimmune myasthenia gravis in rats by neonatal FcR blockade. J Immunol 2007;178(8): 5390-8
99. Mezo AR, McDonnell KA, Hehir CA, et al. Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn. Proc Natl Acad Sci USA 2008;105(7): 2337-42
100. Ghetie V, Popov S, Borvak J, et al. Increasing the serum persistence of an IgG fragment by random mutagenesis. Nat Biotechnol 1997;15(7): 637-40
101. Zalevsky J, Chamberlain AK, Horton HM, et al. Enhanced antibody half-life improves in vivo activity. Nat Biotechnol 2010;28(2): 157-9
102. Lazar GA, Dang W, Karki S, et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA 2006;103(11): 4005-10
103. Niederer HA, Willcocks LC, Rayner TF, et al. Copy number, linkage disequilibrium and disease association in the FCGR locus. Hum Mol Genet 2010;19(16): 3282-94
104. Clark MR, Clarkson SB, Ory PA, et al. Molecular basis for a polymorphism involving Fc receptor II on human monocytes. J Immunol 1989;143(5): 1731-4
105. Warmerdam PA, van de Winkel JG, Gosselin EJ, et al. Molecular basis for a polymorphism of human Fc gamma receptor II (CD32). J Exp Med 1990;172(1): 19-25
106. Wu J, Edberg JC, Redecha PB, et al. A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 1997;100(5): 1059-70
107. Koene HR, Kleijer M, Algra J, et al. Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype. Blood 1997;90(3): 1109-14
108. Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti- CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002;99(3): 754-8
109. Hatjiharissi E, Xu L, Santos DD, et al. Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V/V and V/F polymorphism. Blood 2007;110(7): 2561-4
110. Ruyssen-Witrand A, Rouanet S, Combe B, et al. Fcgamma receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab. Ann Rheum Dis 2012;71(6): 875-7
111. Canete JD, Suarez B, Hernandez MV, et al. Influence of variants of Fc gamma receptors IIA and IIIA on the American College of Rheumatology and European League Against Rheumatism responses to anti-tumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis 2009;68(10): 1547-52
112. Tutuncu Z, Kavanaugh A, Zvaifler N, et al. Fcgamma receptor type IIIA polymorphisms influence treatment outcomes in patients with inflammatory arthritis treated with tumor necrosis factor alpha-blocking agents. Arthritis Rheum 2005;52(9): 2693-6
113. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345(10): 747-55
114. Novaretti MC, Dinardo CL. Clinical applications of immunoglobulin: update. Rev Bras Hematol Hemoter 2011;33(3): 221-30
115. Jin F, Balthasar JP. Mechanisms of intravenous immunoglobulin action in immune thrombocytopenic purpura. Hum Immunol 2005;66(4): 403-10
116. Debre M, Bonnet MC, Fridman WH, et al. Infusion of Fc gamma fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 1993;342(8877): 945-9
117. Crow AR, Song S, Siragam V, et al. Mechanisms of action of intravenous immunoglobulin in the treatment of immune thrombocytopenia. Pediatr Blood Cancer 2006;47(5 Suppl): 710-13
118. Siragam V, Crow AR, Brinc D, et al. Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells. Nat Med 2006;12(6): 688-92
119. Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001;291(5503): 484-6
120. Kaneko Y, Nimmerjahn F, Madaio MP, et al. Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J Exp Med 2006;203(3): 789-97
121. Bruhns P, Samuelsson A, Pollard JW, et al. Colony-stimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 2003;18(4): 573-81
122. Crow AR, Song S, Freedman J, et al. IVIg-mediated amelioration of murine ITP via FcgammaRIIB is independent of SHIP1, SHP-1, and Btk activity. Blood 2003;102(2): 558-60
123. Shimomura M, Hasegawa S, Seki Y, et al. Intravenous immunoglobulin does not increase FcgammaRIIB expression levels on monocytes in children with immune thrombocytopenia. Clin Exp Immunol 2012;169(1): 33-7
124. Hansen R.J, Balthasar JP. Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor. Thromb Haemost 2002;88(6): 898-9
125. Li N, Zhao M, J, et al. Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J Clin Invest 2005;115(12): 3440-50
126. Akilesh S, Petkova S, Sproule TJ, et al. The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J Clin Invest 2004;113(9): 1328-33
127. Crow AR, Suppa SJ, Chen X, et al. The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody-mediated amelioration of murine immune thrombocytopenia. Blood 2011;118(24): 6403-6
128. Seow CJ, Chue SC, Wong WS. Piceatannol, a Syk-selective tyrosine kinase inhibitor, attenuated antigen challenge of guinea pig airways in vitro. Eur J Pharmacol 2002;443(1-3): 189-96
129. Yamamoto N, Takeshita K, Shichijo M, et al. The orally available spleen tyrosine kinase inhibitor 2-[7-(3,4- dimethoxyphenyl)-imidazo[1,2-c] pyrimidin-5-ylamino]nicotinamide dihydrochloride (BAY 61-3606) blocks antigen-induced airway inflammation in rodents. J Pharmacol Exp Ther 2003;306(3): 1174-81
130. Braselmann S, Taylor V, Zhao H, et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complexmediated inflammation. J Pharmacol Exp Ther 2006;319(3): 998-1008
131. Weinblatt ME, Kavanaugh A, Genovese MC, et al. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med 2010;363(14): 1303-12
132. Mocsai A, Ruland J, Tybulewicz VL. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol 2010;10(6): 387-402
133. Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 2010;107(29): 13075-80
134. Chang BY, Huang MM, Francesco M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Res Ther 2011;13(4):R115
135. Liu Y, Masuda E, Blank MC, et al. Cytokine-mediated regulation of activating and inhibitory Fc gamma receptors in human monocytes. J Leukoc Biol 2005;77(5): 767-76
136. Belostocki K, Pricop L, Redecha PB, et al. Infliximab treatment shifts the balance between stimulatory and inhibitory Fcgamma receptor type II isoforms on neutrophils in patients with rheumatoid arthritis. Arthritis Rheum 2008;58(2): 384-8
137. Rudge EU, Cutler AJ, Pritchard NR, et al. Interleukin 4 reduces expression of inhibitory receptors on B cells and abolishes CD22 and Fc gamma RIImediated B cell suppression. J Exp Med 2002;195(8): 1079-85
138. Allen JB, Wong HL, Guyre PM, et al. Association of circulating receptor Fc gamma RIII-positive monocytes in AIDS patients with elevated levels of transforming growth factor-beta. J Clin Invest 1991;87(5): 1773-9
139. Kerst JM, van de Winkel JG, Evans AH, et al. Granulocyte colony-stimulating factor induces hFc gamma RI (CD64 antigen)-positive neutrophils via an effect on myeloid precursor cells. Blood 1993;81(6): 1457-64
140. Guyre PM, Morganelli PM, Miller R. Recombinant immune interferon increases immunoglobulin G Fc receptors on cultured human mononuclear phagocytes. J Clin Invest 1983;72(1): 393-7
141. Valerius T, Repp R, de Wit TP, et al. Involvement of the high-affinity receptor for IgG (Fc gamma RI; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colonystimulating factor therapy. Blood 1993;82(3): 931-9
142. Goulding NJ, Knight SM, Godolphin JL, et al. Increase in neutrophil Fc gamma receptor I expression following interferon gamma treatment in rheumatoid arthritis. Ann Rheum Dis 1992;51(4): 465-8
143. Shushakova N, Skokowa J, Schulman J, et al. C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease. J Clin Invest 2002;110(12): 1823-30
144. Tsuboi N, Ernandez T, Li X, et al. Regulation of human neutrophil Fcgamma receptor IIa by C5a receptor promotes inflammatory arthritis in mice. Arthritis Rheum 2011;63(2): 467-78
145. Xie T, Liang J, Liu N, et al. MicroRNA-127 inhibits lung inflammation by targeting IgG Fcgamma receptor I. J Immunol 2012;188(5): 2437-44
146. Juliano RL, Dixit VR, Kang H, et al. Epigenetic manipulation of gene expression: a toolkit for cell biologists. J Cell Biol 2005;169(6): 847-57
147. Iguchi A, Fukuda N, Takahashi T, et al. RNA binding properties of novel gene silencing pyrrole-imidazole polyamides. Biol Pharm Bull 2013;36(7): 1152-8
148. Wigle TJ, Copeland RA. Drugging the human methylome: an emerging modality for reversible control of aberrant gene transcription. Curr Opin Chem Biol 2013;17(3): 369-78
149. Avalos AM, Uccellini MB, Lenert P, et al. FcgammaRIIB regulation of BCR/TLR-dependent autoreactive B-cell responses. Eur J Immunol 2010;40(10): 2692-8
150. Means TK, Latz E, Hayashi F, et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest 2005;115(2): 407-17
151. Schroeder JT, Bieneman AP, Xiao H, et al. TLR9- and FcepsilonRI-mediated responses oppose one another in plasmacytoid dendritic cells by downregulating receptor expression. J Immunol 2005;175(9): 5724-31
152. Wenink MH, Santegoets KC, Roelofs MF, et al. The inhibitory Fc gamma IIb receptor dampens TLR4- mediated immune responses and is selectively up-regulated on dendritic cells from rheumatoid arthritis patients with quiescent disease. J Immunol 2009;183(7): 4509-20
153. Zhang Y, Liu S, Liu J, et al. Immune complex/Ig negatively regulate TLR4- triggered inflammatory response in macrophages through Fc gamma RIIb- dependent PGE2 production. J Immunol 2009;182(1): 554-62
154. Chu CL, Yu YL, Shen KY, et al. Increased TLR responses in dendritic cells lacking the ITAM-containing adapters DAP12 and FcRgamma. Eur J Immunol 2008;38(1): 166-73
155. Dunn-Siegrist I, Leger O, Daubeuf B, et al. Pivotal involvement of Fcgamma receptor IIA in the neutralization of lipopolysaccharide signaling via a potent novel anti-TLR4 monoclonal antibody 15C1. J Biol Chem 2007;282(48): 34817-27
156. Krupa A, Fudala R, Florence JM, et al. Bruton's tyrosine kinase mediates FcgammaRIIa/Toll-like receptor-4 receptor crosstalk in human neutrophils. Am J Respir Cell Mol Biol 2013;48(2): 240-9
157. Rittirsch D, Flierl MA, Day DE, et al. Cross-talk between TLR4 and FcgammaReceptorIII (CD16) pathways. PLoS Pathog 2009;5(6):e1000464
158. Wijngaarden S, van de Winkel JG, Jacobs KM, et al. A shift in the balance of inhibitory and activating Fcgamma receptors on monocytes toward the inhibitory Fcgamma receptor IIb is associated with prevention of monocyte activation in rheumatoid arthritis. Arthritis Rheum 2004;50(12): 3878-87
159. van der Pol WL, van den Berg LH, Scheepers RH, et al. IgG receptor IIa alleles determine susceptibility and severity of Guillain-Barre syndrome. Neurology 2000;54(8): 1661-5
160. Li X, Ptacek TS, Brown EE, et al. Fcgamma receptors: structure, function and role as genetic risk factors in SLE. Genes Immun 2009;10(5): 380-9
161. Brun JG, Madland TM, Vedeler CA. Immunoglobulin G fc-receptor (FcgammaR) IIA, IIIA, and IIIB polymorphisms related to disease severity in rheumatoid arthritis. J Rheumatol 2002;29(6): 1135-40
162. Dijstelbloem HM, Scheepers RH, Oost WW, et al. Fcgamma receptor polymorphisms in Wegener's granulomatosis: risk factors for disease relapse. Arthritis Rheum 1999;42(9): 1823-7
163. Karassa FB, Trikalinos TA, Ioannidis JP, et al. Role of the Fcgamma receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Arthritis Rheum 2002;46(6): 1563-71
164. Shrestha S, Wiener H, Shendre A, et al. Role of activating FcgammaR gene polymorphisms in Kawasaki disease susceptibility and intravenous immunoglobulin response. Circ Cardiovasc Genet 2012;5(3): 309-16
165. Khor CC, Davila S, Breunis WB, et al. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat Genet 2011;43(12): 1241-6
166. Onouchi Y, Ozaki K, Burns JC, et al. A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat Genet 2012;44(5): 517-21
167. Saruhan-Direskeneli G, Hughes T, Aksu K, et al. Identification of multiple genetic susceptibility Loci in takayasu arteritis. Am J Hum Genet 2013;93(2): 298-305
168. Edberg JC, Langefeld CD, Wu J, et al. Genetic linkage and association of Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. Arthritis Rheum 2002;46(8): 2132-40
169. Morgan AW, Barrett JH, Griffiths B, et al. Analysis of Fcgamma receptor haplotypes in rheumatoid arthritis: FCGR3A remains a major susceptibility gene at this locus, with an additional contribution from FCGR3B. Arthritis Res Ther 2006;8(1):R5
170. Jonsen A, Gunnarsson I, Gullstrand B, et al. Association between SLE nephritis and polymorphic variants of the CRP and FcgammaRIIIa genes. Rheumatology (Oxford) 2007;46(9): 1417-21
171. Hatta Y, Tsuchiya N, Ohashi J, et al. Association of Fc gamma receptor IIIB, but not of Fc gamma receptor IIA and IIIA polymorphisms with systemic lupus erythematosus in Japanese. Genes Immun 1999;1(1): 53-60
172. Foster CB, Zhu S, Erichsen HC, et al. Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura: a pilot study. Br J Haematol 2001;113(3): 596-9
173. Willcocks LC, Lyons PA, Clatworthy MR, et al. Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J Exp Med 2008;205(7): 1573-82
174. Tse WY, Abadeh S, Jefferis R, et al. Neutrophil FcgammaRIIIb allelic polymorphism in anti-neutrophil cytoplasmic antibody (ANCA)-positive systemic vasculitis. Clin Exp Immunol 2000;119(3): 574-7
175. Wu J, Ji C, Xie F, et al. FcalphaRI (CD89) alleles determine the proinflammatory potential of serum IgA. J Immunol 2007;178(6): 3973-82