Fcγ receptors: Genetic variation, function, and disease

Immunological Reviews

Volumn 268, Issue 1, 2015, Pages 6-24

  Hargreaves, Chantal E ^a   Rose Zerilli, Matthew J J ^a   Machado, Lee R ^b,c   Iriyama, Chisako ^d   Hollox, Edward J ^b   Cragg, Mark S ^a   Strefford, Jonathan C ^a  

^a UNIVERSITY OF SOUTHAMPTON   (United Kingdom)

^b UNIVERSITY OF LEICESTER   (United Kingdom)

^c UNIVERSITY OF NORTHAMPTON   (United Kingdom)

^d NAGOYA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

Antibodies; Fc receptors; Genetics; Immunotherapy

Indexed keywords

AUTOANTIBODY; CETUXIMAB; CYCLOPHOSPHAMIDE; DOXORUBICIN; FC RECEPTOR; FC RECEPTOR IIA; FC RECEPTOR IIB; FC RECEPTOR IIC; FC RECEPTOR IIIA; FC RECEPTOR IIIB; IMMUNOGLOBULIN; MATERNAL ANTIBODY; MONOCLONAL ANTIBODY; NEUTROPHIL CYTOPLASMIC ANTIBODY; PREDNISONE; RITUXIMAB; TRASTUZUMAB; UNCLASSIFIED DRUG; VINCRISTINE;

ADAPTIVE IMMUNITY; AMINO ACID SUBSTITUTION; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ANTIGEN PRESENTING CELL; AUTOIMMUNE DISEASE; AUTOIMMUNITY; BINDING AFFINITY; CANCER COMBINATION CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CANCER SUSCEPTIBILITY; COPY NUMBER VARIATION; ETHNIC DIFFERENCE; EVOLUTION; FOLLICULAR LYMPHOMA; GENE DUPLICATION; GENE LINKAGE DISEQUILIBRIUM; GENE SEQUENCE; GENETIC SCREENING; GENETIC VARIABILITY; GENOTYPE; GRAVES DISEASE; HAPLOTYPE; HIGH THROUGHPUT SEQUENCING; HOMOZYGOTE; HUMAN; HUMORAL IMMUNITY; IDIOPATHIC THROMBOCYTOPENIC PURPURA; IMMUNOPATHOLOGY; IMMUNOTHERAPY; INDEL MUTATION; INNATE IMMUNITY; LARGE CELL LYMPHOMA; LIPID RAFT; LUPUS ERYTHEMATOSUS NEPHRITIS; MACROPHAGE; MEMORY CELL; METASTATIC COLORECTAL CANCER; MONOCYTE; MUCOCUTANEOUS LYMPH NODE SYNDROME; MULTIGENE FAMILY; MULTIPLEX LIGATION DEPENDENT PROBE AMPLIFICATION; NATURAL KILLER CELL; NEUTROPENIA; NEXT GENERATION SEQUENCING; NONHODGKIN LYMPHOMA; NONHUMAN; PARALOG RATIO TEST; PARALOGY; POLYMERASE CHAIN REACTION; PRACTICE GUIDELINE; PREVALENCE; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN FAMILY; PYROSEQUENCING; RECEPTOR BINDING; RECEPTOR GENE; REVIEW; RHEUMATOID ARTHRITIS; SANGER SEQUENCING; SEQUENCE HOMOLOGY; SINGLE NUCLEOTIDE POLYMORPHISM; SJOEGREN SYNDROME; SYSTEMIC LUPUS ERYTHEMATOSUS; SYSTEMIC VASCULITIS; ULCERATIVE COLITIS; WEGENER GRANULOMATOSIS; ANIMAL; DISEASE PREDISPOSITION; GENE DOSAGE; GENE LOCUS; GENETIC VARIATION; GENETICS; IMMUNE SYSTEM; IMMUNOLOGY; METABOLISM; MOLECULAR EVOLUTION; MOUSE; PROCEDURES;

ANIMALS; ANTIGEN-PRESENTING CELLS; DISEASE SUSCEPTIBILITY; EVOLUTION, MOLECULAR; GENE DOSAGE; GENETIC LOCI; GENETIC TESTING; GENETIC VARIATION; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; HUMANS; IMMUNE SYSTEM; IMMUNOTHERAPY; MICE; MULTIGENE FAMILY; RECEPTORS, IGG;

EID: 84945306288     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12341     Document Type: Review

References (180)

1. Vogelpoel LT, Baeten DL, de Jong EC, denDunnen J. Control of cytokine productionby human Fc gamma receptors: implications for pathogen defense andautoimmunity. Front Immunol 2015;6:79.
2. Nimmerjahn F, Ravetch JV. FcgammaRs in healthand disease. Curr Top Microbiol Immunol 2011;350:105-125.
3. Nimmerjahn F, Gordan S, Lux A. FcgammaRdependent mechanisms of cytotoxic, agonistic, and neutralizing antibodyactivities. Trends Immunol 2015;36:325-336.
4. Bruhns P, etal. Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood 2009;113:3716-3725.
5. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 2008;8:34-47.
6. Guilliams M, Bruhns P, Saeys Y, Hammad H, Lambrecht BN. The function of Fcgammareceptors in dendritic cells and macrophages. Nat Rev Immunol 2014;14:94-108.
7. Kurosaki T, Ravetch JV. A single amino acid in the glycosyl phosphatidylinositol attachment domain determines the membrane topology ofFc gamma RIII. Nature 1989;342:805-807.
8. Nimmerjahn F, Ravetch JV. Fc-receptors as regulators of immunity. Adv Immunol 2007;96:179-204.
9. Smith KG, Clatworthy MR. FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol 2010;10:328-343.
10. Sammartino L, Webber LM, Hogarth PM, McKenzie IF, Garson OM. Assignment of the gene coding for human FcRII (CD32) to bands q23q24 on chromosome 1. Immunogenetics 1988;28:380-381.
11. Qiu WQ, de Bruin D, Brownstein BH, Pearse R, Ravetch JV. Organization of the human and mouse low-affinity Fc gamma R genes: duplication and recombination. Science 1990;248:732-735.
12. Su K, Wu J, Edberg JC, McKenzie SE, Kimberly RP. Genomic organization of classical human low-affinity Fcgamma receptor genes. Genes Immun 2002;3(Suppl):S51-S56.
13. Machado LR, etal. Evolutionary history of copy-number-variable locus for the low-affinity Fcgamma receptor: mutation rate, autoimmune disease, and the legacy of helminth infection. Am J Hum Genet 2012;90:973-985.
14. Edberg JC, etal. Genetic linkage and association of Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. Arthritis Rheum 2002;46:2132-2140.
15. Thabet MM, etal. Contribution of Fcγ receptor IIIA gene 158V/F polymorphism and copy number variation to the risk of ACPA-positive rheumatoid arthritis. Ann Rheum Dis 2009;68:1775-1780.
16. Sareneva I, etal. Linkage and association study of FcgammaR polymorphisms in celiac disease. Tissue Antigens 2009;73:54-58.
17. Willcocks LC, etal. Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J Exp Med 2008;205:1573-1582.
18. Fanciulli M, etal. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet 2007;39:721-723.
19. Mueller M, etal. Genomic pathology of SLE-associated copy-number variation at the FCGR2C/FCGR3B/FCGR2B locus. Am J Hum Genet 2013;92:28-40.
20. Floto RA, etal. Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts. Nat Med 2005;11:1056-1058.
21. Niederer HA, etal. Copy number, linkage disequilibrium and disease association in the FCGR locus. Hum Mol Genet 2010;19:3282-3294.
22. Willcocks LC, etal. A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus. Proc Natl Acad Sci USA 2010;107:7881-7885.
23. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003;21:3940-3947.
24. Bibeau F, etal. Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 2009;27:1122-1129.
25. Cartron G, etal. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002;99:754-758.
26. Mellor JD, Brown MP, Irving HR, Zalcberg JR, Dobrovic A. A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. J Hematol Oncol 2013;6:1.
27. Sharp AJ, etal. Segmental duplications and copy-number variation in the human genome. Am J Hum Genet 2005;77:78-88.
28. Takai S, etal. Human high-affinity FcγRI (CD64) gene mapped to chromosome 1q21.2-q21.3 by fluorescence insitu hybridization. Hum Genet 1994;93:13-15.
29. Maresco DL, Chang E, Theil KS, Francke U, Anderson CL. The three genes of the human FCGR1 gene family encoding Fc gamma RI flank the centromere of chromosome 1 at 1p12 and1q21. Cytogenet Cell Genet 1996;73:157-163.
30. van der Poel CE, etal. Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG. Blood 2010;116:5327-5333.
31. Genomes Project C, etal. An integrated map of genetic variation from 1, 092 human genomes. Nature 2012;491:56-65.
32. Akula S, Mohammadamin S, Hellman L. Fc receptors for immunoglobulins and their appearance during vertebrate evolution. PLoS ONE 2014;9:e96903.
33. Fayngerts S, Najakshin A, Taranin A. Species-specific evolution of the FcR family in endothermic vertebrates. Immunogenetics 2007;59:493-506.
34. Warmerdam PA, Nabben NM, van de Graaf SA, van de Winkel JG, Capel PJ. The human low affinity immunoglobulin G Fc receptor IIC gene is a result of an unequal crossover event. J Biol Chem 1993;268:7346-7349.
35. Gessner JE, Grussenmeyer T, Kolanus W, Schmidt RE. The human low affinity immunoglobulin G Fc receptor III-A and III-B genes. Molecular characterization of the promoter regions. J Biol Chem 1995;270:1350-1361.
36. Nguyen H, Merriman TR, Black MA. CNVrd, a Read-Depth algorithm for assigning copy-number at the FCGR locus: population-specific tagging of copy number variation at FCGR3B. PLoS ONE 2013;8:e63219.
37. Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV. FcγRIV: a novel FcR with distinct IgG subclass specificity. Immunity 2005;23:41-51.
38. Osman N, Kozak CA, McKenzie IF, Hogarth PM. Structure and mapping of the gene encoding mouse high affinity Fc gamma RI and chromosomal location of the human Fc gamma RI gene. J Immunol 1992;148:1570-1575.
39. Kulczycki A Jr, etal. Genomic organization of mouse Fc gamma receptor genes. Proc Natl Acad Sci USA 1990;87:2856-2860.
40. Jiang Y, etal. Genetically determined aberrant down-regulation of FcγRIIB1 in germinal center B cells associated with hyper-IgG and IgG autoantibodies in murine systemic lupus erythematosus. Int Immunol 1999;11:1685-1691.
41. Jiang Y, etal. Polymorphisms in IgG Fc receptor IIB regulatory regions associated with autoimmune susceptibility. Immunogenetics 2000;51:429-435.
42. Xiu Y, etal. Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses. J Immunol 2002;169:4340-4346.
43. Espéli M, etal. Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity. J Exp Med 2012;209:2307-2319.
44. McGaha TL, Sorrentino B, Ravetch JV. Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 2005;307:590-593.
45. Brownlie RJ, etal. Distinct cell-specific control of autoimmunity and infection by Fc gamma RIIb. J Exp Med 2008;205:883-895.
46. Boross P, etal. The inhibiting Fc receptor for IgG, FcγRIIB, is a modifier of autoimmune susceptibility. J Immunol 2011;187:1304-1313.
47. Clynes R, Calvani N, Croker BP, Richards HB. Modulation of the immune response in pristane-induced lupus by expression of activation and inhibitory Fc receptors. Clin Exp Immunol 2005;141:230-237.
48. Pritchard NR, Cutler AJ, Uribe S, Chadban SJ, Morley BJ, Smith KGC. Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcγRII. Curr Biol 2000;10:227-230.
49. Dahal LN, Roghanian A, Beers SA, Cragg MS. FcγR requirements leading to successful immunotherapy. Immunol Rev 2015;268:104-122.
50. Breunis WB, etal. Copy number variation at the FCGR locus includes FCGR3A, FCGR2C and FCGR3B but not FCGR2A and FCGR2B. Hum Mutat 2009;30:E640-E650.
51. Clark MR, Clarkson SB, Ory PA, Stollman N, Goldstein IM. Molecular basis for a polymorphism involving Fc receptor II on human monocytes. J Immunol 1989;143:1731-1734.
52. Maxwell KF, etal. Crystal structure of the human leukocyte Fc receptor, Fc gammaRIIa. Nat Struct Biol 1999;6:437-442.
53. Warmerdam PA, van de Winkel JG, Vlug A, Westerdaal NA, Capel PJ. A single amino acid in the second Ig-like domain of the human Fc gamma receptor II is critical for human IgG2 binding. J Immunol 1991;147:1338-1343.
54. Clark MR, Stuart SG, Kimberly RP, Ory PA, Goldstein IM. A single amino acid distinguishes the high-responder from the low-responder form of Fc receptor II on human monocytes. Eur J Immunol 1991;21:1911-1916.
55. Duan J, etal. A genetic variant rs1801274 in FCGR2A as a potential risk marker for Kawasaki disease: a case-control study and meta-analysis. PLoS ONE 2014;9:e103329.
56. Khor CC, etal. Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat Genet 2011;43:1241-1246.
57. Yesmin K, etal. Association of FcGRIIa with Graves' disease: a potential role for dysregulated autoantibody clearance in disease onset/progression. Clin Endocrinol 2010;73:119-125.
58. McGovern DP, etal. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 2010;42:332-337.
59. Kuo HC, etal. Identification of an association between genomic hypomethylation of FCGR2A and susceptibility to Kawasaki disease and intravenous immunoglobulin resistance by DNA methylation array. Arthritis Rheumatol 2015;67:828-836.
60. van der Heijden J, etal. A novel splice variant of FcgammaRIIa: a risk factor for anaphylaxis in patients with hypogammaglobulinemia. J Allergy Clin Immunol 2013;131:1408-1416 e1405.
61. Brooks DG, Qiu 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.
62. Flinsenberg TW, etal. A novel FcgammaRIIa Q27W gene variant is associated with common variable immune deficiency through defective FcgammaRIIa downstream signaling. Clin Immunol 2014;155:108-117.
63. Minskoff SA, Matter K, Mellman I. Fc gamma RII-B1 regulates the presentation of B cell receptor-bound antigens. J Immunol 1998;161:2079-2083.
64. Amigorena S, etal. Cytoplasmic domain heterogeneity and functions of IgG Fc receptorsin B lymphocytes. Science 1992;256:1808-1812.
65. Su K, etal. 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;172:7186-7191.
66. Breunis WB, etal. Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura. Blood 2008;111:1029-1038.
67. Su K, Li X, Edberg JC, Wu J, Ferguson P, Kimberly RP. 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;172:7192-7199.
68. Mackay M, etal. Selective dysregulation of the Fc gamma IIB receptor on memory B cells in SLE. J Exp Med 2006;203:2157-2164.
69. Takai T, Ono M, Hikida M, Ohmori H, Ravetch JV. Augmented humoral and anaphylactic responses in Fc[gamma]RII-deficient mice. Nature 1996;379:346-349.
70. Yuasa T, etal. Deletion of fcgamma receptor IIB renders H-2(b) mice susceptible to collagen-induced arthritis. J Exp Med 1999;189:187-194.
71. Bolland S, Ravetch JV. Spontaneous autoimmune disease in FcγRIIB-deficient mice results from strain-specific epistasis. Immunity 2000;13:277-285.
72. Blank M, etal. Decreased transcription of the human FCGR2B gene mediated by the -343G/C promoter polymorphism and association with systemic lupus erythematosus. Hum Genet 2005;117:220-227.
73. van Mirre E, etal. Neutrophil responsiveness to IgG, as determined by fixed ratios of mRNA levels for activating and inhibitory FcgammaRII (CD32), is stable over time and unaffected by cytokines. Blood 2006;108:584-590.
74. Kyogoku C, etal. Fcgamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum 2002;46:1242-1254.
75. Niederer HA, Clatworthy MR, Willcocks LC, Smith KG. FcgammaRIIB, FcgammaRIIIB, and systemic lupus erythematosus. Ann N Y Acad Sci 2010;1183:69-88.
76. Li X, etal. A novel polymorphism in the Fcgamma receptor IIB (CD32B) transmembrane region alters receptor signaling. Arthritis Rheum 2003;48:3242-3252.
77. Kono H, etal. FcgammaRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet 2005;14:2881-2892.
78. Xu L, etal. Through an ITIM-independent mechanism the FcgammaRIIB blocks B cell activation by disrupting the colocalized microclustering of the B cell receptor and CD19. J Immunol 2014;192:5179-5191.
79. Van den Herik-Oudijk IE, Capel PJ, van der Bruggen T, Van de Winkel JG. Identification of signaling motifs within human Fc gamma RIIa and Fc gamma RIIb isoforms. Blood 1995;85:2202-2211.
80. Bruhns P, Vely F, Malbec O, Fridman WH, Vivier E, Daeron M. Molecular basis of the recruitment of the SH2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 by fcgamma RIIB. J Biol Chem 2000;275:37357-37364.
81. Muta T, Kurosaki T, Misulovin Z, Sanchez M, Nussenzweig MC, Ravetch JV. A 13-amino-acid motif in the cytoplasmic domain of Fc gamma RIIB modulates B-cell receptor signalling. Nature 1994;369:340.
82. Clatworthy MR, etal. Systemic lupus erythematosus-associated defects in the inhibitory receptor FcgammaRIIb reduce susceptibility to malaria. Proc Natl Acad Sci USA 2007;104:7169-7174.
83. Siriboonrit U, etal. Association of Fcgamma receptor IIb and IIIb polymorphisms with susceptibility to systemic lupus erythematosus in Thais. Tissue Antigens 2003;61:374-383.
84. Chen J-Y, etal. Association of a transmembrane polymorphism of Fcγ receptor IIb (FCGR2B) with systemic lupus erythematosus in Taiwanese patients. Arthritis Rheum 2006;54:3908-3917.
85. Lau CS, Yin G, Mok MY. Ethnic and geographical differences in systemic lupus erythematosus: an overview. Lupus 2006;15:715-719.
86. Baerenwaldt A, etal. Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system invivo. Proc Natl Acad Sci USA 2011;108:18772-18777.
87. Metes D, Ernst LK, Chambers WH, Sulica A, Herberman RB, Morel PA. Expression of functional CD32 molecules on human NK cells is determined by an allelic polymorphism of the FcgammaRIIC gene. Blood 1998;91:2369-2380.
88. Stuart SG, Simister NE, Clarkson SB, Kacinski BM, Shapiro M, Mellman I. Human IgG Fc receptor (hFcRII; CD32) exists as multiple isoforms in macrophages, lymphocytes and IgG-transporting placental epithelium. EMBO J 1989;8:3657-3666.
89. van der Heijden J, Breunis WB, Geissler J, de Boer M, van den Berg TK, Kuijpers TW. Phenotypic variation in IgG receptors by nonclassical FCGR2C alleles. J Immunol 2012;188:1318-1324.
90. Metes D, etal. Ligand binding specificities and signal transduction pathways of Fc gamma receptor IIc isoforms: the CD32 isoforms expressed by human NK cells. Eur J Immunol 1999;29:2842-2852.
91. Ernst L, Metes D, Herberman R, Morel P. Allelic polymorphisms in the FcγRIIC gene can influence its function on normal human natural killer cells. J Mol Med 2002;80:248-257.
92. Stewart-Akers AM, Cunningham A, Wasko MC, Morel PA. Fc[gamma]R expression on NK cells influences disease severity in rheumatoid arthritis. Genes Immun 2004;5:521-529.
93. Li X, etal. Allelic-dependent expression of an activating Fc receptor on B cells enhances humoral immune responses. Sci Transl Med 2013;5:216ra175.
94. Metes D, etal. Identification of the CD32/FcγRIIc-Q13/STP13 polymorphism using an allele-specific restriction enzyme digestion assay. J Immunol Methods 2001;258:85-95.
95. Li SS, etal. FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial. J Clin Invest 2014;124:3879-3890.
96. Wu J, etal. A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 1997;100:1059-1070.
97. Li LH, Yuan H, Pan HF, Li WX, Li XP, Ye DQ. Role of the Fcgamma receptor IIIA-V/F158 polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Scand J Rheumatol 2010;39:148-154.
98. de Haas M, etal. A triallelic Fc gamma receptor type IIIA polymorphism influences the binding of human IgG by NK cell Fc gamma RIIIa. J Immunol 1996;156:2948-2955.
99. Dong C, etal. Fcγ receptor IIIa single-nucleotide polymorphisms and haplotypes affect human IgG binding and are associated with lupus nephritis in African Americans. Arthritis Rheumatol 2014;66:1291-1299.
100. Lassaunière R, Shalekoff S, Tiemessen CT. A novel FCGR3A intragenic haplotype is associated with increased FcγRIIIa/CD16a cell surface density and population differences. Hum Immunol 2013;74:627-634.
101. Ravetch JV, Perussia B. 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 1989;170:481-497.
102. Meknache N, Jönsson F, Laurent J, Guinnepain M-T, Daëron M. Human basophils express the glycosylphosphatidylinositol-anchored low-affinity IgG receptor FcγRIIIB (CD16B). J Immunol 2009;182:2542-2550.
103. Ory PA, Clark MR, Kwoh EE, Clarkson SB, Goldstein IM. Sequences of complementary DNAs that encode the NA1 and NA2 forms of Fc receptor III on human neutrophils. J Clin Invest 1989;84:1688-1691.
104. Ory PA, Goldstein IM, Kwoh EE, Clarkson SB. Characterization of polymorphic forms of Fc receptor III on human neutrophils. J Clin Invest 1989;83:1676-1681.
105. Bux J. Human neutrophil alloantigens. Vox Sang 2008;94:277-285.
106. Salmon JE, Edberg JC, Kimberly RP. Fc gamma receptor III on human neutrophils. Allelic variants have functionally distinct capacities. J Clin Invest 1990;85:1287-1295.
107. Bredius RG, etal. Role of neutrophil Fc gamma RIIa (CD32) and Fc gamma RIIIb (CD16) polymorphic forms in phagocytosis of human IgG1- and IgG3-opsonized bacteria and erythrocytes. Immunology 1994;83:624-630.
108. Bux J, etal. Characterization of a new alloantigen (SH) on the human neutrophil Fc gamma receptor IIIb. Blood 1997;89:1027-1034.
109. Koene HR, Kleijer M, Roos D, de Haas M, Von dem Borne AE. Fc gamma RIIIB gene duplication: evidence for presence and expression of three distinct Fc gamma RIIIB genes in NA(1+, 2+)SH(+) individuals. Blood 1998;91:673-679.
110. Flesch BK, Doose S, Siebert R, Ntambi E, Neppert J. FCGR3 variants and expression of human neutrophil antigen-1a, -1b, and -1c in the populations of northern Germany and Uganda. Transfusion 2002;42:469-475.
111. Reil A, Sachs UJ, Siahanidou T, Flesch BK, Bux J. HNA-1d: a new human neutrophil antigen located on Fcgamma receptor IIIb associated with neonatal immune neutropenia. Transfusion 2013;53:2145-2151.
112. Tse WY, Abadeh S, Jefferis R, Savage CO, Adu D. Neutrophil FcgammaRIIIb allelic polymorphism in anti-neutrophil cytoplasmic antibody (ANCA)-positive systemic vasculitis. Clin Exp Immunol 2000;119:574-577.
113. Morris DL, etal. Evidence for both copy number and allelic (NA1/NA2) risk at the FCGR3B locus in systemic lupus erythematosus. Eur J Hum Genet 2010;18:1027-1031.
114. Salmon JE, Edberg JC, Brogle NL, Kimberly RP. Allelic polymorphisms of human Fc gamma receptor IIA and Fc gamma receptor IIIB. Independent mechanisms for differences in human phagocyte function. J Clin Invest 1992;89:1274-1281.
115. Huizinga TW, etal. Maternal genomic neutrophil FcRIII deficiency leading to neonatal isoimmune neutropenia. Blood 1990;76:1927-1932.
116. Stroncek DF, etal. Alloimmune neonatal neutropenia due to an antibody to the neutrophil Fc-gamma receptor III with maternal deficiency of CD16 antigen. Blood 1991;77:1572-1580.
117. Fromont P, etal. Frequency of the polymorphonuclear neutrophil Fc gamma receptor III deficiency in the French population and its involvement in the development of neonatal alloimmune neutropenia. Blood 1992;79:2131-2134.
118. Redon R, etal. Global variation in copy number in the human genome. Nature 2006;444:444-454.
119. Conrad DF, etal. Origins and functional impact of copy number variation in the human genome. Nature 2010;464:704-712.
120. Hastings PJ, Lupski JR, Rosenberg SM, Ira G. Mechanisms of change in gene copy number. Nat Rev Genet 2009;10:551-564.
121. Hollox EJ, Hoh BP. Human gene copy number variation and infectious disease. Hum Genet 2014;133:1217-1233.
122. Bailey JA, etal. Recent segmental duplications in the human genome. Science 2002;297:1003-1007.
123. Hollox EJ, Detering JC, Dehnugara T. An integrated approach for measuring copy number variation at the FCGR3 (CD16) locus. Hum Mutat 2009;30:477-484.
124. de Haas M, Kleijer M, van Zwieten R, Roos D, von dem Borne AE. Neutrophil Fc gamma RIIIb deficiency, nature, and clinical consequences: a study of 21 individuals from 14 families. Blood 1995;86:2403-2413.
125. Nagelkerke SQ, etal. Nonallelic homologous recombination of the FCGR2/3 locus results in copy number variation and novel chimeric FCGR2 genes with aberrant functional expression. Genes Immun 2015; doi: 10.1038/gene.2015.25.
126. Lindsay SJ, Khajavi M, Lupski JR, Hurles ME. A chromosomal rearrangement hotspot can be identified from population genetic variation and is coincident with a hotspot for allelic recombination. Am J Hum Genet 2006;79:890-902.
127. Molokhia M, etal. FCGR3B copy number variation is associated with systemic lupus erythematosus risk in Afro-Caribbeans. Rheumatology 2011;50:1206-1210.
128. Chen J-Y, etal. Association of FCGR3A and FCGR3B copy number variations with systemic lupus erythematosus and rheumatoid arthritis in taiwanese patients. Arthritis Rheumatol 2014;66:3113-3121.
129. Robinson JI, etal. Confirmation of association of FCGR3B but not FCGR3A copy number with susceptibility to autoantibody positive rheumatoid arthritis. Hum Mutat 2012;33:741-749.
130. McKinney C, Merriman TR. Meta-analysis confirms a role for deletion in FCGR3B in autoimmune phenotypes. Hum Mol Genet 2012;21:2370-2376.
131. Aitman TJ, etal. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 2006;439:851-855.
132. Nossent JC, Becker-Merok A, Rischmueller M, Lester S. Susceptibility for lupus nephritis by low copy number of the FCGR3B gene is linked to increased levels of pathogenic autoantibodies. Autoimmune Dis 2013;2013:6.
133. Franke L, etal. Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes. Eur J Hum Genet 2015; doi: 10.1038/ejhg.2015.95. [Epub ahead of print].
134. Nossent JC, Rischmueller M, Lester S. Low copy number of the Fc-gamma receptor 3B gene FCGR3B is a risk factor for primary Sjogren's syndrome. J Rheumatol 2012;39:2142-2147.
135. Asano K, etal. Impact of allele copy number of polymorphisms in FCGR3A and FCGR3B genes on susceptibility to ulcerative colitis. Inflamm Bowel Dis 2013;19:2061-2068.
136. Haldorsen K, etal. No association of primary Sjogren/'s syndrome with Fc[gamma] receptor gene variants. Genes Immun 2013;14:234-237.
137. Marques RB, etal. Genetic variation of the Fc gamma receptor 3B gene and association with rheumatoid arthritis. PLoS ONE 2010;5:e13173.
138. Bournazos S, etal. Copy number variation of FCGR3B is associated with susceptibility to idiopathic pulmonary fibrosis. Respiration 2011;81:142-149.
139. van der Poel CE, Spaapen RM, van de Winkel JG, Leusen JH. Functional characteristics of the high affinity IgG receptor, FcgammaRI. J Immunol 2011;186:2699-2704.
140. Lu J, Chu J, Zou Z, Hamacher NB, Rixon MW, Sun PD. Structure of FcgammaRI in complex with Fc reveals the importance of glycan recognition for high-affinity IgG binding. Proc Natl Acad Sci USA 2015;112:833-838.
141. van de Winkel JG, de Wit TP, Ernst LK, Capel PJ, Ceuppens JL. Molecular basis for a familial defect in phagocyte expression of IgG receptor I (CD64). J Immunol 1995;154:2896-2903.
142. Ioan-Facsinay A, etal. FcgammaRI (CD64) contributes substantially to severity of arthritis, hypersensitivity responses, and protection from bacterial infection. Immunity 2002;16:391-402.
143. Mittal R, etal. Fcgamma receptor I alpha chain (CD64) expression in macrophages is critical for the onset of meningitis by Escherichia coli K1. PLoS Pathog 2010;6:e1001203.
144. McIntosh RS, etal. The importance of human FcgammaRI in mediating protection to malaria. PLoS Pathog 2007;3:e72.
145. Li Y, etal. Increased expression of FcgammaRI/CD64 on circulating monocytes parallels ongoing inflammation and nephritis in lupus. Arthritis Res Ther 2009;11:R6.
146. Yunis JJ, Prakash O. The origin of man: a chromosomal pictorial legacy. Science 1982;215:1525-1530.
147. Maresco DL, Blue LE, Culley LL, Kimberly RP, Anderson CL, Theil KS. Localization of FCGR1 encoding Fcgamma receptor class I in primates: molecular evidence for two pericentric inversions during the evolution of human chromosome 1. Cytogenet Cell Genet 1998;82:71-74.
148. van Vugt MJ, Reefman E, Zeelenberg I, Boonen G, Leusen JH, van de Winkel JG. The alternatively spliced CD64 transcript FcgammaRIb2 does not specify a surface-expressed isoform. Eur J Immunol 1999;29:143-149.
149. Ernst LK, Duchemin AM, Miller KL, Anderson CL. Molecular characterization of six variant Fcgamma receptor class I (CD64) transcripts. Mol Immunol 1998;35:943-954.
150. Sudmant PH, etal. Diversity of human copy number variation and multicopy genes. Science 2010;330:641-646.
151. Nimmerjahn F, Ravetch JV. Antibodies, Fc receptors and cancer. Curr Opin Immunol 2007;19:239-245.
152. Nimmerjahn F, Ravetch JV. Translating basic mechanisms of IgG effector activity into next generation cancer therapies. Cancer Immun 2012;12:13.
153. Lee YH, Bae SC, Song GG. Functional FCGR3A 158 V/F and IL-6 -174 C/G polymorphisms predict response to biologic therapy in patients with rheumatoid arthritis: a meta-analysis. Rheumatol Int 2014;34:1409-1415.
154. Quartuccio L, etal. The 158VV Fcgamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis: results of an Italian multicentre study. Ann Rheum Dis 2014;73:716-721.
155. Ruyssen-Witrand A, etal. Fcgamma receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab. Ann Rheum Dis 2012;71:875-877.
156. Persky DO, etal. Fc gamma receptor 3a genotype predicts overall survival in follicular lymphoma patients treated on SWOG trials with combined monoclonal antibody plus chemotherapy but not chemotherapy alone. Haematologica 2012;97:937-942.
157. Ghesquières H, etal. Clinical outcome of patients with follicular lymphoma receiving chemoimmunotherapy in the PRIMA study is not affected by FCGR3A and FCGR2A polymorphisms. Blood 2012;120:2650-2657.
158. Prochazka V, etal. FcgammaRIIIA receptor genotype does not influence an outcome in patients with follicular lymphoma treated with risk-adapted immunochemotherapy. Neoplasma 2011;58:263-270.
159. Carlotti E, etal. FcgammaRIIIA and FcgammaRIIA polymorphisms do not predict clinical outcome of follicular non-Hodgkin's lymphoma patients treated with sequential CHOP and rituximab. Haematologica 2007;92:1127-1130.
160. Liu F, etal. FCGR3A 158V/F polymorphism and response to frontline R-CHOP therapy in diffuse large B-cell lymphoma. DNA Cell Biol 2014;33:616-623.
161. Musolino A, etal. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 2008;26:1789-1796.
162. Tamura K, etal. FcgammaR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer. Ann Oncol 2011;22:1302-1307.
163. Hurvitz SA, etal. Analysis of Fcgamma receptor IIIa and IIa polymorphisms: lack of correlation with outcome in trastuzumab-treated breast cancer patients. Clin Cancer Res 2012;18:3478-3486.
164. Zhang W, etal. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor-expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 2007;25:3712-3718.
165. Park SJ, etal. Genetic polymorphisms of FcγRIIa and FcγRIIIa are not predictive of clinical outcomes after cetuximab plus irinotecan chemotherapy in patients with metastatic colorectal cancer. Oncology 2012;82:83-89.
166. Weng WK, Levy R. Genetic polymorphism of the inhibitory IgG Fc receptor FcgammaRIIb is not associated with clinical outcome in patients with follicular lymphoma treated with rituximab. Leukemia Lymphoma 2009;50:723-727.
167. Vaughan AT, etal. Inhibitory FcgammaRIIb (CD32b) becomes activated by therapeutic mAb in both cis and trans and drives internalization according to antibody specificity. Blood 2014;123:669-677.
168. Trounstine ML, etal. Reactivity of cloned, expressed human Fc gamma RIII isoforms with monoclonal antibodies which distinguish cell-type-specific and allelic forms of Fc gamma RIII. Int Immunol 1990;2:303-310.
169. Alizadeh BZ, etal. Functional variants of Fc gamma receptor (FCGR2A) and FCGR3A are not associated with susceptibility to systemic sclerosis in a large European Study (EUSTAR). J Rheumatol 2010;37:1673-1679.
170. Magnusson V, etal. Both risk alleles for FcgammaRIIA and FcgammaRIIIA are susceptibility factors for SLE: a unifying hypothesis. Genes Immun 2004;5:130-137.
171. Treangen TJ, Salzberg SL. Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nat Rev Genet 2012;13:36-46.
172. Wang M, etal. PacBio-LITS: a large-insert targeted sequencing method for characterizationof human disease-associated chromosomal structural variations. BMC Genom 2015;16:214.
173. Hindson BJ, etal. High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem 2011;83:8604-8610.
174. Sykes PJ, Neoh SH, Brisco MJ, Hughes E, Condon J, Morley AA. Quantitation of targets for PCR by use of limiting dilution. Biotechniques 1992;13:444-449.
175. Pinheiro LB, etal. Evaluation of a droplet digital polymerase chain reaction format for DNA copy number quantification. Anal Chem 2012;84:1003-1011.
176. Hoshino T, Inagaki F. Molecular quantification of environmental DNA using microfluidics and digital PCR. Syst Appl Microbiol 2012;35:390-395.
177. Nadauld L, etal. Quantitative and sensitive detection of cancer genome amplifications fromformalin fixed paraffin embedded tumors with droplet digital PCR. Transl Med 2012;2:107.
178. Huggett JF, etal. The digital MIQE guidelines: minimum information for publication of quantitative digital PCR experiments. Clin Chem 2013;59:892-902.
179. Ottolini B, etal. Evidence of convergent evolution in humans and macaques supports an adaptive role for copy number variation of the β-defensin-2 gene. Genome Biol Evol 2014;6:3025-3038.
180. Gupta RM, Musunuru K. Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9. J Clin Invest 2014;124:4154-4161.