Transmembrane domain dependent inhibitory function of FcγRIIB

Abstract

FcγRIIB, the only inhibitory IgG Fc receptor, functions to suppress the hyper-activation of immune cells. Numerous studies have illustrated its inhibitory function through the ITIM motif in the cytoplasmic tail of FcγRIIB. However, later studies revealed that in addition to the ITIM, the transmembrane (TM) domain of FcγRIIB is also indispensable for its inhibitory function. Indeed, recent epidemiological studies revealed that a non-synonymous single nucleotide polymorphism (rs1050501) within the TM domain of FcγRIIB, responsible for the I232T substitution, is associated with the susceptibility to systemic lupus erythematosus (SLE). In this review, we will summarize these epidemiological and functional studies of FcγRIIB-I232T in the past few years, and will further discuss the mechanisms accounting for the functional loss of FcγRIIB-I232T. Our review will help the reader gain a deeper understanding of the importance of the TM domain in mediating the inhibitory function of FcγRIIB and may provide insights to a new therapeutic target for the associated diseases.

Key words： B cell; FcγRIIB; transmembrane domain; systemic lupus erythematosus; autoimmune disease

References

1 Amigorena S, Bonnerot C, Choquet D, Fridman WH, Teillaud JL (1989) Fc-Gamma-Rii expression in resting and activated lymphocytes-B. Eur J Immunol 19:1379–1385

2 Ballesteros JA, Deupi X, Olivella M, Haaksma EEJ, Pardo L (2000) Serine and threonine residues bend alpha-helices in the chi(1) = g(−) conformation. Biophys J 79:2754–2760

3 Batista FD, Neuberger MS (2000) B cells extract and present immobilized antigen: implications for affinity discrimination. EMBO J 19:513–520

4 Blank U, Launay P, Benhamou M, Monteiro RC (2009) Inhibitory ITAMs as novel regulators of immunity. Immunol Rev 232:59–71

5 Bolland S, Ravetch JV (2000) Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity 13:277–285

6 Bruin M, Bierings M, Uiterwaal C, Revesz T, Bode L, Wiesman ME, Kuijpers T, Tamminga R, de Haas M (2004) Platelet count, previous infection and FCGR2B genotype predict development of chronic disease in newly diagnosed idiopathic thrombocytopenia in childhood: results of a prospective study. Br J Haematol 127:561–567

7 Chen JY, Wang CM, Wu JM, Ho HH, Luo SF (2006) Association of rheumatoid factor production with FcgammaRIIIa polymorphism in Taiwanese rheumatoid arthritis. Clin Exp Immunol 144:10–16

8 Chen JY, Wang CM, Ma CC, Hsu LA, Ho HH, Wu YJJ, Kuo SN, Wu J (2008) A transmembrane polymorphism in Fc gamma RIIb (FCGR2B) is associated with the production of anti-cyclic citrullinated peptide autoantibodies in Taiwanese RA. Genes Immun 9:680–688

9 Chu ZT, Tsuchiya N, Kyogoku C, Ohashi J, Qian YP, Xu SB, Mao CZ, Chu JY, Tokunaga K (2004) Association of Fcgamma receptor IIb polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian populations. Tissue Antigens 63:21–27

10 Clatworthy MR, Willcocks L, Urban B, Langhorne J, Williams TN, Peshu N, Watkins NA, Floto RA, Smith KG (2007) Systemic lupus erythematosus-associated defects in the inhibitory receptor FcgammaRIIb reduce susceptibility to malaria. Proc Natl Acad Sci USA 104:7169–7174

11 Daeron M (1997) Fc receptor biology. Annu Rev Immunol 15:203–234

12 Daeron M, Malbec O, Latour S, Bonnerot C, Segal DM, Fridman WH (1993) Distinct intracytoplasmic sequences are required for endocytosis and phagocytosis via murine Fc gamma RII in mast cells. Int Immunol 5:1393–1401

13 Floto RA, Clatworthy MR, Heilbronn KR, Rosner DR, MacAry PA, Rankin A, Lehner PJ, Ouwehand WH, Allen JM, Watkins NA, Smith KGC (2005) Loss of function of a lupus-associated Fc gamma RIIb polymorphism through exclusion from lipid rafts. Nat Med 11:1056–1058

14 Fong DC, Brauweiler A, Minskoff SA, Bruhns P, Tamir I, Mellman I, Daeron M, Cambier JC (2000) Mutational analysis reveals multiple distinct sites within Fc gamma receptor IIB that function in inhibitory signaling. J Immunol 165:4453–4462

15 Georgiou G, Bahra SS, Mackie AR, Wolfe CA, O’Shea P, Ladha S, Fernandez N, Cherry RJ (2002) Measurement of the lateral diffusion of human MHC class I molecules on HeLa cells by fluorescence recovery after photobleaching using a phycoerythrin probe. Biophys J 82:1828–1834

16 Harder T, Scheiffele P, Verkade P, Simons K (1998) Lipid domain structure of the plasma membrane revealed by patching of membrane components. J Cell Biol 141:929–942

17 Hippen KL, Buhl AM, Dambrosio D, Nakamura K, Persin C, Cambier JC (1997) Fc gamma RIIB1 inhibition of BCR-mediated phosphoinositide hydrolysis and Ca2+ mobilization is integrated by CD19 dephosphorylation. Immunity 7:49–58

18 Kono H, Suzuki T, Yamamoto K, Okada M, Yamamoto T, Honda Z (2002) Spatial raft coalescence represents an initial step in Fc gamma R signaling. J Immunol 169:193–203

19 Kono H, Kyogoku C, Suzuki T, Tsuchiya N, Honda H, Yamamoto K, Tokunaga K, Honda Z (2005) 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 14:2881–2892

20 Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H, Yamaguchi A, Fukazawa T, Jansen MD, Hashimoto H, van de Winkel JG (2002a) Fcgamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum 46:1242–1254

21 Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H, Yamaguchi A, Fukazawa T, Jansen MD, Hashimoto H, van de Winkel JGJ (2002b) Fc gamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus- Contribution of FCGR2B to genetic susceptibility. Arthritis Rheum 46:1242–1254

22 Kyogoku C, Tsuchiya N, Matsuta K, Tokunaga K (2002c) Studies on the association of Fc gamma receptor IIA, IIB, IIIA and IIIB polymorphisms with rheumatoid arthritis in the Japanese: evidence for a genetic interaction between HLA-DRB1 and FCGR3A. Genes Immun 3:488–493

23 Kyogoku C, Tsuchiya N, Wu H, Tsao BP, Tokunaga K (2004) Association of Fcgamma receptor IIA, but not IIB and IIIA, polymorphisms with systemic lupus erythematosus: a familybased association study in Caucasians. Arthritis Rheum 50:671–673

24 Lehmann B, Schwab I, Bohm S, Lux A, Biburger M, Nimmerjahn F (2012) FcgammaRIIB: a modulator of cell activation and humoral tolerance. Expert Rev Clin Immunol 8:243–254

25 Li XR,Wu JM, Ptacek T, Redden DT, Brown EE, Alarcon GS, Ramsey-Goldman R, Petri MA, Reveille JD, Kaslow RA, (2013) Allelicdependent expression of an activating Fc receptor on B cells enhances humoral immune responses. Sci Transl Med 5

26 Liu WL, Sohn HW, Tolar P, Meckel T, Pierce SK (2010) Antigeninduced oligomerization of the B cell receptor is an early target of Fc gamma RIIB inhibition. J Immunol 184:1977–1989

27 Lu J, Chu J, Zou Z,Hamacher NB, Rixon MW, Sun PD (2015) Structure of FcgammaRI in complex with Fc reveals the importance of glycan recognition for high-affinity IgG binding. Proc Natl Acad Sci USA 112:833–838

28 Mimura Y, Sondermann P, Ghirlando R, Lund J, Young SP, Goodall M, Jefferis R (2001) Role of oligosaccharide residues of IgG1-Fc in Fc gamma RIIb binding. J Biol Chem 276:45539–45547

29 Niederer HA, Clatworthy MR, Willcocks LC, Smith KG (2010a) FcgammaRIIB, FcgammaRIIIB, and systemic lupus erythematosus. Ann N Y Acad Sci 1183:69–88

30 Niederer HA, Willcocks LC, Rayner TF, Yang W, Lau YL, Williams TN, Scott JA, Urban BC, Peshu N, Dunstan SJ (2010b) Copy number, linkage disequilibrium and disease association in the FCGR locus. Hum Mol Genet 19:3282–3294

31 Nimmerjahn F, Ravetch JV (2008) Fc gamma receptors as regulators of immune responses. Nat Rev Immunol 8:34–47

32 Nimmerjahn F, Ravetch JV (2011) FcγRs in health and disease. Curr Top Microbiol Immunol 350:105–125

33 Pan F, Zhang K, Li X, Xu J, Hao J, Ye D (2006) Association of Fcgamma receptor IIB gene polymorphism with genetic susceptibility to systemic lupus erythematosus in Chinese populations–a family-based association study. J Dermatol Sci 43:35–41

34 Peress NS (1993) Identification of Fc gamma RI, II and III on normal human brain ramified microglia and on microglia in senile plaques in Alzheimer’s disease. J Neuroimmunol 48:71–79

35 Pincetic A, Bournazos S, DiLillo DJ, Maamary J, Wang TT, Dahan R, Fiebiger BM, Ravetch JV (2014a) Type I and type II Fc receptors regulate innate and adaptive immunity. Nat Immunol 15:707–716

36 Pincetic A, Bournazos S, Dilillo DJ, Maamary J, Wang TT, Dahan R, Fiebiger BM, Ravetch JV (2014b) Type I and type II Fc receptors regulate innate and adaptive immunity. Nat Immunol 15:707

37 Radstake TRDJ, Franke B, Wenink MH, Nabbe KCAA, Coenen MJH, Welsing P, Bonvini E, Koenig S, van den Berg WB, Barrera P, van Riel PLCM (2006) The functional variant of the inhibitory Fc gamma receptor IIb (CD32B) is associated with the rate of radiologic joint damage and dendritic cell function in rheumatoid arthritis. Arthritis Rheum 54:3828–3837

38 Ravetch JV, Kinet JP (1991) Fc receptors. Annu Rev Immunol 9:457–492

39 Siriboonrit U, Tsuchiya N, Sirikong M, Kyogoku C, Bejrachandra S, Suthipinittharm P,Luangtrakool K, Srinak D, Thongpradit R, Fujiwara K (2003) Association of Fcgamma receptor IIb and IIIb polymorphisms with susceptibility to systemic lupus erythematosus in Thais. Tissue Antigens 61:374–383

40 Smith KG, Clatworthy MR (2010a) FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol 10:328–343

41 Smith KGC, Clatworthy MR (2010b) Fc[gamma]RIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol 10:328–343

42 Sohn HW, Pierce SK, Tzeng SJ (2008a) Live cell imaging reveals that the inhibitory Fc gamma RIIB destabilizes B cell receptor membrane-lipid blocks immune synapse formation. J Immunol 180:793–799

43 Sohn HW, Tolar P, Pierce SK (2008b) Membrane heterogeneities in the formation of B cell receptor-Lyn kinase microclusters and the immune synapse. J Cell Biol 182:367–379

44 Starbeck-Miller GR, Badovinac VP, Barber DL, Harty JT (2014) Cutting edge: expression of FcgammaRIIB tempers memory CD8 T cell function in vivo. J Immunol 192:35–39

45 Tackenberg B, Jelcic I, Baerenwaldt A, Oertel WH, Sommer N, Nimmerjahn F, Lunemann JD (2009) Impaired inhibitory Fc gamma receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy. Proc Natl Acad Sci USA 106:4788–4792

46 Tanimura N, Nagafuku M, Minaki Y, Umeda Y, Hayashi F, Sakakura J, Kato A, Liddicoat DR, Ogata M, Hamaoka T, Kosugi A (2003) Dynamic changes in the mobility of LAT in aggregated lipid rafts upon T cell activation. J Cell Biol 160:125–135

47 Tolar P, Sohn HW, Pierce SK(2005) The initiation of antigen-inducedB cell antigen receptor signaling viewed in living cells by fluorescence resonance energy transfer. Nat Immunol 6:1168–1176

48 Warmerdam PAM, Nabben NMJM, Vandegraaf SAR, Vandewinkel JGJ, Capel PJA (1993) The human low affinity immunoglobulin-G Fc receptor-Iic gene is a result of an unequal crossover event. J Biol Chem 268:7346–7349

49 Willcocks LC, Carr EJ, Niederer HA, Rayner TF, Williams TN, Yang WL, Scott JAG, Urban BC, Peshu N, Vyse TJ(2010) A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus. Proc Natl Acad Sci USA 107:7881–7885

50 Xu L, Li G, Wang J, Fan Y, Wan Z, Zhang S, Shaheen S, Li J, Wang L, Yue C (2014) 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 192:5179–5191

51 Xu L, Xia M, Guo J, Sun X, Li H, Xu C, Gu X, Zhang H, Yi J, Fang Y (2016) Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism FcgammaRIIB-T232. J Exp Med 213:2707–2727