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Science 307 (5709): 590-593

Copyright © 2005 by the American Association for the Advancement of Science

Restoration of Tolerance in Lupus by Targeted Inhibitory Receptor Expression

Tracy L. McGaha,1 Brian Sorrentino,2 Jeffrey V. Ravetch1*

Abstract: Lupus, a multigenic autoimmune condition in which a breakdown of tolerance results in the development of autoantibodies, leads to a variety of pathologic outcomes. Despite the heterogeneity of factors influencing disease susceptibility, we demonstrate that the partial restoration of inhibitory Fc receptor (FcgRIIB) levels on B cells in lupus-prone mouse strains is sufficient to restore tolerance and prevent autoimmunity. FcgRIIB regulates a common B cell checkpoint in genetically diverse lupus-prone mouse strains, and modest changes in its expression can result in either tolerance or autoimmunity. Therefore, increasing Fc{gamma}RIIB levels on B cells may be an effective way to treat autoimmune diseases.

1 Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
2 St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.

* To whom correspondence should be addressed. E-mail: ravetch{at}

Inhibitory Fc{gamma} Receptor Is Required for the Maintenance of Tolerance through Distinct Mechanisms.
F. Li, P. Smith, and J. V. Ravetch (2014)
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Siglec-G Deficiency Leads to More Severe Collagen-Induced Arthritis and Earlier Onset of Lupus-like Symptoms in MRL/lpr Mice.
S. Bokers, A. Urbat, C. Daniel, K. Amann, K. G. C. Smith, M. Espeli, and L. Nitschke (2014)
J. Immunol. 192, 2994-3002
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B. Ravishankar, R. Shinde, H. Liu, K. Chaudhary, J. Bradley, H. P. Lemos, P. Chandler, M. Tanaka, D. H. Munn, A. L. Mellor, et al. (2014)
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X. Li, J. Wu, T. Ptacek, D. T. Redden, E. E. Brown, G. S. Alarcon, R. Ramsey-Goldman, M. A. Petri, J. D. Reveille, R. A. Kaslow, et al. (2013)
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   Abstract »    Full Text »    PDF »
Quorum Sensing Contributes to Activated IgM-Secreting B Cell Homeostasis.
C. Montaudouin, M. Anson, Y. Hao, S. V. Duncker, T. Fernandez, E. Gaudin, M. Ehrenstein, W. G. Kerr, J.-H. Colle, P. Bruhns, et al. (2013)
J. Immunol. 190, 106-114
   Abstract »    Full Text »    PDF »
Regulation of Allograft Survival by Inhibitory Fc{gamma}RIIb Signaling.
C. J. Callaghan, T. S. Win, R. Motallebzadeh, T. M. Conlon, M. Chhabra, I. Harper, S. Sivaganesh, E. M. Bolton, J. A. Bradley, R. J. Brownlie, et al. (2012)
J. Immunol. 189, 5694-5702
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Analysis of a wild mouse promoter variant reveals a novel role for Fc{gamma}RIIb in the control of the germinal center and autoimmunity.
M. Espeli, M. R. Clatworthy, S. Bokers, K. E. Lawlor, A. J. Cutler, F. Kontgen, P. A. Lyons, and K. G. C. Smith (2012)
J. Exp. Med. 209, 2307-2319
   Abstract »    Full Text »    PDF »
Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase.
B. Ravishankar, H. Liu, R. Shinde, P. Chandler, B. Baban, M. Tanaka, D. H. Munn, A. L. Mellor, M. C. I. Karlsson, and T. L. McGaha (2012)
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   Abstract »    Full Text »    PDF »
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A. Baerenwaldt, A. Lux, H. Danzer, B. M. Spriewald, E. Ullrich, G. Heidkamp, D. Dudziak, and F. Nimmerjahn (2011)
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   Abstract »    Full Text »    PDF »
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P. Boross, V. L. Arandhara, J. Martin-Ramirez, M.-L. Santiago-Raber, F. Carlucci, R. Flierman, J. van der Kaa, C. Breukel, J. W. C. Claassens, M. Camps, et al. (2011)
J. Immunol. 187, 1304-1313
   Abstract »    Full Text »    PDF »
Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity.
O. Bloom, K. F. Cheng, M. He, A. Papatheodorou, B. T. Volpe, B. Diamond, and Y. Al-Abed (2011)
PNAS 108, 10255-10259
   Abstract »    Full Text »    PDF »
Marginal zone macrophages suppress innate and adaptive immunity to apoptotic cells in the spleen.
T. L. McGaha, Y. Chen, B. Ravishankar, N. van Rooijen, and M. C. I. Karlsson (2011)
Blood 117, 5403-5412
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H. M. Horton, S. Y. Chu, E. C. Ortiz, E. Pong, S. Cemerski, I. W. L. Leung, N. Jacob, J. Zalevsky, J. R. Desjarlais, W. Stohl, et al. (2011)
J. Immunol. 186, 4223-4233
   Abstract »    Full Text »    PDF »
High-dose dexamethasone shifts the balance of stimulatory and inhibitory Fc{gamma} receptors on monocytes in patients with primary immune thrombocytopenia.
X.-g. Liu, S.-h. Ma, J.-z. Sun, J. Ren, Y. Shi, L. Sun, X.-y. Dong, P. Qin, C.-s. Guo, M. Hou, et al. (2011)
Blood 117, 2061-2069
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Development of self-reactive germinal center B cells and plasma cells in autoimmune Fc{gamma}RIIB-deficient mice.
T. Tiller, J. Kofer, C. Kreschel, C. E. Busse, S. Riebel, S. Wickert, F. Oden, M. M. M. Mertes, M. Ehlers, and H. Wardemann (2010)
J. Exp. Med. 207, 2767-2778
   Abstract »    Full Text »    PDF »
Mouse Models of Systemic Lupus Erythematosus Reveal a Complex Pathogenesis.
J. B. Rottman and C. R. Willis (2010)
Veterinary Pathology 47, 664-676
   Abstract »    Full Text »    PDF »
A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus.
L. C. Willcocks, E. J. Carr, H. A. Niederer, T. F. Rayner, T. N. Williams, W. Yang, J. A. G. Scott, B. C. Urban, N. Peshu, T. J. Vyse, et al. (2010)
PNAS 107, 7881-7885
   Abstract »    Full Text »    PDF »
The danger model in deciphering autoimmunity.
A. A. Tveita (2010)
Rheumatology 49, 632-639
   Abstract »    Full Text »    PDF »
Impaired inhibitory Fc{gamma} receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy.
B. Tackenberg, I. Jelcic, A. Baerenwaldt, W. H. Oertel, N. Sommer, F. Nimmerjahn, and J. D. Lunemann (2009)
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   Abstract »    Full Text »    PDF »
Increased IL-12 inhibits B cells' differentiation to germinal center cells and promotes differentiation to short-lived plasmablasts.
S. J. Kim, M. Caton, C. Wang, M. Khalil, Z.-J. Zhou, J. Hardin, and B. Diamond (2008)
J. Exp. Med. 205, 2437-2448
   Abstract »    Full Text »    PDF »
Fc{gamma}RIIB Deficiency Leads to Autoimmunity and a Defective Response to Apoptosis in Mrl-MpJ Mice.
T. L. McGaha, M. C. I. Karlsson, and J. V. Ravetch (2008)
J. Immunol. 180, 5670-5679
   Abstract »    Full Text »    PDF »
Distinct cell-specific control of autoimmunity and infection by Fc{gamma}RIIb.
R. J. Brownlie, K. E. Lawlor, H. A. Niederer, A. J. Cutler, Z. Xiang, M. R. Clatworthy, R. A. Floto, D. R. Greaves, P. A. Lyons, and K. G.C. Smith (2008)
J. Exp. Med. 205, 883-895
   Abstract »    Full Text »    PDF »
A Lupus-Suppressor BALB/c Locus Restricts IgG2 Autoantibodies without Altering Intrinsic B Cell-Tolerance Mechanisms.
T. Tarasenko, H. K. Kole, and S. Bolland (2008)
J. Immunol. 180, 3807-3814
   Abstract »    Full Text »    PDF »
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Y. Yamaguchi, K. Fujio, H. Shoda, A. Okamoto, N. H. Tsuno, K. Takahashi, and K. Yamamoto (2007)
J. Immunol. 179, 7128-7136
   Abstract »    Full Text »    PDF »
BAFF and MyD88 signals promote a lupuslike disease independent of T cells.
J. R. Groom, C. A. Fletcher, S. N. Walters, S. T. Grey, S. V. Watt, M. J. Sweet, M. J. Smyth, C. R. Mackay, and F. Mackay (2007)
J. Exp. Med. 204, 1959-1971
   Abstract »    Full Text »    PDF »
Selective blockade of the inhibitory Fc{gamma} receptor (Fc{gamma}RIIB) in human dendritic cells and monocytes induces a type I interferon response program.
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   Abstract »    Full Text »    PDF »
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D. D. Desai, S. O. Harbers, M. Flores, L. Colonna, M. P. Downie, A. Bergtold, S. Jung, and R. Clynes (2007)
J. Immunol. 178, 6217-6226
   Abstract »    Full Text »    PDF »
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C. Wei, J. Anolik, A. Cappione, B. Zheng, A. Pugh-Bernard, J. Brooks, E.-H. Lee, E. C. B. Milner, and I. Sanz (2007)
J. Immunol. 178, 6624-6633
   Abstract »    Full Text »    PDF »
Follicular exclusion of autoreactive B cells requires Fc{gamma}RIIb.
E. Paul, A. Nelde, A. Verschoor, and M. C. Carroll (2007)
Int. Immunol. 19, 365-373
   Abstract »    Full Text »    PDF »
Expression Profile of Fc{gamma}RIIb on Leukocytes and Its Dysregulation in Systemic Lupus Erythematosus.
K. Su, H. Yang, X. Li, X. Li, A. W. Gibson, J. M. Cafardi, T. Zhou, J. C. Edberg, and R. P. Kimberly (2007)
J. Immunol. 178, 3272-3280
   Abstract »    Full Text »    PDF »
Fc{gamma} Receptors Play a Dominant Role in Protective Tumor Immunity against a Virus-Encoded Tumor-Specific Antigen in a Murine Model of Experimental Pulmonary Metastases.
D. B. Lowe, M. H. Shearer, C. A. Jumper, R. K. Bright, and R. C. Kennedy (2007)
J. Virol. 81, 1313-1318
   Abstract »    Full Text »    PDF »
The Role of Activating Protein 1 in the Transcriptional Regulation of the Human FCGR2B Promoter Mediated by the -343 G -> C Polymorphism Associated with Systemic Lupus Erythematosus.
M. Olferiev, E. Masuda, S. Tanaka, M. C. Blank, and L. Pricop (2007)
J. Biol. Chem. 282, 1738-1746
   Abstract »    Full Text »    PDF »
Selective dysregulation of the Fc{gamma}IIB receptor on memory B cells in SLE.
M. Mackay, A. Stanevsky, T. Wang, C. Aranow, M. Li, S. Koenig, J. V. Ravetch, and B. Diamond (2006)
J. Exp. Med. 203, 2157-2164
   Abstract »    Full Text »    PDF »
Genetic Dissection of the Effects of Stimulatory and Inhibitory IgG Fc Receptors on Murine Lupus.
Q. Lin, Y. Xiu, Y. Jiang, H. Tsurui, K. Nakamura, S. Kodera, M. Ohtsuji, N. Ohtsuji, W. Shiroiwa, K. Tsukamoto, et al. (2006)
J. Immunol. 177, 1646-1654
   Abstract »    Full Text »    PDF »
Polymorphisms of the FCRL3 gene in a Spanish population of systemic lupus erythematosus patients.
E. Sanchez, J. L. Callejas, J. M. Sabio, M. de Haro, M. Camps, E. de Ramon, F. J. Garcia-Hernandez, B. Koeleman, J. Martin, and M. F. Gonzalez-Escribano (2006)
Rheumatology 45, 1044-1046
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An epistatic effect of the female specific loci on the development of autoimmune vasculitis and antinuclear autoantibody in murine lupus.
M-C Zhang, N Misu, H Furukawa, Y Watanabe, M Terada, H Komori, T Miyazaki, M Nose, and M Ono (2006)
Ann Rheum Dis 65, 495-500
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TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE.
M. Ehlers, H. Fukuyama, T. L. McGaha, A. Aderem, and J. V. Ravetch (2006)
J. Exp. Med. 203, 553-561
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Immunologic Control of Tumors by In Vivo Fc{gamma} Receptor-Targeted Antigen Loading in Conjunction with Double-Stranded RNA-Mediated Immune Modulation.
A. Bot, D. Smith, B. Phillips, S. Bot, C. Bona, and H. Zaghouani (2006)
J. Immunol. 176, 1363-1374
   Abstract »    Full Text »    PDF »
Hydronephrosis associated with antiurothelial and antinuclear autoantibodies in BALB/c-Fcgr2b-/-Pdcd1-/- mice.
T. Okazaki, Y. Otaka, J. Wang, H. Hiai, T. Takai, J. V. Ravetch, and T. Honjo (2005)
J. Exp. Med. 202, 1643-1648
   Abstract »    Full Text »    PDF »

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