The Inhibiting Fc Receptor for IgG, FcγRIIB, Is a Modifier of Autoimmune Susceptibility

被引：89

作者：

Boross, Peter ^{[1
]}

Arandhara, Victoria L. ^{[1
]}

Martin-Ramirez, Javier ^{[1
]}

Santiago-Raber, Marie-Laure ^{[2
]}

Carlucci, Francesco ^{[3
]}

Flierman, Roelof ^{[4
]}

van der Kaa, Jos ^{[1
]}

Breukel, Cor ^{[1
]}

Claassens, Jill W. C. ^{[1
]}

Camps, Marcel ^{[5
]}

Lubberts, Erik ^{[6
,7
]}

Salvatori, Daniela ^{[8
]}

Rastaldi, Maria Pia ^{[9
,10
]}

Ossendorp, Ferry ^{[5
]}

Daha, Mohamed R. ^{[4
]}

Cook, H. Terence ^{[3
]}

Izui, Shozo ^{[2
]}

Botto, Marina ^{[3
]}

Verbeek, J. Sjef ^{[1
]}

机构：

[1] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZA Leiden, Netherlands

[2] Univ Geneva, Dept Pathol & Immunol, CH-1211 Geneva, Switzerland

[3] Univ London Imperial Coll Sci Technol & Med, Ctr Complement & Inflammat Res, Div Immunol & Inflammat, London W12 0NN, England

[4] Leiden Univ, Med Ctr, Dept Nephrol, NL-2333 ZA Leiden, Netherlands

[5] Leiden Univ, Med Ctr, Dept Immunohematol, NL-2333 ZA Leiden, Netherlands

[6] Erasmus MC Univ Med Ctr, Dept Rheumatol, NL-3000 CA Rotterdam, Netherlands

[7] Erasmus MC Univ Med Ctr, Dept Immunol, NL-3000 CA Rotterdam, Netherlands

[8] Leiden Univ, Med Ctr, Dept Anat, NL-2333 ZA Leiden, Netherlands

[9] Osped Maggiore Policlin, Fdn Inst Ricovero & Cura Carattere Sci Ca Granda, Lab Ric Nefrol, I-20122 Milan, Italy

[10] Fdn DAmico Ric Malattie Renali, I-20122 Milan, Italy

来源：

JOURNAL OF IMMUNOLOGY | 2011年 / 187卷 / 03期

关键词：

SYSTEMIC-LUPUS-ERYTHEMATOSUS; CENTER B-CELLS; DEFICIENT MICE; PROMOTER HAPLOTYPE; DENDRITIC CELLS; MURINE LUPUS; PRONE MICE; EXPRESSION; IIB; POLYMORPHISMS;

D O I：

10.4049/jimmunol.1101194

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Fc gamma RIIB-deficient mice generated in 129 background (Fc gamma RIIB(129)(-/-)) if back-crossed into C57BL/6 background exhibit a hyperactive phenotype and develop lethal lupus. Both in mice and humans, the Fc gamma r2b gene is located within a genomic interval on chromosome 1 associated with lupus susceptibility. In mice, the 129-derived haplotype of this interval, named Sle16, causes loss of self-tolerance in the context of the B6 genome, hampering the analysis of the specific contribution of Fc gamma RIIB deficiency to the development of lupus in Fc gamma RIIB(129)(-/-) mice. Moreover, in humans genetic linkage studies revealed contradictory results regarding the association of "loss of function" mutations in the Fc gamma r2b gene and susceptibility to systemic lupus erythematosis. In this study, we demonstrate that Fc gamma RIIB(-/-) mice generated by gene targeting in B6-derived ES cells (Fc gamma RIIB(B6)(-/-)), lacking the 129-derived flanking Sle16 region, exhibit a hyperactive phenotype but fail to develop lupus indicating that in Fc gamma RIIB(129)(-/-) mice, not Fc gamma RIIB deficiency but epistatic interactions between the C57BL/6 genome and the 129-derived Fc gamma r2b flanking region cause loss of tolerance. The contribution to the development of autoimmune disease by the resulting autoreactive B cells is amplified by the absence of Fc gamma RIIB, culminating in lethal lupus. In the presence of the Yaa lupus-susceptibility locus, Fc gamma RIIB(B6)(-/-) mice do develop lethal lupus, confirming that FcgRIIB deficiency only amplifies spontaneous autoimmunity determined by other loci. The Journal of Immunology, 2011, 187: 1304-1313.

引用

页码：1304 / 1313

页数：10

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