Presumptive Role of 129 Strain-Derived Sle16 Locus in Rheumatoid Arthritis in a New Mouse Model With Fcγ Receptor Type IIb-Deficient C57BL/6 Genetic Background
Presumptive Role of 129 Strain-Derived Sle16 Locus in Rheumatoid Arthritis in a New Mouse Model With Fcγ Receptor Type IIb-Deficient C57BL/6 Genetic Background
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DOI：
10.1002/art.30485
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发表时间：
2011-10-01
影响因子：
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通讯作者：
Hirose, Sachiko
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文献类型：
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作者：
Sato-Hayashizaki, Aya;Ohtsuji, Mareki;Hirose, Sachiko
目标。Fc γ受体IIb型（Fc γ RIIb）是B细胞的主要负调节因子，据报道，Fc γ RIIb表达缺乏可在C57BL/6 （B6）遗传背景的小鼠中诱导系统性红斑狼疮（SLE）。129株衍生的Sle16位点位于1号染色体端粒区，包括多态性的Fcgr2b，当存在于B6背景时，赋予了系统性自身免疫的易感性。我们进行了这项研究，以研究Sle16位点对Fc γ riib缺陷B6小鼠自身免疫性疾病的影响。我们通过将原构建的Fc γ riib缺陷小鼠在杂交种（129 × B6）背景下选择性回交到B6背景中，建立了2系Fc γ riib缺陷B6基因小鼠株（KO1和KO2）。虽然两者都缺乏Fc γ RIIb表达，但KO1和KO2菌株携带的129株衍生端粒染色体1段的长度不同，该端粒染色体1段位于零突变的Fcgr2b基因的两侧；KO1菌株在Sle16基因座中携带129株衍生的类似6.3 mb的间隔，而KO2菌株的该间隔来自B6。出乎意料的是，两株毒株均未发展为SLE；相反，KO1毒株，而不是KO2毒株，在12月龄时自发发展为严重的类风湿关节炎（RA），发病率达到bbb90 %。目前的研究表明，尽管不能完全排除其他遗传多态性的参与，但在具有B6遗传背景的新小鼠模型中，Fcgr2b-null突变与位于远端Sle16位点的129株衍生间隔中的多态性基因之间的互作作用有助于RA易感性。
Objective. Fc gamma receptor type IIb (Fc gamma RIIb) is a major negative regulator of B cells, and the lack of Fc gamma RIIb expression has been reported to induce systemic lupus erythematosus (SLE) in mice of the C57BL/6 (B6) genetic background. The 129 strain-derived Sle16 locus on the telomeric region of chromosome 1 including polymorphic Fcgr2b confers the predisposition to systemic autoimmunity when present on the B6 background. We undertook this study to examine the effect of the Sle16 locus on autoimmune disease in Fc gamma RIIb-deficient B6 mice.Methods. We established 2 lines of Fc gamma RIIb-deficient B6 congenic mouse strains (KO1 and KO2) by selective backcrossing of the originally constructed Fc gamma RIIb-deficient mice on a hybrid (129 x B6) background into a B6 background. Although both lack Fc gamma RIIb expression, the KO1 and KO2 strains carry different lengths of the 129 strain-derived telomeric chromosome 1 segment flanked to the null-mutated Fcgr2b gene; the KO1 strain carries a 129 strain-derived similar to 6.3-Mb interval distal from the null-mutated Fcgr2b gene within the Sle16 locus, while this interval in the KO2 strain is of B6 origin.Results. Unexpectedly, both strains failed to develop SLE; instead, the KO1 strain, but not the KO2 strain, spontaneously developed severe rheumatoid arthritis (RA) with an incidence reaching >90% at age 12 months.Conclusion. The current study shows evidence that the epistatic interaction between the Fcgr2b-null mutation and a polymorphic gene(s) in the 129 strain-derived interval located in the distal Sle16 locus contributes to RA susceptibility in a new mouse model with the B6 genetic background, although the participation of other genetic polymorphisms cannot be totally excluded.