Sato-Hayashizaki Aya, Ohtsuji Mareki, Lin Qingshun, Hou Rong, Ohtsuji Naomi, Nishikawa Keiko, Tsurui Hiromichi, Sudo Katsuko, Ono Masao, Izui Shozo, Shirai Toshikazu, Takai Toshiyuki, Nishimura Hiroyuki, Hirose Sachiko
Department of Pathology, Juntendo University, School of Medicine, Tokyo, Japan.
Arthritis Rheum. 2011 Oct;63(10):2930-8. doi: 10.1002/art.30485.
Fcγ receptor type IIb (FcγRIIb) is a major negative regulator of B cells, and the lack of FcγRIIb 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 FcγRIIb-deficient B6 mice.
We established 2 lines of FcγRIIb-deficient B6 congenic mouse strains (KO1 and KO2) by selective backcrossing of the originally constructed FcγRIIb-deficient mice on a hybrid (129×B6) background into a B6 background. Although both lack FcγRIIb 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 ∼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.
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.
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.
Fcγ受体IIb型（FcγRIIb）是B细胞的主要负调节因子，据报道，在C57BL/6（B6）遗传背景的小鼠中，缺乏FcγRIIb表达会诱发系统性红斑狼疮（SLE）。位于1号染色体端粒区域的源自129品系的Sle16基因座，包括多态性Fcgr2b，当存在于B6背景中时，会赋予系统性自身免疫易感性。我们进行这项研究以检查Sle16基因座对FcγRIIb缺陷型B6小鼠自身免疫性疾病的影响。
我们通过将最初构建的杂交（129×B6）背景的FcγRIIb缺陷型小鼠选择性回交到B6背景中，建立了2系FcγRIIb缺陷型B6同源小鼠品系（KO1和KO2）。尽管两者都缺乏FcγRIIb表达，但KO1和KO2品系携带不同长度的源自129品系的1号染色体端粒片段，其侧翼为无效突变的Fcgr2b基因；KO1品系在Sle16基因座内携带一个源自129品系的、距离无效突变的Fcgr2b基因远端约6.3 Mb的区间，而KO2品系的这个区间源自B6。
出乎意料的是，两个品系均未发生SLE；相反，KO1品系而非KO2品系自发发生了严重的类风湿性关节炎（RA），在12个月龄时发病率达到>90%。
当前研究表明，在具有B6遗传背景的新小鼠模型中，Fcgr2b无效突变与位于远端Sle16基因座的源自129品系区间内的一个多态基因之间的上位相互作用导致了RA易感性，尽管不能完全排除其他遗传多态性的参与。
