Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
Institute of Laboratory Animal Science, Hannover Medical School, 30625, Hannover, Germany.
Immunol Res. 2018 Aug;66(4):462-470. doi: 10.1007/s12026-018-9015-6.
The LEW.1AR1-iddm rat is an animal model of human type 1 diabetes, which arose through a spontaneous mutation in the Dock8 gene within the MHC congenic background strain LEW.1AR1. This mutation not only mediates diabetes development but also leads to a variable T cell frequency in peripheral blood. In this study, the immune cell frequencies of primary and secondary lymphatic organs of LEW.1AR1-iddm rats were analysed at days 40 and 60 and compared to other MHC congenic LEW rat strains. In LEW.1AR1-iddm rats, the secondary lymphatic organs such as lymph nodes and spleen showed a reduced, around 15% in comparison to all other strains, but very variable T cell frequency, mirroring the fluctuating T cell content in blood. On the other hand, the frequency of B cells was increased by 10% in the lymph nodes and by 5% in the spleen. Thus, the decreasing number of T cells in blood could not be caused by an increase of T cells in secondary lymphatic organs. The frequency of single- or double-positive T cells in the thymus was unaffected. The T cell frequencies in the other analysed strains were more stable and mostly higher in all secondary lymphatic organs. Obviously, the Dock8 mutation leads to variabilities of T cell frequencies in blood as well as in secondary lymphatic organs. In conclusion, the Dock8 mutation was responsible for changed immune cell frequencies in different compartments and together with the RT1B/D haplotype causing immune imbalances and development of autoimmune diabetes.
LEW.1AR1-iddm 大鼠是一种人类 1 型糖尿病的动物模型，它是通过 MHC 同基因背景品系 LEW.1AR1 中的 Dock8 基因突变自发产生的。这种突变不仅介导糖尿病的发生，还导致外周血中 T 细胞频率的变化。在这项研究中，分析了 LEW.1AR1-iddm 大鼠在第 40 天和第 60 天的初级和次级淋巴器官中的免疫细胞频率，并与其他 MHC 同基因 LEW 大鼠品系进行了比较。在 LEW.1AR1-iddm 大鼠中，次级淋巴器官如淋巴结和脾脏的 T 细胞频率降低，与所有其他品系相比约为 15%，但非常可变，反映了血液中 T 细胞含量的波动。另一方面，淋巴结中的 B 细胞频率增加了 10%，脾脏中的 B 细胞频率增加了 5%。因此，血液中 T 细胞数量的减少不能归因于次级淋巴器官中 T 细胞的增加。胸腺中单阳性或双阳性 T 细胞的频率不受影响。在其他分析的品系中，T 细胞频率更稳定，且在所有次级淋巴器官中大多较高。显然，Dock8 突变导致了血液和次级淋巴器官中 T 细胞频率的变化。总之，Dock8 突变导致了不同部位免疫细胞频率的改变，与 RT1B/D 单倍型一起导致了免疫失衡和自身免疫性糖尿病的发展。
