Abe K, Wechs S, Kalaydjiev S, Franz T J, Busch D H, Fuchs H, Soewarto D, Behrendt H, Wagner S, Jakob T, Hrabé de Angelis M
Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Rheumatology (Oxford). 2008 Mar;47(3):292-300. doi: 10.1093/rheumatology/kem358.
In a large-scale ENU (N-ethyl-N-nitrosourea) mouse mutagenesis programme, we previously have identified and characterized a novel mutation Ali18 that causes inflammatory arthritis like lesions in peripheral joints. In this study, we analysed the immune system of Ali18 mice to understand mechanisms underlying the spontaneous inflammation.
Humoral and cellular components of the immune system were phenotyped by ELISA and flow cytometry. The contribution of the immune system for phenotype expression was analysed in disease transfer experiments. The involvement of the adaptive immune system was investigated in Ali18;Rag1 double mutants and the influence of environmental factors was analysed in Ali18 mice reared under germ-free conditions.
Bone marrow cells from Ali18 mice were able to transfer the disease phenotype to naïve wild-type recipients suggesting that cellular components of the reconstituted immune system were sufficient to induce arthritis. Ali18 mice revealed abnormal leucocyte populations including lymphocytes and granulocytes, as well as increased plasma IL-5 and IgE levels. Ali18;Rag1 double homozygous mutants, which lack mature lymphocytes, still developed arthritis, suggesting that the phenotype is independent of the adaptive immune system. In addition, the arthritis phenotype appeared to be independent from environmental conditions as demonstrated in mice reared under germ-free conditions.
The Ali18 mutation induces inflammatory arthritis through bone marrow-derived cells. However, non-pro-inflammatory cytokine cascades and mature lymphocyte independent-mechanisms are crucial for initiation and progression of the phenotype. Ali18 mice may thus represent a model to study mechanisms involved in seronegative arthritis induced by cells of the innate immune system.
在一项大规模ENU（N-乙基-N-亚硝基脲）小鼠诱变计划中，我们之前已鉴定并表征了一种新型突变体Ali18，它会在外周关节引发类似炎性关节炎的病变。在本研究中，我们分析了Ali18小鼠的免疫系统，以了解自发炎症背后的机制。
通过ELISA和流式细胞术对免疫系统的体液和细胞成分进行表型分析。在疾病转移实验中分析了免疫系统对表型表达的作用。在Ali18;Rag1双突变体中研究了适应性免疫系统的参与情况，并在无菌条件下饲养的Ali18小鼠中分析了环境因素的影响。
来自Ali18小鼠的骨髓细胞能够将疾病表型转移至未经处理的野生型受体，这表明重建免疫系统的细胞成分足以诱发关节炎。Ali18小鼠显示出异常的白细胞群体，包括淋巴细胞和粒细胞，同时血浆IL-5和IgE水平升高。缺乏成熟淋巴细胞的Ali18;Rag1双纯合突变体仍会发展为关节炎，这表明该表型与适应性免疫系统无关。此外，如在无菌条件下饲养的小鼠所示，关节炎表型似乎与环境条件无关。
Ali18突变通过骨髓来源的细胞诱发炎性关节炎。然而，非促炎性细胞因子级联反应和成熟淋巴细胞非依赖性机制对于该表型的起始和进展至关重要。因此，Ali18小鼠可能代表一种模型，用于研究先天性免疫系统细胞诱导的血清阴性关节炎所涉及的机制。
