Taneja Veena, Taneja Neelam, Behrens Marshall, Pan Suchong, Trejo Tad, Griffiths Marie, Luthra Harvinder, David Chella S
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
J Immunol. 2003 Oct 15;171(8):4431-8. doi: 10.4049/jimmunol.171.8.4431.
To investigate the role of HLA-DR4 in predisposition to arthritis, we generated transgenic mice carrying DRB10401 and DRB10402 genes. We have previously shown that DRB10401 molecule renders B10.RQB3 (H2A(q)) mice susceptible to porcine and human type II collagen-induced arthritis. We report that the introduction of DRB10402 transgene does not lead to development of arthritis in mice when they are immunized with porcine and human type II collagen. In addition, DRB10402 protects B10.RQB3 mice against developing arthritis with bovine type II collagen. These data show that DRB1 can modulate the disease mediated by A(q). In vivo depletion of DRB10402 did not lead to induction of collagen-induced arthritis in transgenic mice. In vitro cytokine analysis shows that mice protected from collagen-induced arthritis produce lower amounts of Th1 and higher levels of Th2 type cytokines upon immunization with type II collagen. Protection of mice was also related to higher apoptosis in DW10 mice as indicated by higher amounts of BclII in response to type II collagen. On the basis of our observations in HLA transgenic mice, we hypothesize that DRB1 polymorphism can modulate disease by shaping the T cell repertoire in thymus and select autoreactive T cells.
为了研究HLA - DR4在关节炎易感性中的作用，我们构建了携带DRB10401和DRB10402基因的转基因小鼠。我们之前已经表明，DRB10401分子使B10.RQB3（H2A(q)）小鼠易患猪和人II型胶原诱导的关节炎。我们报告，当用猪和人II型胶原免疫时，DRB10402转基因的导入不会导致小鼠发生关节炎。此外，DRB10402可保护B10.RQB3小鼠免受牛II型胶原诱导的关节炎。这些数据表明，DRB1可以调节由A(q)介导的疾病。在转基因小鼠体内去除DRB10402不会导致胶原诱导的关节炎。体外细胞因子分析表明，免受胶原诱导关节炎的小鼠在用II型胶原免疫后产生较低量的Th1和较高水平的Th2型细胞因子。如对II型胶原反应中较高量的BclII所示，小鼠的保护也与DW10小鼠中较高的细胞凋亡有关。基于我们在HLA转基因小鼠中的观察，我们推测DRB1多态性可通过塑造胸腺中的T细胞库和选择自身反应性T细胞来调节疾病。
