Bradley D S, Das P, Griffiths M M, Luthra H S, David C S
Department of Immunology, Mayo Clinic and Medical School, Rochester, MN 55905, USA.
J Immunol. 1998 Nov 1;161(9):5046-53.
We have generated transgenic (tg) mice expressing HLA-DQ8alphabeta (DQA10301/DQB0302) or HLA-DQ6alphabeta (DQA10103/DQB10601) molecules lacking endogenous murine class II expression (A beta0) to investigate the ability of these HLA class II to present type II collagen (CII) and induce collagen-induced arthritis. The DQ8alphabeta tg mice responded strongly to CII, developing severe arthritis, while DQ6alphabeta tg mice were nonresponsive to CII. The addition of the mixed haplotype DQ8alpha6beta molecule did not significantly influence CII reactivity. To examine the interaction of DQ6alphabeta and DQ8alphabeta molecules in vivo, we generated double tg DQ6alphabeta/8alphabeta (A beta0) mice expressing both the alpha- and beta-chains of DQ6 and DQ8 molecules by mating DQ6alphabeta (A beta0) and DQ8alphabeta (A beta0) tg mice. CII-immunized DQ6alphabeta/8alphabeta tg mice developed severe experimental polychondritis, exhibiting both polyarthritis and auricular chondritis. The clinical, serologic, and histologic manifestations of experimental polychondritis are similar to those symptoms in human relapsing polychondritis. The susceptibility of DQ6alphabeta/8alphabeta tg mice compared with resistance in the parental strains suggests that expression of both the DQ6alphabeta and DQ8alphabeta tgs, unique to the DQ6alphabeta8alphabeta tg strain, is important in susceptibility to experimental polychondritis. The DQ6alphabeta/8alphabeta tg mice provide a model to investigate putative autoantigens and the mechanisms of pathogenesis involved in relapsing polychondritis as well as the influence of the expression of multiple HLA class II molecules on the disease process.
我们已培育出表达HLA - DQ8αβ（DQA10301/DQB0302）或HLA - DQ6αβ（DQA10103/DQB10601）分子且缺乏内源性小鼠II类表达（Aβ0）的转基因（tg）小鼠，以研究这些HLA II类分子呈递II型胶原（CII）并诱导胶原诱导性关节炎的能力。DQ8αβ tg小鼠对CII反应强烈，发展为严重关节炎，而DQ6αβ tg小鼠对CII无反应。添加混合单倍型DQ8α6β分子对CII反应性无显著影响。为了在体内研究DQ6αβ和DQ8αβ分子的相互作用，我们通过将DQ6αβ（Aβ0）和DQ8αβ（Aβ0）tg小鼠交配，培育出同时表达DQ6和DQ8分子的α链和β链的双转基因DQ6αβ/8αβ（Aβ0）小鼠。用CII免疫的DQ6αβ/8αβ tg小鼠发展为严重的实验性多软骨炎，表现出多关节炎和耳软骨炎。实验性多软骨炎的临床、血清学和组织学表现与人类复发性多软骨炎的症状相似。与亲代菌株的抗性相比，DQ6αβ/8αβ tg小鼠的易感性表明，DQ6αβ/8αβ tg菌株特有的DQ6αβ和DQ8αβ tg的表达在实验性多软骨炎的易感性中起重要作用。DQ6αβ/8αβ tg小鼠为研究复发性多软骨炎中假定的自身抗原和发病机制以及多种HLA II类分子的表达对疾病进程的影响提供了一个模型。
