Waterfield J D, Fairhurst M, Chu R, Levy J G
Immunology. 1987 Jun;61(2):173-8.
MRL-+, MRL-lpr and B6-lpr have been shown to be useful models in studying systemic lupus erythematosus. MRL-lpr and B6-lpr differ from their congenic counterparts by the presence and expression of the homozygous recessive lymphoproliferation (lpr) gene. One manifestation of this gene is a massive T-cell proliferation that results in a generalized lymphadenopathy in older animals. A paradox that has developed out of the work utilizing the congenic mice is that the gene responsible for lymphoproliferation also appears to be responsible for the inability of T cells to respond to proliferative signals in vitro. In this paper we investigate the basis for this hyporesponsiveness in antigen-induced activation of proliferation and antibody synthesis. We have demonstrated that spleen cells from both MRL-+ and MRL-lpr mice gave minimal stimulation in a one-way mixed lymphocyte reaction against allogeneic T cells. These findings were extended to include antigen-specific proliferation involving antigen that must be processed and presented to responder lymphocytes in a H-2 restricted manner. Thus, MRL-+ and MRL-lpr spleen cells pulsed with ferredoxin also failed to stimulate ferredoxin-primed T cells from B10.Br animals in vitro. We then investigated whether any T-cell defect(s) was also contributing to this proliferative hyporesponsiveness. T lymphocytes from the spleen of MRL-+, 2-month-old MRL-lpr, and 6-month-old MRL-lpr were tested in a one-way mixed lymphocyte reaction. It was found that only the MRL-+ T cells gave responses approaching normal, suggesting lpr gene involvement in T-cell non-responsiveness. This was confirmed by the demonstration of an age-onset T-cell proliferative hyporesponsiveness in B6-lpr mice. This lpr gene-linked non-responsiveness was also shown to extend to T-cell helper function in a positive allogeneic effect assay. We can conclude from these studies that antigenic nonresponsiveness in MRL congenic mice can be explained by two defects: the failure of antigen-presenting cells in MRL-+ and MRL-lpr mice to provide the necessary signal(s) to immunocompetent T cells, this defect not being associated with the lpr gene, and the lpr gene controlled outgrowth of a unique T-cell population that cannot respond in our assay systems.
MRL-+、MRL-lpr和B6-lpr已被证明是研究系统性红斑狼疮的有用模型。MRL-lpr和B6-lpr与其同源对照品系的不同之处在于纯合隐性淋巴细胞增殖（lpr）基因的存在和表达。该基因的一个表现是大量T细胞增殖，这导致老年动物出现全身性淋巴结病。利用同源小鼠开展的研究产生了一个矛盾现象，即负责淋巴细胞增殖的基因似乎也导致T细胞在体外无法对增殖信号作出反应。在本文中，我们研究了在抗原诱导的增殖和抗体合成激活过程中这种低反应性的基础。我们已经证明，MRL-+和MRL-lpr小鼠的脾细胞在针对同种异体T细胞的单向混合淋巴细胞反应中产生的刺激最小。这些发现扩展到包括涉及必须以H-2限制性方式加工并呈递给反应性淋巴细胞的抗原的抗原特异性增殖。因此，用铁氧化还原蛋白脉冲处理的MRL-+和MRL-lpr脾细胞在体外也未能刺激来自B10.Br动物的经铁氧化还原蛋白致敏的T细胞。然后，我们研究了是否有任何T细胞缺陷也导致了这种增殖性低反应性。对MRL-+、2月龄MRL-lpr和6月龄MRL-lpr小鼠脾脏中的T淋巴细胞进行单向混合淋巴细胞反应测试。发现只有MRL-+ T细胞的反应接近正常，这表明lpr基因与T细胞无反应性有关。B6-lpr小鼠中随年龄出现的T细胞增殖性低反应性证明了这一点。在阳性同种异体效应试验中，这种与lpr基因相关的无反应性也扩展到T细胞辅助功能。从这些研究中我们可以得出结论，MRL同源小鼠中的抗原无反应性可以由两个缺陷来解释：MRL-+和MRL-lpr小鼠中的抗原呈递细胞未能向免疫活性T细胞提供必要的信号，这个缺陷与lpr基因无关；以及lpr基因控制的一个独特T细胞群体的生长，该群体在我们的检测系统中无反应。
