Mountz J D, Mushinski J F, Smith H R, Klinman D M, Steinberg A D
J Immunol. 1985 Oct;135(4):2417-22.
This study explores the relationship between autoimmunity and the myb proto-oncogene, a gene important for T cell development. The lpr/lpr mice had very large amounts of myb RNA in the lymph node (LN) cells; but unexpectedly, they had abnormally low levels of myb RNA in the thymus, an organ normally rich in myb RNA. Mice with the gld/gld genotype had high myb RNA levels in peripheral LN, similar to lpr/lpr mice, but had normal thymic myb RNA levels. Both lpr/lpr and gld/gld mice and an AILD patient with lymphadenopathy and high myb RNA in peripheral blood cells were treated with cyclophosphamide (CY). In all cases, the CY eliminated the lymphadenopathy and corrected the abnormal myb expression. However, there were significant differences in the clinical and cellular responses to this drug. A single large dose of CY led to marked regression of the lymphadenopathy of gld/gld mice and long-term amelioration of their autoimmune syndrome. In contrast, similar treatment of lpr/lpr mice failed to alter either the lymphadenopathy or the disease process. Consistent with these clinical findings, LN myb was normalized in gld/gld mice by a single injection of CY, whereas there was no effect on myb expression in lpr/lpr mice. The AILD patient reacted much like the gld/gld mice in that myb RNA levels in the peripheral blood, and bone marrow returned to normal after only three doses of CY. The lymphadenopathy and high levels of LN myb mRNA of the lpr/lpr mice could be normalized; this occurred only after long-term treatment with CY. These events were accompanied by an increase in thymic myb mRNA from low levels. These studies have combined a molecular probe with CY therapy to provide insights into the cellular bases for lymphoproliferative autoimmune diseases.
本研究探讨自身免疫与myb原癌基因之间的关系，myb原癌基因对T细胞发育至关重要。lpr/lpr小鼠的淋巴结（LN）细胞中有大量myb RNA；但出乎意料的是，它们胸腺中的myb RNA水平异常低，而胸腺是一个通常富含myb RNA的器官。具有gld/gld基因型的小鼠外周LN中的myb RNA水平较高，与lpr/lpr小鼠相似，但胸腺myb RNA水平正常。lpr/lpr和gld/gld小鼠以及一名患有淋巴结病且外周血细胞中myb RNA水平较高的自身免疫性淋巴增殖性疾病（AILD）患者均接受了环磷酰胺（CY）治疗。在所有病例中，CY消除了淋巴结病并纠正了异常的myb表达。然而，对这种药物的临床和细胞反应存在显著差异。单次大剂量CY导致gld/gld小鼠的淋巴结病明显消退，其自身免疫综合征得到长期改善。相比之下，对lpr/lpr小鼠进行类似治疗未能改变淋巴结病或疾病进程。与这些临床发现一致，单次注射CY可使gld/gld小鼠的LN myb恢复正常，而对lpr/lpr小鼠的myb表达没有影响。该AILD患者的反应与gld/gld小鼠非常相似，即仅在三剂CY后，外周血和骨髓中的myb RNA水平就恢复了正常。lpr/lpr小鼠的淋巴结病和LN myb mRNA的高水平可以恢复正常；这仅在长期使用CY治疗后才会发生。这些事件伴随着胸腺myb mRNA从低水平增加。这些研究将分子探针与CY疗法相结合，以深入了解淋巴增殖性自身免疫性疾病的细胞基础。
