Allen R D, Marshall J D, Roths J B, Sidman C L
Jackson Laboratory, Bar Harbor, Maine 04609.
J Exp Med. 1990 Nov 1;172(5):1367-75. doi: 10.1084/jem.172.5.1367.
Homozygosity for either of the lymphoproliferation (lpr) or generalized lymphoproliferative disease (gld) mutations of mice causes the development of systemic lupus erythematosus-like autoimmune syndromes that are characterized by severe lymphadenopathy and highly elevated serum immunoglobulin levels. Although the mutations are nonallelic, analysis of homozygous lpr/lpr and gld/gld mice on the same strain background has indicated that the pathology and severity of the autoimmune syndromes induced by these mutations are indistinguishable. To explain this, it has previously been suggested that lpr and gld may represent mutations in molecules involved in sequential steps of an intracellular metabolic pathway of T cells. We have now investigated the behavior of both lpr and gld in a variety of bone marrow chimeras and have found that functional differences between lpr and gld become apparent after bone marrow transfer. Transfer of lpr/lpr bone marrow to irradiated congenic +/+ recipients caused the development of a graft-vs.-host-like lymphoid wasting syndrome, whereas transfer of gld/gld bone marrow to +/+ recipients resulted in development of a gld-like autoimmune syndrome. Additionally, gld/gld hosts behaved like +/+ hosts irrespective of the genotype of the donor bone marrow, whereas lpr/lpr hosts behaved unlike +/+ hosts when reconstituted with either lpr/lpr, gld/gld, or +/+ bone marrow. These are the first clear differences between these two mutations yet described. Our studies indicate that the molecule altered by the gld mutation is expressed only by bone marrow-derived cells, whereas the molecule altered by the lpr mutation is expressed by both bone marrow-derived cells and by one or more peripheral radioresistant cell populations. To reconcile these differences with the fact that homozygous lpr/lpr and gld/gld mice are indistinguishable, we suggest an alternative model for the relationship between the lpr and gld mutations in which the two molecules affected represent an interacting ligand-receptor pair expressed by different cells.
小鼠的淋巴细胞增殖（lpr）或全身性淋巴细胞增殖性疾病（gld）突变中的任何一个的纯合性都会导致系统性红斑狼疮样自身免疫综合征的发展，其特征是严重的淋巴结病和血清免疫球蛋白水平高度升高。尽管这些突变是非等位基因的，但对同一品系背景下的纯合lpr/lpr和gld/gld小鼠的分析表明，由这些突变诱导的自身免疫综合征的病理和严重程度是无法区分的。为了解释这一点，以前有人提出lpr和gld可能代表参与T细胞细胞内代谢途径连续步骤的分子中的突变。我们现在研究了lpr和gld在各种骨髓嵌合体中的行为，发现lpr和gld之间的功能差异在骨髓移植后变得明显。将lpr/lpr骨髓移植到经照射的同基因+/+受体中会导致移植物抗宿主样淋巴细胞消耗综合征的发展，而将gld/gld骨髓移植到+/+受体中则会导致gld样自身免疫综合征的发展。此外，gld/gld宿主的行为与+/+宿主相似，而与供体骨髓的基因型无关，而当用lpr/lpr、gld/gld或+/+骨髓重建时，lpr/lpr宿主的行为与+/+宿主不同。这些是迄今为止描述的这两种突变之间的首次明显差异。我们的研究表明，由gld突变改变的分子仅由骨髓来源的细胞表达，而由lpr突变改变的分子由骨髓来源的细胞以及一个或多个外周抗辐射细胞群体表达。为了使这些差异与纯合lpr/lpr和gld/gld小鼠无法区分这一事实相协调，我们提出了一个关于lpr和gld突变之间关系的替代模型，其中受影响的两个分子代表由不同细胞表达的相互作用的配体-受体对。
