Differences defined by bone marrow transplantation suggest that lpr and gld are mutations of genes encoding an interacting pair of molecules.
Differences defined by bone marrow transplantation suggest that lpr and gld are mutations of genes encoding an interacting pair of molecules.
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DOI：
10.1084/jem.172.5.1367
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发表时间：
1990-11-01
期刊：
影响因子：
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通讯作者：
Sidman CL
中科院分区：
文献类型：
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作者：
Allen RD;Marshall JD;Roths JB;Sidman CL
小鼠淋巴细胞增生（lpr）或全身性淋巴细胞增生性疾病（gld）突变的纯合性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。虽然突变是非等位基因的，但在相同品系背景下对纯合子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学和严重程度是不可区分的。为了解释这一点，先前已经提出lpr和gld可能代表参与T细胞的细胞内代谢途径的连续步骤的分子中的突变。我们现在已经研究了lpr和gld在各种骨髓嵌合体中的行为，发现lpr和gld在骨髓移植后的功能差异变得明显。将lpr/lpr骨髓移植到经辐照的同源+/+受体中，宿主样淋巴消耗综合征，而将GLD/GLD骨髓转移到+/+受体导致GLD样自身免疫综合征的发展。此外，gld/gld宿主的行为与供体骨髓的基因型无关，而lpr/lpr宿主在用lpr/lpr、gld/gld或+/+骨髓重建时的行为与+/+宿主不同。这是这两种突变之间第一次明确的差异。我们的研究表明，gld突变改变的分子仅由骨髓来源的细胞表达，而lpr突变改变的分子由骨髓来源的细胞和一个或多个外周抗辐射细胞群表达。为了调和这些差异与纯合子lpr/lpr和gld/gld小鼠难以区分的事实，我们提出了lpr和gld突变之间关系的另一种模型，其中受影响的两种分子代表由不同细胞表达的相互作用的配体-受体对。
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.