Sobel E S, Katagiri T, Katagiri K, Morris S C, Cohen P L, Eisenberg R A
Department of Microbiology/Immunology, University of North Carolina, Chapel Hill 27599.
J Exp Med. 1991 Jun 1;173(6):1441-9. doi: 10.1084/jem.173.6.1441.
Mice homozygous for the gene lpr develop marked lymphadenopathy and a spectrum of autoantibodies closely resembling that of human systemic lupus erythematosus. The unusual T cell phenotype of the expanded lymphocyte population and the T-dependence of several antibodies in this strain have suggested that primary T cell abnormalities underlie the autoimmune syndrome. Using double chimeras, we now show that expression of the lpr gene in B cells is absolutely necessary for autoantibody production. Combinations of anti-Thy 1.2 + C' treated bone marrow from congenic strains of C57BL/6 mice, differing only at the immunoglobulin heavy chain (Igh) and lpr loci, were transferred into lethally irradiated B6/lpr mice. Double chimerism was documented by allotype-specific surface IgD and IgM immunofluorescence assay of peripheral blood and by allotype-specific enzyme-linked immunosorbent assay for total IgM in serum. Despite the presence of both +/+ and lpr B cells, IgM and IgG2a anti-chromatin as well as IgM anti-IgG were entirely the products of lpr B cells. Total serum IgG2a and IgG1 were also dominated by the lpr phenotype but not to the same extent. A similar experiment using B6/lpr-Igha recipients confirmed these findings. Additional experiments in which B6/lpr recipients were infused with ratios of donor bone marrow favoring B6.C20 +/+ over B6/lpr showed that even though +/+ B cells were overrepresented, autoantibodies were only of the lpr allotype. In addition, in the presence of lpr B cells, normal B cells showed little response to an exogenous, T cell-dependent antigen. The data thus indicate that lpr B cells manifest an intrinsic abnormality which is essential for autoantibody production in the lpr model.
纯合子基因lpr的小鼠会出现明显的淋巴结病以及一系列与人类系统性红斑狼疮极为相似的自身抗体。该品系中扩增的淋巴细胞群体具有异常的T细胞表型，且几种抗体具有T细胞依赖性，这表明原发性T细胞异常是自身免疫综合征的基础。通过构建双嵌合体，我们现在表明B细胞中lpr基因的表达对于自身抗体的产生绝对必要。将仅在免疫球蛋白重链（Igh）和lpr位点不同的C57BL/6同基因品系的抗Thy 1.2 + C'处理的骨髓组合移植到经致死性照射的B6/lpr小鼠中。通过外周血的同种异型特异性表面IgD和IgM免疫荧光测定以及血清中总IgM的同种异型特异性酶联免疫吸附测定来记录双嵌合现象。尽管同时存在+/+和lpr B细胞，但IgM和IgG2a抗染色质以及IgM抗IgG完全是lpr B细胞的产物。血清总IgG2a和IgG1也以lpr表型为主，但程度不同。使用B6/lpr-Igha受体进行的类似实验证实了这些发现。另外的实验中，向B6/lpr受体输注有利于B6.C20 +/+而非B6/lpr的供体骨髓比例，结果表明即使+/+ B细胞占优势，自身抗体也仅为lpr同种异型。此外，在存在lpr B细胞的情况下，正常B细胞对外源性T细胞依赖性抗原几乎没有反应。因此，数据表明lpr B细胞表现出一种内在异常，这对于lpr模型中自身抗体的产生至关重要。
