Autoimmunity associated with TGF-beta 1-deficiency in mice is dependent on MHC class II antigen expression

被引:170
作者
Letterio, JJ
Geiser, AG
Kulkarni, AB
Dang, H
Kong, LP
Nakabayashi, T
Mackall, CL
Gress, RE
Roberts, AB
机构
[1] ELI LILLY & CO,LILLY CORP CTR,LILLY RES LABS,INDIANAPOLIS,IN 46285
[2] NIDR,GENE TARGETING RES & CORE FACIL,NIH,BETHESDA,MD 20892
[3] UNIV TEXAS,HLTH SCI CTR,DEPT MED,DIV CLIN IMMUNOL,SAN ANTONIO,TX 78284
[4] NCI,EXPT IMMUNOL BRANCH,NIH,BETHESDA,MD 20892
关键词
leukocyte; myeloid; hematopoiesis; inflammation; metaplasia;
D O I
10.1172/JCI119017
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The progressive inflammatory process found in transforming growth factor beta 1 (TGF-beta 1>-deficient mice is associated with several manifestations of autoimmunity, including circulating antibodies to nuclear antigens, immune complex deposition, and increased expression of both class I and class II major histocompatibility complex (MHC) antigens. The contribution of MHC class II antigens to the genesis of this phenotype has been determined by crossing the TGF-beta 1-null [TGF-beta 1((-/-))] genotype into the MHC class II-deficient [MHC-II(-/-)] background, Mice homozygous for both the TGF-beta 1 null allele and the class II null allele [TGF-beta 1((-/-));MHC-II(-/-)] are without evidence of inflammatory infiltrates, circulating autoantibodies, or glomerular immune complex deposits, Instead, these animals exhibit extensive extramedullary hematopoiesis with progressive splenomegaly and adenopathy, surviving only slightly longer than TGF-beta 1((-/-));MHC-II(+/+) mice. The role of CD4(+) T cells, which are also absent in MHC class II-deficient mice, is directly demonstrated through the administration of anti-CD4 monoclonal antibodies in class II-positive, TGF-beta 1((-/-)) mice. The observed reduction in inflammation and improved survival emphasize the significance of CD4(+) cells in the pathogenesis of the autoimmune process and suggest that the additional absence of class II antigens in TGF-beta 1((-/-));MHC-II(-/-) mice may contribute to their extreme myeloid metaplasia. Thus, MHC class II antigens are essential for the expression of autoimmunity in TGF-beta 1-deficient mice, and normally may cooperate with TGF-beta 1 to regulate hematopoiesis.
引用
收藏
页码:2109 / 2119
页数:11
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