PREVENTION OF SYSTEMIC LUPUS-ERYTHEMATOSUS IN AUTOIMMUNE BXSB MICE BY A TRANSGENE ENCODING I-E-ALPHA-CHAIN

被引:62
作者
MERINO, R
IWAMOTO, M
FOSSATI, L
MUNIESA, P
ARAKI, K
TAKAHASHI, S
HUARTE, J
YAMAMURA, KI
VASSALLI, JD
IZUI, S
机构
[1] UNIV GENEVA,CTR MED UNIV,DEPT PATHOL,1 RUE MICHEL SERVET,CH-1211 GENEVA 4,SWITZERLAND
[2] UNIV GENEVA,CTR MED UNIV,DEPT MORPHOL,CH-1211 GENEVA 4,SWITZERLAND
[3] KUMAMOTO UNIV,SCH MED,INST MOLEC EMBRYOL & GENET,KUMAMOTO 862,JAPAN
关键词
D O I
10.1084/jem.178.4.1189
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Males from the BXSB murine strain (H-2b) spontaneously develop an autoimmune syndrome with features of systemic lupus erythematosus (SLE), which results in part from the action of a mutant gene (Yaa) located on the Y chromosome. Like other H-2b mice, the BXSB strain does not express the class II major histocompatibility complex antigen, I-E. Here we report that the expression of I-E (Ealpha(d)Ebeta(b)) in BXSB males bearing an Ealpha(d) transgene prevents hypergammaglobulinemia, autoantibody production, and subsequent autoimmune glomerulonephritis. These transgenic mice bear on the majority of their B cells not only I-E molecules, but also an I-E alpha chain-derived peptide presented by a higher number of I-A(b) molecules, as recognized by the Y-Ae monoclonal antibody. The I-E+ B cells appear less activated in vivo than the I-E- B cells, a minor population. This limited activation of the I-E+ B cells does not reflect a functional deficiency of this cell population, since it can be stimulated to IgM production in vitro by lipopolysaccharides at an even higher level than the I-E- B cell population. The development of the autoimmune syndrome in the transgenic and nontransgenic bone marrow chimeric mice argues against the possibility that the induction of regulatory T cells or clonal deletion of potential autoreactive T cells as a result of I-E expression is a mechanism of the protection conferred by the Ealpha(d) transgene. We propose a novel mechanism by which the Ealpha(d) transgene protects BXSB mice against SLE: overexpression of I-E alpha chains results in the generation of excessive amounts of a peptide displaying a high affinity to the I-A(b) molecule, thereby competing with pathogenic autoantigen-derived peptides for presentation by B lymphocytes and preventing their excessive stimulation.
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页码:1189 / 1197
页数:9
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