PREVENTION OF MURINE LUPUS BY AN I-E ALPHA-CHAIN TRANSGENE - PROTECTIVE ROLE OF I-E ALPHA-CHAIN-DERIVED PEPTIDES WITH A HIGH-AFFINITY TO I-A(B) MOLECULES

The expression of a transgene encoding the I-E alpha chain prevents a lupus-like autoimmune syndrome in BSXB mice. However, it had not been elucidated whether the E alpha(d) . transgene-mediated protective effe ct results from I-E expressin or from the generation I-E alpha chain-d erived peptides (E alpha peptide) displaying high affinity for the I-A (b) molecule. To address this question. two different BXSB lines expre ssing the transgene at low or high levels were crossed with lupus-pron e MRL mice; this resulted in three types of (MRL x BXSB)F-1 mice. diff ering in the expression levels of I-E molecules and of E alpha peptide s presented by I-A(b) molecules. Comparative analysis of these three ( MRL x BXSB)F-1 mice as well as several BXSB transgenic lines showed th at the E alpha(d) transgene-mediated protection paralleled the express ion levels of E alpha peptide presented by I-A(b) molecules. but not o f I-E molecules on B cells. In addition, use of transgenic and nontran sgenic double bone marrow chimeras showed a selective activation of no ntransgenic B cells during I-A(b)-restricted T cell-dependent immune r esponses, while both transgenic and nontrangenic B cells were comparab ly activated during T cell-independent responses. These results favor a model of autoimmunity prevention based on competition for antigen pr esentation. in which excessive generation of E alpha peptides prevents . because of their high affinity to the I-A molecules, activation of p otential autoreactive T and B cells.