The principal objective of this investigator is to understand the regulation of anti-Sm and anti-single stranded (ss) DNA B-cells in normal mice, and to identify the stage at which tolerance to these antigens is lost in autoimmune mice. Responses to Sm and ssDNA are characteristic of human SLE and MRL/Mp-lpr/lpr (MRL/lpr) mice that spontaneously develop an SLE-like disease. We have generated Ig H chain Transgenic (Tg) mice using a H chain gene rearrangement that encodes antibodies specific for Sm and ssDNA. These mice develop large numbers of splenic anti-Sm and anti-ssDNA B-cells, but do not spontaneously secrete autoantibody. Thus, they are regulated in the periphery, but the mechanism appears to be different from any so-far described. The investigator proposes that these cells are eliminated at a late stage in B-cell differentiation, during the transition from an immature B-cell to a mature B-cell.
In Aim 1, he will test predictions of this hypothesis using double Tg mice in which every B-cell has the same specificity and affinity for Sm. Functional anti-Sm T-cells are present in these Ig Tg mice, and therefore in Aim 2 he will determine whether exclusion is Fas dependent and T-cell mediated. In the third aim, he will test the hypothesis that the strength of the tolerogenic signal is affected by the response modulators CD19 and CD22. This will be accomplished by altering the availability of these proteins by crossing the anti-Sm Tg mice with CD19 Tg and CD22 knockout mice. In the fourth aim, he will use retroviral gene transfer to introduce the SmD gene in mouse bone marrow to test the hypothesis that the defect in B-cell tolerance in MRL/lpr mice is manifest only in exclusion from the mature B-cell subset, not in other forms of B-cell tolerance, central deletion or anergy. He will induce central deletion of anti-Sm B-cells in MRL/lpr mice and determine whether this blocks the spontaneous development of the anti-Sm response.
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