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* Department of Medicine, Division of Rheumatology,
Wistar Institute, and
Department of Medicine, Penn Center for Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia, PA 19104; and
Department of Molecular Biology, Princeton University, Princeton, NJ 08544
Anti-dsDNA Abs are specific diagnostic markers of systemic lupus
erythematosus, and are also implicated in kidney pathology. Anti-dsDNA
B cells have been shown to be tolerized in nonautoimmune mice. The
immunodysregulation that causes these cells to break tolerance is
presumably part of the fundamental defects in systemic lupus
erythematosus. To explore these mechanisms, we used the chronic
graft-versus-host model mediated by MHC class II differences. Induction
of chronic graft-vs-host in anti-DNA H chain knockin (3H9.KI)
transgenic mice on a nonautoimmune background resulted in specific
activation of anti-dsDNA B cells, as evidenced by high titers of
soluble Ab in sera and a high frequency (70%) of anti-dsDNA B cell
clones recovered as hybridomas. In addition, the
+-anti-dsDNA B cells developed increased
expression of cell surface activation markers, and concentrated in the
T cell area of the follicle with an Ab-forming cell-compatible
phenotype. Genetic analysis of the hybridoma clones showed strong
evidence of secondary rearrangements of the L chain associated with
anti-dsDNA reactivity. Thus, our study indicates that alloreactive
T cell help can break tolerance in a complex manner, involving several
events.
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