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*
Division of Medicine, Hadassah University Hospital, Faculty of Medicine of the Hebrew University, Jerusalem, Israel; and
Institute for Genetics, University of Köln, Köln, Germany
To study the relative contributions of clonal deletion, clonal
anergy, and receptor editing to tolerance induction in autoreactive B
cells and their dependence on B cell receptor affinity, we have
constructed "knock in" mice in which germline encoded or
somatically mutated, rearranged anti-DNA heavy (H) chains were
targeted to the H chain locus of the mouse. The targeted H chains were
expressed on the vast majority of bone marrow (BM) and splenic B
cells and were capable of Ig class switching and the acquisition of
somatic mutations. A quantitative analysis of B cell populations in the
BM as well as of J
utilization and DNA binding of hybridoma Abs
suggested that immature B cell deletion and light (L) chain editing
were the major mechanisms affecting tolerance. Unexpectedly, these
mechanisms were less effective in targeted mice expressing the
somatically mutated, anti-DNA H chain than in mice expressing the
germline-encoded H chain, possibly due to the greater abundance of high
affinity, anti-DNA immature B cells in the BM. Consequently,
autoreactive B cells that showed features of clonal anergy could be
recovered in the periphery of these mice. Our results suggest that
clonal deletion and receptor editing are interrelated mechanisms that
act in concert to eliminate autoreactive B cells from the immune
system. Clonal anergy may serve as a back-up mechanism for central
tolerance, or it may represent an intermediate step in clonal
deletion.
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