B-CELL DELETION, ANERGY, AND RECEPTOR EDITING IN KNOCK IN MICE TARGETED WITH A GERMLINE-ENCODED OR SOMATICALLY MUTATED ANTI-DNA HEAVY-CHAIN

To study the relative contributions of clonal deletion, clonal anergy, and receptor editing to tolerance induction in autoreactive B cells a nd their dependence on B cell receptor affinity, we have constructed ' 'knock in'' mice in which germline encoded or somatically mutated, rea rranged anti-DNA heavy (H) chains were targeted to the ii chain locus of the mouse. The targeted H chains were expressed on the vast majorit y of bone marrow (BM) and splenic B cells and were capable of Ig class switching and the acquisition of somatic mutations. A quantitative an alysis of Il cell populations in the BM as well as of JK utilization a nd DNA binding of hybridoma Abs suggested that immature B cell deletio n and light (L) chain editing were the major mechanisms affecting tole rance. Unexpectedly, these mechanisms were less effective in targeted mice expressing the somatically mutated, anti-DNA II chain than in mic e expressing the germline-encoded H chain, possibly due to the greater abundance of high affinity, anti-DNA immature B cells in the BM, Cons equently, autoreactive B cells that showed features of clonal anergy c ould 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 tol erance, or it may represent an intermediate step in clonal deletion.