To investigate the manner in which B cells with light (L) chains undergo receptor editing, we have studied hybridoma panels from 56R͞-deleted (kdel) mice. 56R͞kdel mice only produce four L chains (1, 2, 3, and X). They also have a simplified heavy (H) chain repertoire: All B cells start out with a 56R anti-DNA H chain. A few frankly autoreactive 56R 1 cells appear to escape into the periphery, but the majority of the peripheral B cell repertoire in 56R͞kdel is made up of B cells expressing the 56R H chain with the X L chain. Surprisingly, 56R X B cells are multireactive, binding to a variety of self and nonself antigens, including dsDNA (albeit at reduced affinity compared with the other L chains). Another significant population in the 56R͞kdel mouse consists of allelically included B cells that express X along with another L chain. The multireactivity of both 56R X and 56R X͞1 receptors could contribute to autoimmunity if these B cells were to become activated. Also found among 56R͞kdel hybridomas are clones that have inactivated the H chain and secrete only L chains. These clones may represent products of exhaustive rearrangement. Multireactivity, allelic inclusion, and L chain secretion are three consequences of editing at the locus that may predispose toward the development of autoimmunity.olerance to self-antigens can be achieved by replacing autoreactive heavy (H) chain and light (L) chain V genes with V genes coding for nonself receptors, a mechanism called receptor editing (1-4). Several recent studies support a pivotal role for receptor editing in the generation of a tolerant B cell repertoire (5-7). The L chain locus uses the nested organization of V and J gene segments for secondary rearrangements that can replace or inactivate a VJ that contributes to autoreactivity ( Fig. 3 Top, which is published as supporting information on the PNAS web site). editing can also delete and͞or inactivate an autoreactive chain by rearrangement to the de (human) or to RS (mouse) (8-10). Secondary rearrangements to J and deleting elements are presumed to be unidirectional; hence, editing enriches the repertoire in J5 rearrangements. Editing also increases the frequency of B cells that are rearranged at both alleles (3,(11)(12)(13). Rearrangement at the second L chain isotype, , can rescue -inactivated and -deleted B cells (1,14).L chain genes also contribute to autoreactivity and require editing. The mouse locus has two separate clusters, each consisting of V and JC gene segments (Fig. 3 Middle) (15, 16). In one cluster, V1 rearranges either to J1 or J3. In the other cluster, V2 or VX rearranges to J2 (15). Rearrangements that leapfrog across clusters (for example, V2 to J1) are very infrequent (15). Thus a B cell with a rearrangement that yields a self-reactive receptor is in a dangerous position because of its inability to delete the primary rearrangement.H chain variable region gene segment (V H ) genes can also be edited because a VDJ gene can be replaced by secondary rearrangement of an upstream V H to a partial RS...