Immunoglobulin somatic variation; studies of receptor editing in a human B cell lymphoma.

Abstract

In order to study mechanisms of immunoglobulin somatic variation in committed immunoglobulin (Ig) expressing B cells, we used the fluorescent activated cell sorter to isolate rare variants from a surface Ig positive (sIg+) diffuse large cell B lymphoma cell line (mu lambda+). These variants were either negative for sIg expression (sIg-) or expressed sIg which differed from the original parental tumor cell line, both in idiotypes and Ig lambda isotypes (sIg+Id-). In the following report we review the results from the studies of these variants. DNA analysis showed that all variants had new Ig lambda gene rearrangements, which had occurred either on a previously excluded allele, or on the productively rearranged allele of the parental cell line. The sIg- variants, which had undergone nonfunctional Ig lambda rearrangements on the expressed parental allele, and thereby deleted the productive rearrangement, continued to functionally rearrange the same allele and regenerated sIg expression. While the parental cell line expressed low levels of the recombination activating genes, RAG1 and RAG2, expression of these genes were considerably upregulated in both the immunoglobulin negative and the idiotypic variants. Somatic immunoglobulin V gene hypermutation did not contribute to the observed immunoglobulin somatic variation. These results demonstrate that, through differential expression of the RAG genes, sIg+ B cells are able to somatically alter their sIg receptors through secondary Ig lambda gene rearrangements. This mechanism may allow B cells with non-selectable, or auto-reactive, antigen receptors to alter these receptors (receptor editing). Ongoing Ig gene rearrangement may limit the usefulness of immunotherapeutic approaches directed at the antigen receptor in some diffuse large cell lymphomas.