IMMUNOGLOBULIN SOMATIC VARIATION - STUDIES OF RECEPTOR EDITING IN A HUMAN B-CELL LYMPHOMA

In order to study mechanisms of immunoglobulin somatic variation in co mmitted immunoglobulin (Ig) expressing B cells, we used the fluorescen t activated cell sorter to isolate rare variants from a surface Ig pos itive (sIg+) diffuse large cell B lymphoma cell line (mulambda+). Thes e variants were either negative for sIg expression (sIg-) or expressed sIg which differed from the original parental tumor cell line, both i n idiotypes and IgA isotypes (sIg+Id-). In the following report we rev iew the results from the studies of these variants. DNA analysis showe d that all variants had new Iglambda gene rearrangements, which had oc curred either on a previously excluded allele, or on the productively rearranged allele of the parental cell line. The sIg- variants, which had undergone nonfunctional Iglambda rearrangements on the expressed p arental allele, and thereby deleted the productive rearrangement, cont inued to functionally rearrange the same allele and regenerated sIg ex pression. While the parental cell line expressed low levels of the rec ombination 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 di d not contribute to the observed immunoglobulin somatic variation. The se results demonstrate that, through differential expression of the RA G genes, sIg+ B cells are able to somatically alter their sIg receptor s through secondary Iglambda gene rearrangements. This mechanism may a llow B cells with non-selectable, or auto-reactive, antigen receptors to alter these receptors (receptor editing). Ongoing Ig gene rearrange ment may limit the usefulness of immunotherapeutic approaches directed at the antigen receptor in some diffuse large cell lymphomas.