Immunoglobulin kappa variable region gene selection during early human B cell development in health and systemic lupus erythematosus. Issue 2 (June 2015) - Hehle, Verena
Highlights: Groups of immunoglobulin kappa light chain gene (IGK) rearrangements were compared. Positive and negative selection of IGK gene segments during repertoire development was identified. Productive rearrangements of IGKs can be rejected in favour of rearrangement of IGL. Although IGKV4.1 may not be selected against during B cell development, expression may be suppressed. Suppression of expression of IGKV4.1 appears to be defective in SLE. Abstract: The unique specificity of the B cell receptor is generated by an ordered sequence of gene rearrangement events. Once IGH genes have rearranged, rearrangement at the IGK locus is initiated followed by the IGL locus if functional IGK rearrangement is not achieved. Receptor specificity can subsequently be altered by secondary light chain editing based on the features of the heavy and light chain combination. The final profile of expressed genes is not random and biases in this profile are associated with several autoimmune diseases. However, how and when biases are created is not known. To increase our understanding of the processes of selection and editing of IGK rearrangements, we compared four groups of rearrangements of IGK acquired by next generation sequencing. First, expressed rearrangements of IGK from cDNA of IGK expressing B cells. Second, productive rearrangements of IGK from DNA of the same kappa expressing B cells. Third, non-productive rearrangements of IGK from DNA of IGK and IGL expressing B cells, and fourth productively rearranged IGK from DNA of IGL expressing B cells. The latter group would have been rejected during B cell development in favour of rearrangement at the IGL locus and are therefore selected against. We saw evidence that rearranged IGK segments can be selected at a checkpoint where the decision to rearrange the IGL locus is made. In addition, our data suggest that mechanisms regulating the expression or not of IGK rearrangements may also contribute to repertoire development and also that this latter component of the selection process is defective in SLE.