Crossing the SJL lambda locus into kappa‐knockout mice reveals a dysfunction of the lambda 1‐containing immunoglobulin receptor in B cell differentiation.

Abstract

Mice of the SJL strain produce ∼50 times less serum λ1 immunoglobulin light chains than other mouse strains. The defect is genetically linked to the λ locus, but it is unknown whether it is due to regulatory alterations or known structural changes. We find no mutation in the SJL λ3-1 enhancer which regulates both λ1 and λ3. To investigate the defect further, the production of λ light chains was amplified by crossing SJL with N-knockout mice. In N-knockout mice with the wildtype λ locus (N-|- λ+/+), the majority of serum light chains are λ1. In contrast, N-knockout mice with the SJL λ locus (N-/- λs/s) show a pronounced expression of λ2 and λ3, with only some expression of λ1. The results show that the SJL defect is λ1 specific, since the linked λ3 expression is normal. As the transcription and rearrangement of λ1 appear normal in SJL, the defective λ1 synthesis is most likely due to a point mutation in the λ1 constant region resulting in a glycine to valine substitution. At the cellular level, in N-knockout mice with the SJL λ locus there are fewer immature, and especially mature, λ1 B cells and the production of λ1 plasma cells is strongly inhibited. The λ1 specificity of the defect suggests that the point mutation in SJL Cλ1 creates an immunoglobulin receptor complex which is dysfunctional in B cell differentiation.