The primary antibody repertoire of kappa-deficient mice is characterized by non-stochastic Vlamda1 + V(H) gene family pairings and a higher degree of self-reactivity.

Abstract

We have investigated the primary antibody repertoire of genetically manipulated 129/Sv kappa-deficient (JCkappaD) mice, in order to understand the contributions of the lambda-light chain, in the absence of an otherwise predominant kappa-light chain, to the development of humoral immunity. The expression of Vlambda1 gene (lambda1 and lambda3 subtypes) and the Vlambda1 + V(H) (J558, 36-60, V(H)11 and S107) gene family associations were studied in 7.43 x 10(3) mitogen-activated splenic B-lymphocyte clones of JCkappaD origin. Furthermore, the functional significance of the exclusive expression of the lambda-light chain, in the peripheral B-cell repertoire of JCkappaD mice, was analysed by determining natural autoantibody specificities in the circulating serum immunoglobulin and the frequency of autoreactive B-lymphocyte clones in the peripheral B-lymphocyte repertoire. These experiments revealed that: first, of the three available Vlambda genes at the lambda locus, the Vlambda1 gene is the one that is expressed most frequently (59.9%); second, non-random Vlambda1 + V(H) (J558, 36-60) gene family pairings occur in kappa-deficient mice; and third, a higher degree of self-reactivity is generated as a result of exclusive use of the lambda-light chain, as evidenced by higher levels of serum natural autoantibodies as well as a high frequency of autoreactive B-lymphocyte clones in kappa-deficient (129/Sv JCkappaD) mice. These observations suggest that the high murine kappa/lambda ratio in mice may, apart from high sequence diversity at the kappa-locus, be a result of endogenous selection against the lambda-light chain to restrict self-reactivity within the homeostatic threshold.