THE PRIMARY ANTIBODY REPERTOIRE OF KAPPA-DEFICIENT MICE IS CHARACTERIZED BY NONSTOCHASTIC V(LAMBDA)1-H GENE FAMILY PAIRINGS AND A HIGHER DEGREE OF SELF-REACTIVITY(V)

We have investigated the primary antibody repertoire of genetically ma nipulated 129/Sv kappa-deficient (JC(kappa)D) mice, in order to unders tand the contributions of the lambda-light chain, in the absence of an otherwise predominant kappa-light chain, to the development of humora l immunity. The expression of V(lambda)1 gene (lambda(1) and lambda(3) subtypes) and the V(lambda)1 + V-H (J558, 36-60, V(H)11 and S107) gen e family associations were studied in 7.43x10(3) mitogen-activated spl enic B-lymphocyte clones of JC(kappa)D origin. Furthermore, the functi onal significance of the exclusive expression of the lambda-light chai n, in the peripheral B-cell repertoire of JC(kappa)D mice, was analyse d by determining natural autoantibody specificities in the circulating serum immunoglobulin and the frequency of autoreactive B-lymphocyte c lones in the peripheral B-lymphocyte repertoire. These experiments rev ealed that: first, of the three available V-lambda genes at the lambda locus, the V(lambda)1 gene is the one that is expressed most frequent ly (59.9%); second, non-random V(lambda)1 + VH (J558, 36-60) gene fami ly pairings occur in kappa-deficient mice; and third, a higher degree of self-reactivity is generated as a result of exclusive use of the la mbda-light chain, as evidenced by higher levels of serum natural autoa ntibodies as well as a high frequency of autoreactive B-lymphocyte clo nes in kappa-deficient (129/Sv JC(kappa)D) mice. These observations su ggest 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 w ithin the homeostatic threshold.