Dominance of intrinsic genetic factors in shaping the human immunoglobulin V λ repertoire 1 1Edited by J. Karn

The expressed human immunoglobulin V λ repertoire demonstrates a strong bias in the use of individual V λ segments. Mechanisms that underlie such biases can be divided into two categories: intrinsic genetic processes that lead to the preferential rearrangement and/or expression of certain segments; and selection following light chain expression. Here, we have used two approaches to investigate the factors that shape the human V λ repertoire. Firstly, we characterised 136 V λ rearrangements (59 productive and 77 non-productive) amplified from the human genomic DNA of peripheral blood cells. Secondly, we analysed V λ segment use in a library of 2000 cDNA clones from a transgenic mouse containing a 380 kb region (including 15 functional V λ segments) from the human immunoglobulin λ locus. By hybridisation and sequencing we found that the patterns of use of human V λ segments in the transgenic mouse were similar to those found in the expressed human peripheral blood repertoire and in productive and non-productive genomic DNA rearrangements. These data indicate the importance of intrinsic genetic factors in shaping the human V λ repertoire and highlight the remarkable conservation of the molecular mechanisms involved in the production of the antibody repertoire in mouse and man. Therefore, transgenic mice represent a good model for analysis of the human antibody repertoire and for the production of human antibodies.