Assembly of IgH CDR3: mechanism, regulation, and influence on antibody diversity

Abstract

The most variable portion of immunoglobulin molecules is the third complementarity determining region (CDR3) of the heavy chain. This is simply because CDR3 encompasses the region of the rearranged gene where the three gene segments (VH-DH-JH) are joined. Since imprecisions exist in the recombinase reaction, significant differences can be generated at the sites of recombination. This results in the generation of antigen receptor molecules which can differ in their antigen specificity even though they derive from the same germline information. In sum, the significance of the inaccuracy in recombination is that antibodies which are reactive to different antigens can be derived from identical genetic information. This explains how the immune system (using only a limited amount of genetic information) can generate antibodies to virtually any antigen. Though the basic phenomenon of VH-DH-JH assembly has been appreciated for years, two recent findings demonstrate that the generation of CDR3 is more complex than originally believed. First, junctional modification is not a stochastic process as was initially presumed, but is in part developmentally regulated. Second, it has now been well documented that more complex recombinations (for example VH-DH-DH-JH, VH-DH-invDH-JH, etc.) are involved in generating the third hypervariable region of the heavy chain. Not only do these unusual rearrangements--which break the so-called "12/23" recombination rule--occur, but interestingly, certain predicted rearrangements (even some which do follow the "12/23" recombination rule) cannot be demonstrated and apparently do not occur. To date, there is no adequate explanation for the lack of these predicted recombinations. These results have important implications for both the generation of antibody diversity and the recombinase reaction itself.