Date of Award
Doctor of Philosophy (PhD)
B lymphocytes are the antibody producing cells of the immune system. During B cell lymphopoiesis in the bone marrow, immunoglobulin molecules are assembled from V, D, and J gene segments through a process known as V(D)J recombination. Because of its stochastic nature, V(D)J recombination is expected to create self-reactive specificities. In targeted animals carrying autoantibodies, these specificities were shown to be silenced by deletion, anergy, and receptor editing. While anergy and deletion physically eliminate the autoreactive clone, receptor editing salvages it by replacing its immunoglobulin receptor through ongoing V(D)J recombination. Once a functional non-self -reactive receptor is generated, B lymphocytes migrate to the periphery. Upon antigen encounter, B cells undergo another recombination process, class switching, by replacing their heavy chain p constant region with downstream isotypes, such as y, a, or e. The isotype choice is dictated by a variety of mitogens and cytokines produced during the immune response. In the first part of this thesis, I describe experiments that elucidate the role of DNA double-stranded break repair in class switch recombination. In the second part, I determine how frequently B cell receptors are successfully replaced in vivo by editing. Finally, I provide evidence that secondary gene recombination, as well as allelic exclusion of light chain genes is under transcriptional regulation.
Casellas, Rafael, "Transcription, Editing, and Switching of Antibody Genes" (2002). Student Theses and Dissertations. 321.