B cell and repertoire development. Although at first glance the power of the mechanisms used to diversify the B- and T-cell antigen receptors appear to generate repertoires of random diversity, closer examination reveals striking constraints that are preserved across evolution. The implication is that violation of these constraint programs could lead to immune dysfunction, and thus to disease. My group has used Cre-loxP gene targeting to generate mice wherein the DH locus has been altered for force expression of polyclonal antibody repertoires that lie outside normal constraints. In these mice, B cell numbers are reduced, responses to T-independent antigens decline in a co-dominant manner, and responses to T-dependent antigens and autoantigens are affected in a dominant manner. The mechanisms that underlie these alterations and the contribution of a failure to properly regulate the repertoire are a major focus of the laboratory.
Genetics of primary immune deficiency diseases. A second focus in the laboratory is the use of classic reverse genetics techniques to study human immune deficiency disorders.