Research Program:
Our lab is interested in understanding which molecular factors influence the development and selection of B cells. Aberrant B cell development and selection can lead to immunodeficiency, autoimmunity and cancer.
B lymphocyte development takes place in the bone marrow and depends on the generation of immunoglobulin (Ig) genes through the random rearrangement of Ig gene segments. This process results in the development of both autoreactive and non-autoreactive immature B cells, which undergo a selection process (B cell tolerance) that purges the population of those cells reacting toward self-constituents before they enter the circulation.
Studies utilizing Ig transgenic and knock-in mice have indicated that autoreactive immature B cells undergo tolerance in the form of clonal deletion, receptor editing or anergy. Clonal deletion results in the death of the autoreactive cell. Receptor editing changes the specificity of the cells from autoreactive to non-autoreactive through secondary Ig gene rearrangement(s). Anergy renders autoreactive B cells non-functional.
Although each of these mechanisms are physiological tools in achieving B cell tolerance, their relevance to each other has not been yet explored. Thus, the extent of clonal deletion and that of receptor editing and anergy have not been properly measured in a normal B cell population.
We have recently found that autoreactive B cells reacting with ubiquitous membrane-bound antigens undergo receptor editing without cell loss. This finding indicates that clonal deletion is not a significant tolerance mechanism, unless receptor editing is inhibited.
Non-autoreactive B cells undergo “positive” selection, a process that is not well characterized, but that also depends on B cell antigen receptor signaling, resulting in survival and differentiation of immature B cells and in their migration into the spleen. We are investigating what is the nature of this “positive” signal and whether it is qualitatively different from the “negative” signal mediated by antigen binding.
The significance of these studies relies on the fact that perturbation of B cell tolerance can result in the development and activation of mature autoreactive B cells, which are mediators of autoimmune diseases. In fact, we find that autoantibodies-producing B cells can be positively selected into the peripheral lymphoid compartment when they co-express non-autoreactive antibodies. We are currently investigating whether and how dual-reactive B cells are activated to secrete autoantibodies and whether these cells are mediators of autoimmunity.
We are also studying the nature and regulation of B cell antigen receptor (BCR) signaling by the use of mouse mutants at the BCR signal transducing element Ig-alpha. In particular, we are investigating regulation of antigen receptor signaling mediated by serine and threonine phosphorylation. Defects in regulation of BCR signaling are associated with immunodeficiency, autoimmunity and cancer.
Selected Publications:
