Balancing Activation and Inhibition

B cell responses to antigen are controlled by a balance of activating and inhibitory signals. One overarching goal of our research is to define the consequences of shifting this balance for normal and autoimmune antibody responses.

For example, we have found that both the accumulation of plasma cells and the lupus-like autoimmune disease that occur in the absence of the inhibitory signaling molecule Lyn depend on the activating tyrosine kinase Btk. We are now defining molecules that lie at the convergence of these activating and inhibitory pathways.

In collaboration with Lee Ann Garrett-Sinha, Ph.D., of the University of Buffalo, we have found that the transcription factor Ets1, an inhibitor of plasma cell differentiation, is one such target. When the balance of activating and inhibitory signaling is shifted and Ets1 levels are either elevated or decreased, reduced antibody levels or autoimmunity ensue respectively.

Ongoing studies involve defining the molecular mechanisms by which activating and inhibitory signaling pathways converge on Ets1, and determining whether autoimmune disease can be prevented by increasing Ets1 expression in B cells.