Our laboratory focuses on two areas of immunology: (1) the role of antigen receptor signaling in B cell development and activation, and (2) the mechanisms of macrophage responses to bacterial lipopolysaccharide (LPS). We are studying the mechanisms by which the B lymphocyte antigen receptor signals contact of antigen to the inside of the cell, the nature of the intracellular signaling reactions generated, and how these signaling reactions promote the responses of the B lymphocyte appropriate to the circumstance in question. The lab is also studying the mechanisms by which macrophages contribute to the initial immune response to bacterial infection by recognizing and responding to certain components of bacterial cell walls, such as lipopolysaccharide (LPS).

Our lab and others have shown that the B cell antigen receptor (BCR) signals by recruiting and activating three types of protein tyrosine kinases, Syk, Btk, and members of the Src-family. The laboratory is currently studying the unique roles of these different tyrosine kinases in regulating B cell activation. The Src-family tyrosine kinases initiate the signaling reactions and recruit the Syk kinase to the receptor, whereupon it becomes activated. Syk plays an essential role in signaling. Surprisingly, B cells from mice lacking the most prevalent Src-family kinase, Lyn, have hyperresponsive B cells and we have recently shown that this reflects a critical role for Lyn in several events that downregulate BCR signaling, whereas its role in initiating BCR signaling can be partially supplied by other Src-family members present in lower amounts. Mice lacking Lyn produce autoantibodies as they age and our lab is currently studying whether this is due to the hyperresponsiveness of the B cells.

The BCR activates a complex array of signaling events and the laboratory is currently studying the mechanisms of engagement of downstream signaling events and how these signaling events mediate effects in the cell. In addition, the extent to which particular signaling events contribute to the biological responses of the B cell, including developmental progression, proliferation, and apoptosis are being studied. For example, it was recently found that the Ras/MAP kinase pathway was important for BCR-induced proliferation of mature B cells, but not for BCR-induced apoptosis of an immature B cell line Approximately one-third of the lab is studying how macrophages respond to LPS. The high affinity response starts with binding of LPS to CD14, a GPI-linked membrane protein. It is generally thought that another membrane molecule is responsible for transmitting the signal across the membrane, but this molecule remains unidentified at this time. Subsequently, there is activation of one or more intracellular tyrosine kinases, although their identities are also unknown. Our group has, however, identified a number of subsequent signaling events, all of which are dependent upon tyrosine kinases, including activation of the three types of MAP kinases, Erk, JNK and p38. Efforts are ongoing to define some of these signaling pathways in more detail and to examine how they participate in activation of cytokine gene expression, production of reactive oxygen and nitrogen compounds, and other biological responses important for innate immunity to bacterial infection.