Stephen H. Clarke
Area of interest
This laboratory is interested in the molecular genetic events involved in the differentiation of antibody-producing B lymphocytes. There are two general areas of investigation. One focuses on the selection events that occur during B cell differentiation and that are responsible for the segregation of B cells into different subsets; the second focuses on the B cell response to self (autoimmune) antigens. Both of these projects use the mouse as a model and rely on immunoglobulin gene transgenic mice.
The process of B cell differentiation involves an ordered sequence of immunoglobulin gene rearrangement; in general, heavy chain gene rearrangements occur first, followed by light chain gene rearrangement. After each rearrangement, the B cell precursor cells are subject to selection and large numbers of these cells are lost by programmed cell death. By following the development of B cells expressing the same VH gene, VH12, we find that most VH12-expressing B cells are eliminated and propose that the survival of pre-B cells after heavy chain rearrangement is dependent on ligand binding (positive selection). The surviving VH12 B cells leave the bone marrow and segregate into one of two subsets: B-2 cells, which are the majority in the mouse, and B-1 cells, which are often specific for self-antigens. Using VH12 transgenic mice, we find that segregation into these subsets depends on the antigen specificity of the cell and therefore must occur after immunoglobulin gene rearrangement.
Our studies of B cell responses to self antigen focus primarily on the autoimmune response to the nuclear protein antigen Sm in autoimmune mice. We have demonstrated an overlap between the anti-Sm and anti-DNA responses in mice; many anti-Sm B cells also bind DNA, and we have demonstrated that clonal expansion of anti-Sm B cells can be driven by either Sm or DNA.