Research Interests
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.

Publications
Ye, J., S.K. McCray, and S.H. Clarke. 1995. The transition of pre-BI to pre-BII cells is dependent on the VH structure of the m /surrogate L chain receptor. EMBO J. 15:1524.

Retter, M.W., P.L. Cohen, R.A. Eisenberg, and S.H. Clarke. 1995. Both Sm and DNA are selecting antigens in the anti-Sm B cell response in autoimmune MRL/lpr mice. J. Immunol. 156:1296.

Kepler, T.B., M. Borrero, B. Rugerio, S.K. McCray, and S.H. Clarke. 1995. Interdependence of N-nucleotide addition and recombination site choice in V(D)J rearrangement. J. Immunol. 157:4451-4457.

Santulli-Marotto, S., M. Retter, R. Gee, M.J. Mamula, and S.H. Clarke. 1997. Autoreactive B cell regulation: peripheral induction of developmental arrest by lupus-associated autoantigens. Immunity. 8:209.

Clarke, S.H., and L.W. Arnold. 1998. B-1 cell development: Evidence for an uncommitted IgM+ B cell precursor in B-1 cell differentiation. J. Exp. Med. 187:1325.

E-mail: shl@med.unc.edu
Telephone: (919) 966-3131
FAX: (919) 962-8103
Address: 626 Mary Ellen Jones Bldg. Chapel Hill, NC

Click here to update this profile