Martin Weigert, Ph.D.

Origins and Regulation of Antibodies Specific for Self-Antigens

Research Summary

Origins and Regulation of Antibodies Specific for Self-Antigens
A typical antigen such as influenza hemagglutinin selects one or a few B cells that express an antibody whose specificity for HA results from somatic mutation of antibody variable region (V) genes or fortuitous combinations of V gene segments. The antibody response to foreign molecules is then derived from the clonal expansion of these B lymphocytes. During clonal expansion,somatic point mutation continues at a high rate (ca. 10-3/base pair division), generating new specificities and modifying the specificity of the original B cell antibody receptor. From the pattern of somatic mutations and the shape of the genealogic trees of somatic mutations, important features of somatic mutation are revealed: (1) Silent mutations are randomly distributed throughout V genes, but replacement mutations are overrepresented in the complementarity determining regions and underrepresented in the framework regions of V genes. This means that positive (antigen) and negative (structure-conserving) selection act upon mutations during clonal expansion. (2) Initiation and termination of high rates of somatic mutation are stochastic. High rates are initiated at different times in different clones and start at different times at different V genes (VL or VH) in a single clone. Mutation rates decrease during clonal expansion, and, again, when this occurs, is unpredictable.

An inevitable outcome of this mechanism of V gene diversification is that antibodies to self-antigens arise during the course of the normal response. This possibility was considered by analysis of the autoantibodies in autoimmune diseases such as systemic lupus erythematosus (SLE). This disease in man and in certain inbred mouse models of autoimmunity is associated with the spontaneous secretion of antibodies directed to self-molecules, such as DNA, and other autoantibodies, such as Rheumatoid Factor, RF. The analysis of the V genes coding for these autoantibodies shows that they have many of the properties of conventional antibodies; they are oligoclonal, highly mutated, and show evidence for selection by self-antigen. This result implies that normal individuals have the potential for generating antibodies specific for self-antigen and that autoimmunity may arise by the failure to regulate self-reactive B lymphocytes. Are self-reactive B cells actively regulated in normal individuals? We have approached this question by constructing transgenic mice with genes coding for autoantibodies representative of those found in SLE or rheumatoid arthritis (RA). These include antibodies specific for single-stranded DNA, for single- and double-stranded DNA, and RF. In the genetic background of normal mice, B cells expressing these transgenes are regulated in different ways, including clonal deletion, clonal anergy and antibody receptor editing. In the genetic background of diseased mice, these self-reactive B cells escape the mechanisms of inactivation. These and new, refined transgenic models allow us now to examine the stage of B cell differentiation at which self reactive B cells are regulated..

Selected Papers

Chen C, Nagy Z, Radic MZ, Hardy RR, Huszar D, Camper SA, Weigert M.  (1995). The site and stage of anti-DNA B-cell deletion. Nature. 373(6511):252-5.

Chen C, Prak EL, Weigert M. (1997). Editing disease-associated autoantibodies. Immunity. 6(1):97-105.

Brard F, Shannon M, Prak EL, Litwin S, Weigert M. (1999). Somatic mutation and light chain rearrangement generate autoimmunity in anti-single-stranded DNA transgenic MRL/lpr mice. J Exp Med. 190(5):691-704.

Li H, Jiang Y, Prak EL, Radic M, Weigert M. (2001). Editors and editing of anti-DNA receptors. Immunity. 15(6):947-57.

Li Y, Li H, Weigert M. (2002). Autoreactive B cells in the marginal zone that express dual receptors. J Exp Med. 195(2):181-8.

Li Y, Li H, Ni D, Weigert M. (2002). Anti-DNA B cells in MRL/lpr mice show altered differentiation and editing pattern. J Exp Med. 196(12):1543-52.

Li H, Jiang Y, Cao H, Radic M, Prak EL, Weigert, M. (2003). Regulation of anti-phosphatidylserine antibodies. Immunity. 18(2):185-92.

Sekiguchi DR, Eisenberg RA, Weigert M. (2003). Secondary heavy chain rearrangement: a mechanism for generating anti-double-stranded DNA B cells. J Exp Med. 197(1):27-39.

Li Y, Louzoun Y, Weigert M. (2004). Editing anti-DNA B cells by Vlambdax. J Exp Med. 199(3):337-46.

Shlomchik MJ, Cooke A, Weigert M. (2004). Autoimmunity: The genes and phenotypes of autoimmunity. Curr Opin Immunol. 16(6):738-40.

Witsch EJ, Cao H, Fukuyama H, Weigert M. (2006). Light chain editing generates polyreactive antibodies in chronic graft-versus-host reaction. J Exp Med. 203(7):1761-72.

Chen C, Li H, Tian Q, Beardall M, Xu Y, Casanova N, Weigert M. (2006). Selection of anti-double-stranded DNA B cells in autoimmune MRL-lpr/lpr mice. J Immunol. 176(9):5183-90.