The overall endeavor of this project is to understand the regulation of anti-nucleosome antibodies in murine models of systemic lupus erythematosus (SLE). This specificity is critical, since the presence of anti-nucleosome antibodies marks the earliest evidence for loss of self-tolerance in SLE patients. (1) The investigators will generate site-directed transgenic mice that express the heavy and/or light chains of an MRL anti-nucleosome antibody. The site directed transgene approach presents an advantage over conventional transgenes in that a single copy of the gene of interest is insert at its proper location in the genome. The investigators will first determine whether these autoreactive specificities are anergized, deleted, or edited when expressed in a normal genetic background. They will assess how self-tolerance is affected when the transgenes are bred onto an autoimmune background. They will also generate site-directed transgenic mice in which the variable regions of the same antibody transgene have been reverted to their germline sequences to mimic the development of autoreactive B-cell precursors. (2) They will use panels of monoclonal antibodies obtained from these transgenic mice to understand structural features of antinuclear antibodies such as the respective roles of the heavy and light chains and of somatic mutations in binding to chromatin antigens. (3) The heavy chain CDR3s of antibodies to nucleosomal epitopes contain many cationic residues that will result from unusual VH-D-JH rearrangements. The investigators will explore whether these atypical rearrangements occur more frequently in B-cells from autoimmune mice or if their increased frequency is merely the result of antigen selection. This will be accomplished by generating and analyzing normal and autoimmune libraries of VH-D-JH rearrangements obtained from newborn mice (prior to the development of the autoimmune process) or from adult pre-B-cells (before antigen selection). The detection of an increased frequency of unusual rearrangements early in the autoimmune process would point to an intrinsic defect in B-cells from autoimmune-prone individuals.
| Monestier, M; Zouali, M (2002) Receptor revision and systemic lupus. Scand J Immunol 55:425-31 |
| Klonowski, K D; Monestier, M (2001) Ig heavy-chain gene revision: leaping towards autoimmunity. Trends Immunol 22:400-5 |
| Bagenstose, L M; Salgame, P; Monestier, M (1999) Cytokine regulation of a rodent model of mercuric chloride-induced autoimmunity. Environ Health Perspect 107 Suppl 5:807-10 |
| Bagenstose, L M; Salgame, P; Monestier, M (1998) Mercury-induced autoimmunity in the absence of IL-4. Clin Exp Immunol 114:9-12 |
