Mice with spontaneous lupus erythematosus- and rheumatoid arthritis-like manifestations are characterized by B cell hyperactivity, hypergammaglobulinemia and autoantibodies against a variety of self-antigens, particularly nuclear antigens and IgG. These autoantibodies appear to be central to disease, forming immune complexes which damage various organs. This proposal focuses on defining, at the clonal level, the molecular generation and structure of these effector molecules. Libraries of monoclonal autoantibody-producing hybridomas will be developed from different genetic background mice with spontaneous lupus/arthritis, and mice with experimentally-induced autoantibody production. The libraries will be screened with nucleic acid probes to define the usage patterns of VH-VL, gene families, joining (J), and complementarity-determining region (CDR) elements. Correlations with autoantibody isotype, antigenic specificity, strain of origin and means of induction will be made. mRNAs encoding heavy (H) and light (L) chains of selected monoclonal autoantibodies and the germline V genes from which they derive will be molecularly cloned, and complete nucleotide sequences of VH-DH-JH and VL-JL elements determined to define the genetic elements encoding their production, their relation to the respective germline elements and the involvement of somatic mutation in autoantibody generation. The contribution of germline genes to autoantibody specificity will be further examined by transfecting cells with functionally-rearranged germline and/or specifically mutagenized V genes, and assaying the expressed Ig products for autoantibody activity. Anti--idiotypic reagents against synthetic peptides from the autoantibodies' CDRs and molecular V region-specific probes will be prepared and used to define the extent of the autoantibody repertoire and the preponderance of certain idiotypes in sera and afflicted tissues, and thus the relationship of autoantibody structure with pathogenicity. These studies at the clonal level will allow definitive conclusions on the relationship of autoantibody structure to pathogenicity, their origin and regulation, and clarify the role of germline and somatic diversification mechanisms in autoimmune pathogenesis.
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| Aït-Azzouzene, Djemel; Kono, Dwight H; Gonzalez-Quintial, Rosana et al. (2010) Deletion of IgG-switched autoreactive B cells and defects in Fas(lpr) lupus mice. J Immunol 185:1015-27 |
| Wickramarachchi, Dilki C; Theofilopoulos, Argyrios N; Kono, Dwight H (2010) Immune pathology associated with altered actin cytoskeleton regulation. Autoimmunity 43:64-75 |
| Barnes, Michael J; Krebs, Philippe; Harris, Nathaniel et al. (2009) Commitment to the regulatory T cell lineage requires CARMA1 in the thymus but not in the periphery. PLoS Biol 7:e51 |
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