Genetic analysis of an antigen-induced model of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with the capacity to impact multiple organ systems. SLE is a complex disorder involving a combination of environmental, gender and genetic factors to initiate disease. A cardinal feature of the disease involves the production of autoantibodies, particularly anti-nuclear antibodies.;The genetic component to SLE is strong. A better understanding of the genetics would shed light on what causes this breakdown in tolerance at the molecular level leading to more efficacious treatment than is currently available.;The heterogeneity of the human population creates tremendous obstacles when attempting to dissect the genetics of a polygenic disease with an environmental component and variable penetrance. Consequently, inbred strains of mice have been exploited by researchers in an effort to simplify the genetic complexity of SLE.;My thesis focused on the development of a genetic model for SLE that was antigen-induced. Previously our lab had developed a peptide mimetope of DNA (DWEYSVWLSN). We had determined that BALB/c mice exhibited a breakdown in tolerance upon immunization with the peptide while DBA/2 mice did not.;Genetic backcross analysis revealed three dominant susceptibility loci in BALB/c. Two of these loci were significantly linked while the third displayed suggestive linkage. Three congenic strains were created on a DBA/2 background corresponding to each susceptibility locus.;Antibody titers taken from the congenic strains proved that the BALB/c phenotype was fully reestablished following peptide immunization in the DBA/2/C9 +/- strain and partially reestablished in the DBA/2/C7 +/- strain. The suggestively linked DBA/2/C4+/- strain failed to mount a significant antibody response. B cells from the DBA/2/C9+/- strain display key phenotypic characteristics required for the development of the responder phenotype, i.e., lower signaling through the B cell receptor and decreased apoptosis triggered by B cell receptor (BCR) crosslinkage. These studies identified a locus that was critical for regulating the strength of BCR signal transduction and the establishment of a B cell repertoire vulnerable to autoimmunity. This locus is partially syntenic to a region on human chromosome 11 that has been suggestively linked to SLE.