Elucidating B Cell Tolerance Defects in Lupus-prone Mice

Systemic lupus erythematosus is a chronic autoimmune disease that impacts multiple tissues through the production of pathogenic anti-nuclear autoantibodies and inflammatory immune complexes. Mouse models that develop lupus-like disease due to the presence of specific lupus susceptibility loci or candidate genes have proven incredibly useful in elucidating how these genetic factors contribute to the complex pathogenesis of SLE. Additionally, the use of immunoglobulin transgenic and knock-in mouse models in conjunction with these lupus-prone strains enables interrogation of the defects in B cell tolerance mechanisms and signalling pathways that lead to SLE development. This thesis examined the impact of genetic loci from the lupus-prone New Zealand Black chromosome 1 congenic strains and of the lupus candidate gene BLK on the maintenance of B cell tolerance and the development of autoimmunity in the context of a nuclear antigen-specific B cell repertoire. It was found that NZB c1 congenic mice with an anergic, ssDNA-specific B cell repertoire had a severely attenuated capacity to breach tolerance to nuclear antigen due to impaired development of Tfh cells relative to the generation of Tfr cells. It was also demonstrated that the autoreactivity of a nuclear antigen-specific B cell repertoire is largely determined by the specificity of the B cell immunoglobulin heavy chain, as B cells from c1 congenic mice with the DNA-specific 3H9 heavy chain were appropriately regulated by B cell tolerance mechanisms in the periphery. Finally, examination of how BLK impacts autoimmunity in the context of nuclear antigen specificity revealed that loss of this molecule enhances both central and peripheral B cell tolerance to anti-DNA B cells. Together, these results underscore the resilience of tolerance mechanisms in the regulation of nuclear antigen-specific B cells and reinforces the concept that the development of profound autoimmunity requires concurrent defects in multiple components of the immune system.Ph.D.2021-07-21 00:00:0