| Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by the presence of IgG autoantibodies to nuclear antigens in the sera of patients. Utilizing a novel SLE mouse model "564Igi" with knocked-in genes for the heavy and light chain of an anti-RNA autoantibody, our laboratory has previously reported that autoantibody production in 564Igi is T cell independent and partially dependent on the RNA receptor TLR7. In this thesis I provide evidence that female 564Igi mice with intact (X-linked) Tlr8 but deficient in Tlr7 and Tlr9, have more IgG bearing lymphocytes and produce more autoantibody than males. This phenotype is reminiscent of human lupus where the disease occurs in females nine times more frequently than in males. Additionally I also show that the concurrent deficiency of Tlr7 and Tlr8 in 564Igi mice leads to a drastic reduction of serum IgG2a and IgG2b autoantibodies, similar to what is observed in Myd88 deficient mice. Lastly, I have evidence that granulopoiesis, which is observed in both human SLE patients and in 564Igi mice, is Tlr7/8 and Myd88 dependent and IL1R type 1 independent. Collectively the data indicate that TLR8 in mice is important for the pathogenesis of SLE. The phenotypic similarities described in this thesis between human and mouse SLE suggest that the potential involvement of TLR8 in human SLE should be seriously considered. |
