The Role of TLR7/8 in Autoantibody Production and Granulopoiesis in Murine SLE.
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 i... read morendependent 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
Thesis (Ph.D.)--Tufts University, 2013.
Submitted to the Dept. of Genetics.
Advisor: Thereza Imanishi-Kari.
Committee: Erik Selsing, Brigitte Huber, Alexander Poltorak, and Ann Marshak-Rothstein.
Keywords: Genetics, and Immunology.read less