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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of anti-nuclear antibodies. SLE is one of many autoimmune disorders that have a strong gender bias, with 70–90% of SLE patients being female. Several explanations have been postulated to account for the severity of autoimmune diseases in females, including hormonal, microbiota, and gene dosage differences. X-linked toll-like receptors (TLRs) have recently been implicated in disease progression in females. Our previous studies using the 564Igi mouse model of SLE on a  Tlr7  and  Tlr9  double knockout background showed that the presence of  Tlr8  on both X chromosomes was required for the production of IgG autoantibodies,  Ifn-I  expression and granulopoiesis in females. Here, we show the results of our investigation into the role of  Tlr8  expression in SLE pathogenesis in 564Igi females. Female mice have an increase in serum pathogenic anti-RNA IgG2a and IgG2b autoantibodies. 564Igi mice have also been shown to have an increase in neutrophils  in vivo , which are major contributors to  Ifn- α   expression. Here, we show that neutrophils from C57BL/6 mice express  Ifn- α   in response to 564 immune complexes and TLR8 activation. Bone marrow-derived macrophages from 564Igi females have a significant increase in  Tlr8  expression compared to male-derived cells, and RNA fluorescence  in situ  hybridization data suggest that  Tlr8  may escape X-inactivation in female-derived macrophages. These results propose a model by which females may be more susceptible to SLE pathogenesis due to inefficient inactivation of  Tlr8 .

Female Bias in Systemic Lupus Erythematosus is Associated with the Differential Expression of X-Linked Toll-Like Receptor 8