AUTHOR=McDonald Gabrielle , Cabal Nicholas , Vannier Augustin , Umiker Benjamin , Yin Raymund H. , Orjalo Arturo V. , Johansson Hans E. , Han Jin-Hwan , Imanishi-Kari Thereza 

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

JOURNAL=Frontiers in Immunology

VOLUME=6

YEAR=2015

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2015.00457

DOI=10.3389/fimmu.2015.00457

ISSN=1664-3224

ABSTRACT=<p>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 <italic>Tlr7</italic> and <italic>Tlr9</italic> double knockout background showed that the presence of <italic>Tlr8</italic> on both X chromosomes was required for the production of IgG autoantibodies, <italic>Ifn-I</italic> expression and granulopoiesis in females. Here, we show the results of our investigation into the role of <italic>Tlr8</italic> 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 <italic>in vivo</italic>, which are major contributors to <italic>Ifn-<italic>α</italic></italic> expression. Here, we show that neutrophils from C57BL/6 mice express <italic>Ifn-<italic>α</italic></italic> in response to 564 immune complexes and TLR8 activation. Bone marrow-derived macrophages from 564Igi females have a significant increase in <italic>Tlr8</italic> expression compared to male-derived cells, and RNA fluorescence <italic>in situ</italic> hybridization data suggest that <italic>Tlr8</italic> 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 <italic>Tlr8</italic>.</p>