Sustained NPSLE development in the absence of systemic lupus-like disease in TLR7- deficient B6.Nba2

Abstract

Abstract Neuropsychiatric Lupus (NPSLE) is a common manifestation of systemic lupus erythematosus (SLE) which includes presentations of cognitive learning and memory deficits and anxiety disorders. The B6.Nba2 mouse model of SLE presents with anxiety and depression. Toll-like receptor (TLR7), a known driver of type I interferons and SLE, drives systemic autoimmunity in the B6.Nba2 model, but whether TLR7-deficient B6.Nba2 mice develop NPSLE remains unknown. Age-matched female B6, B6.Nba2, and B6.Nba2.TLR7 knockout mice (KO) were tested in open field (OFT), elevated plus maze (EPM), Y maze (YM) and novel object recognition (NOR) tests between the ages of 8–32 weeks. To determine levels of systemic autoimmunity and inflammation serum autoantibody and tumor necrosis factor-related of apoptosis (TWEAK) levels were determined by ELISA. Both B6.Nba2 and B6.Nba2.TLR7 KO mice presented with anxiety (OFT, EPM) and dysfunctional spatial memory (YM). B6.Nba2 mice displayed a general memory defect (NOR), but this was not seen in TLR7-KO mice. Only B6.Nba2 mice presented with elevated levels of anti-dsDNA autoantibodies and corresponding DWEYS-reactive antibodies. In contrast, serum levels of TWEAK were elevated in both B6.Nba2 and B6.Nba2.TLR7 KO mice, suggesting that signals other than TLR7 may drive inflammation in this model. In conclusion, both B6.Nba2 and B6.Nba2.TLR7KO presented with elevated serum TWEAK levels, anxiety and memory deficits, despite only B6.Nba2 mice displaying anti-dsDNA and DWEYS-reactive autoantibodies. Thus in this model, NPSLE appear to develop in an autoantibody-independent fashion. Studies are ongoing to determine the nature of TLR7/autoantibody-independent NPSLE. Supported by a grant from the Department of Defense (LR 180040)