|Title:||Transgenic Overexpression of Anti-Double-Stranded DNA Autoantibody and Activation of Toll-Like Receptor 4 in Mice Induce Severe Systemic Lupus Erythematosus Syndromes||Authors:||LEE, TAI-PING
|Keywords:||Systemic lupus erythematosus (SLE);Anti double stranded DNA autoantibody (Anti dsDNA);Single chain variable fragment (scFv);Toll like receptor 4 (TLR4);Lipopolysaccharides (LPS)||Issue Date:||2010||Source:||Journal of Autoimmunity||Start page/Pages:||358-367||Abstract:||
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characteristized by the presence of autoantibodies against double-stranded DNA (anti-dsDNA) in sera at high levels Bacterial infections in SLE are associated with higher morbidity and mortality Our goal was to observe the interaction between these 2 factors in the pathogenesis of lupus We generated transgenic mice with monoclonal anti-dsDNA to investigate the development of lupus By challenging the mice in vitro and in vivo with Toll -like receptor 4 (TLR4) ligand lipopolysaccharides (LPS) we were able to examine the role of bacterial infection in SLE In our study the transgenic mice with a secreted form of anti-dsDNA were found to have higher levels of anti-nuclear antibodies anti-dsDNA blood urea nitrogen and proteinuria The splenocytes of the mice stimulated with LPS secreted more anti-dsDNA IFN-gamma and IL-10 After injecting them with LPS in vivo we further found higher immune complex depositions and IL-10 in the kidneys of the transgenic mice Moreover the LPS-injected transgenic mice had higher mortality rate This is the first transgenic model to demonstrate that only 2 risk factors pathogenic anti-dsDNA and TLR4 activation induce severe SLE syndromes in normal mice through the overproduction of IL-10 and IFN-gamma These findings imply that anti-dsDNA and bacterial infections have pivotal roles in the pathogenesis of SLE the inhibition of TLR4 may be regarded as a therapeutic target
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