Journal
JOURNAL OF AUTOIMMUNITY
Volume 35, Issue 4, Pages 358-367Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2010.07.007
Keywords
Systemic lupus erythematosus (SLE); Anti double stranded DNA autoantibody (Anti dsDNA); Single chain variable fragment (scFv); Toll like receptor 4 (TLR4); Lipopolysaccharides (LPS)
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Funding
- National Science Council [98-2320-B-010-001-MY3, 97-2811-B-010-016]
- Tsou s Foundation [99-P6-30]
- Taipei City Hospital
- Ministry of Education (Aim for the Top University Plan) ROC
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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 (c) 2010 Elsevier Ltd All rights reserved
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