TY - JOUR
T1 - Transgenic overexpression of anti-double-stranded DNA autoantibody and activation of Toll-like receptor 4 in mice induce severe systemic lupus erythematosus syndromes
AU - Lee, Tai Ping
AU - Tang, Shye Jye
AU - Wu, Ming Fang
AU - Song, Ying Chyi
AU - Yu, Chia Li
AU - Sun, Kuang Hui
N1 - Funding Information:
We thank Dr Mi-Hua Tao (Insitute of Biomedical Sciences, Academia Sinica) for providing the pUC9-VH38C13 plasmids and Dr Huey-Kang Sytwu (Department of Microbiology and Immunology, National Defense Medical Center) for providing the pINS-1-anti-CTLA-4 plasmids. This work was supported by grants from the National Science Council ( 98-2320-B-010-001-MY3 ), ( 97-2811-B-010-016 ), VGHUST Joint Research Program, Tsou’s Foundation ( 99-P6-30 ), Taipei City Hospital and the Ministry of Education (Aim for the Top University Plan), ROC.
PY - 2010/12
Y1 - 2010/12
N2 - 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-γ, 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-γ. 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.
AB - 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-γ, 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-γ. 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.
KW - Anti-double-stranded DNA autoantibody (Anti-dsDNA)
KW - Lipopolysaccharides (LPS)
KW - Single chain variable fragment (scFv)
KW - Systemic lupus erythematosus (SLE)
KW - Toll-like receptor 4 (TLR4)
UR - http://www.scopus.com/inward/record.url?scp=77958151180&partnerID=8YFLogxK
U2 - 10.1016/j.jaut.2010.07.007
DO - 10.1016/j.jaut.2010.07.007
M3 - Article
C2 - 20833510
AN - SCOPUS:77958151180
SN - 0896-8411
VL - 35
SP - 358
EP - 367
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
IS - 4
ER -