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  current news   Press   selected story    
     
  27 December 2017  
 
A Novel Human Systemic Lupus Erythematosus Model in Humanised Mice
 
 




Authors
Merry Gunawan1, Zhisheng Her1, Min Liu1, Sue Yee Tan1, Xue Ying Chan1, Wilson Wei Sheng Tan1, Shubasree Dharmaraaja1, Yong Fan2, Chee Bing Ong3, Eva Loh4, Kenneth Tou En Chang4, Thiam Chye Tan5, Jerry Kok Yen Chan6,7, Qingfeng Chen1,2,8*

Author Affiliations
1 Humanized mouse unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and   Research (A*STAR), Singapore
2 Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of   Guangzhou Medical University, Guangzhou, 510150, China
3 Advanced Molecular Pathology Laboratory, Institute of Molecular and Cell Biology, Agency for Science,   Technology and Research (A*STAR), Singapore
4 Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore
5 Department of Obstetrics & Gynaecology, KK Women's and Children's Hospital, Singapore
6 Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore
7 Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore
8 Department of Microbiology and immunology, Yong Loo Lin School of Medicine, National University of   Singapore, Singapore

Published in Scientific Reports on 30 November 2017.

*Corresponding author: Qingfeng Chen. E-mail: qchen@imcb.a-star.edu.sg
https://www.nature.com/articles/s41598-017-16999-7

Abstract
Mouse models have contributed to the bulk of knowledge on Systemic Lupus Erythematosus (SLE). Nevertheless, substantial differences exist between human and mouse immune system. We aimed to establish and characterise a SLE model mediated by human immune system.
Injection of pristane into immunodeficient mice reconstituted with human immune system (humanised mice) recapitulated key SLE features, including: production of human anti-nuclear autoantibodies, lupus nephritis, and pulmonary serositis. There was a reduction in the number of human lymphocytes in peripheral blood, resembling lymphopenia in SLE patients. Concurrently, B cells and T cells were systemically hyperactivated, with a relative expansion of CD27+ and CD27-IgD- memory B cells, increased number of plasmablasts/plasma cells, and accumulation of effector memory T cells. There was also an increased production of human pro-inflammatory cytokines, including: IFN-g, IL-8, IL-18, MCP-1, and IL-6, suggesting their role in SLE pathogenesis. Increased expression of type I IFN signature genes was also found in human hepatocytes.

Altogether, we showed an SLE model that was mediated by human immune system, and which recapitulated key clinical and immunological SLE features. The advancements of humanised mice SLE model would provide an in vivo platform to facilitate translational studies and pre-clinical evaluations of human-specific mechanisms and immunotherapies.

Figure

Figure legend
: Lupus nephritis and pulmonary inflammation. (a) (Left) Kidney sections from hu-mice and NSG with or without pristane injection were H&E stained and pathologically evaluated. Scale bar represents 50µm and images are representative from two independent experiments (control NSG n = 3; pristane NSG n = 3; control hu-mice n = 8; pristane hu-mice n = 12). (Right) Mean glomeruli area was measured from 50 random glomeruli from kidneys of each experimental animal (control NSG n = 3; pristane NSG n = 3; control hu-mice n = 5; pristane hu-mice n = 6). (b) Immunohistochemistry of human IgG and IgM on kidney sections from control and pristane-injected hu-mice Scale bar represents 50µm and images are representative from two independent experiments (control n = 8; pristane n = 12). (c) Protein content in the urine of control and pristane-injected NSG, control and pristane-injected hu-mice at 10 weeks post-pristane injection was measured using Uristix reagent strips. Figure is from two independent experiments (control NSG n = 8; pristane NSG n = 3; control hu-mice n = 8; pristane hu-mice n = 7). (d) Lung sections were H&E stained and pathologically evaluated. Scale bar represents 200µm and images are representative from two independent experiments (control n = 6; pristane n = 5). ** P<0.01.

For more information on Qingfeng CHEN's lab, please click here.