Document Detail


Brief report: increased expression of a short splice variant of CTLA-4 exacerbates lupus in MRL/lpr mice.
MedLine Citation:
PMID:  23203389     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: CTLA-4 is a negative regulator of the immune response expressed by regulatory T (Treg) cells and activated T cells. Polymorphisms in the CTLA4 gene have been associated with autoimmune diseases, including systemic lupus erythematosus. Disease-associated polymorphisms have been shown to affect the production of the different CTLA-4 variants through an effect on alternative splicing. This study was undertaken to evaluate the role of the 1/4 CTLA-4 isoform in lupus-prone mice.
METHODS: We generated an MRL/lpr mouse strain that transgenically overexpresses a short isoform of CTLA-4 (1/4 CTLA-4) by backcrossing C57BL/6.1/4CTLA-4-transgenic mice to the MRL/lpr strain for 9 generations. A new antibody was generated to detect the expression of the 1/4 CTLA-4 isoform. Routine methods were used to evaluate kidney damage, humoral immunity, and cellular immunity.
RESULTS: Expression of the 1/4 CTLA-4 isoform accelerated autoimmune disease. Transgenic mice died earlier, had more severe renal disease, and had higher titers of anti-double-stranded DNA antibodies than wild-type MRL/lpr mice. The acceleration of autoimmunity and disease pathology associated with the presence of the short (1/4) isoform of CTLA-4 was linked to increased numbers of activated T cells and B cells and heightened interferon-γ production, but not to altered expression of the full-length CTLA-4 molecule or Treg cell numbers.
CONCLUSION: Our results indicate that the presence of the alternatively spliced 1/4 CTLA-4 isoform can further promote autoimmunity and autoimmune pathology in lupus-prone mice and suggest that altered splicing of CTLA4 contributes to the expression of autoimmune disease.
Authors:
Kunihiro Ichinose; Zheng Zhang; Tomohiro Koga; Yuang-Taung Juang; Katalin Kis-Tóth; Arlene H Sharpe; Vijay Kuchroo; José C Crispín; George C Tsokos
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  65     ISSN:  1529-0131     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-26     Completed Date:  2013-04-24     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  764-9     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2013 by the American College of Rheumatology.
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MeSH Terms
Descriptor/Qualifier:
Animals
Autoimmunity / genetics*,  immunology
B-Lymphocytes / physiology
CTLA-4 Antigen / genetics*,  metabolism
Female
Gene Expression / immunology
Interferon-gamma / immunology,  metabolism
Lupus Erythematosus, Systemic / genetics*,  immunology,  physiopathology
Lymphocyte Activation / genetics,  immunology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred MRL lpr
RNA Splice Sites / genetics*
T-Lymphocytes, Regulatory / physiology
Grant Support
ID/Acronym/Agency:
P01 AI056299/AI/NIAID NIH HHS; R01 AI049954/AI/NIAID NIH HHS; R01-A-1068787//PHS HHS
Chemical
Reg. No./Substance:
0/CTLA-4 Antigen; 0/Ctla4 protein, mouse; 0/RNA Splice Sites; 82115-62-6/Interferon-gamma
Comments/Corrections

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