@article {542136,
	title = {Brief report: increased expression of a short splice variant of CTLA-4 exacerbates lupus in MRL/lpr mice.},
	journal = {Arthritis Rheum},
	volume = {65},
	number = {3},
	year = {2013},
	month = {2013 Mar},
	pages = {764-9},
	abstract = {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.},
	keywords = {Animals, Autoimmunity, B-Lymphocytes, CTLA-4 Antigen, Female, Gene Expression, Interferon-gamma, Lupus Erythematosus, Systemic, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Mice, Inbred MRL lpr, RNA Splice Sites, T-Lymphocytes, Regulatory},
	issn = {1529-0131},
	doi = {10.1002/art.37790},
	author = {Ichinose, Kunihiro and Zhang, Zheng and Koga, Tomohiro and Juang, Yuang-Taung and Kis-T{\'o}th, Katalin and Sharpe, Arlene H and Kuchroo, Vijay and Crisp{\'\i}n, Jos{\'e} C and Tsokos, George C}
}
