Brief Report: Increased expression of a short splice variant of CTLA‐4 exacerbates lupus in MRL/lpr mice. Issue 3 (25th February 2013)

• Record Type: Journal Article
• Authors: Ichinose, Kunihiro; Zhang, Zheng; Koga, Tomohiro; Juang, Yuang‐Taung; Kis‐Tóth, Katalin; Sharpe, Arlene H.; Kuchroo, Vijay; Crispín, José C.; Tsokos, George C.
• Is Part Of: Arthritis and rheumatism. Volume 65:Issue 3(2013:Mar.)
• Page Start: 764
• Page End: 769
• Publication Date: 2013-02-25
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; Arthritis -- Periodicals; Rheumatic Diseases -- Periodicals; Rhumatisme -- Périodiques; Arthrite -- Périodiques; 616.72
• DOI: 10.1002/art.37790
• Languages: English
• ISSNs: 0004-3591

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="abs1-1" sec-type="section"> <title>Objective</title> <p>CTLA‐4 is a negative regulator of the immune response expressed by regulatory T (Treg) cells and activated T cells. Polymorphisms in the <italic>CTLA4</italic> 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.</p> </sec> <sec id="abs1-2" sec-type="section"> <title>Methods</title> <p>We generated an MRL/<italic>lpr</italic> 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/<italic>lpr</italic> 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.</p> </sec> <sec id="abs1-3" sec-type="section"> <title>Results</title> <p>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/<italic>lpr</italic> 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.</p> </sec> <sec id="abs1-4" sec-type="section"> <title>Conclusion</title> <p>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 <italic>CTLA4</italic> contributes to the expression of autoimmune disease.</p> </sec> </abstract>