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.
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/lprmouse 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/lprmice. 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: Hironori Ueda; Joanna M M Howson; Laura Esposito; Joanne Heward; Hywel Snook; Giselle Chamberlain; Daniel B Rainbow; Kara M D Hunter; Annabel N Smith; Gianfranco Di Genova; Mathias H Herr; Ingrid Dahlman; Felicity Payne; Deborah Smyth; Christopher Lowe; Rebecca C J Twells; Sarah Howlett; Barry Healy; Sarah Nutland; Helen E Rance; Vin Everett; Luc J Smink; Alex C Lam; Heather J Cordell; Neil M Walker; Cristina Bordin; John Hulme; Costantino Motzo; Francesco Cucca; J Fred Hess; Michael L Metzker; Jane Rogers; Simon Gregory; Amit Allahabadia; Ratnasingam Nithiyananthan; Eva Tuomilehto-Wolf; Jaakko Tuomilehto; Polly Bingley; Kathleen M Gillespie; Dag E Undlien; Kjersti S Rønningen; Cristian Guja; Constantin Ionescu-Tîrgovişte; David A Savage; A Peter Maxwell; Dennis J Carson; Chris C Patterson; Jayne A Franklyn; David G Clayton; Laurence B Peterson; Linda S Wicker; John A Todd; Stephen C L Gough Journal: Nature Date: 2003-04-30 Impact factor: 49.962
Authors: T L Walunas; D J Lenschow; C Y Bakker; P S Linsley; G J Freeman; J M Green; C B Thompson; J A Bluestone Journal: Immunity Date: 1994-08 Impact factor: 31.745
Authors: Sue M Liu; Andrew P R Sutherland; Zheng Zhang; Daniel B Rainbow; Francisco J Quintana; Alison M Paterson; Arlene H Sharpe; Mohamed Oukka; Linda S Wicker; Vijay K Kuchroo Journal: J Immunol Date: 2011-11-28 Impact factor: 5.422
Authors: T Takahashi; T Tagami; S Yamazaki; T Uede; J Shimizu; N Sakaguchi; T W Mak; S Sakaguchi Journal: J Exp Med Date: 2000-07-17 Impact factor: 14.307