title: Brief report: increased expression of a short splice variant of CTLA-4 exacerbates lupus in MRL/lpr mice.
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.
  
  
  CONCLUSIONS
  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.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Ichinose
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Koga
authors.forename: Yuang-Taung
authors.initials: YT
authors.lastname: Juang
authors.forename: Katalin
authors.initials: K
authors.lastname: Kis-Tóth
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Vijay
authors.initials: V
authors.lastname: Kuchroo
authors.forename: José C
authors.initials: JC
authors.lastname: Crispín
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000502:physiology; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D022821:RNA Splice Sites / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology
chemical_list: D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D022821:RNA Splice Sites; D007371:Interferon-gamma