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.