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Blockade of CD28/CTLA4-B7 pathway prevented autoantibody-related diseases but not lung disease in MRL/lpr mice
M Takiguchi1, M Murakami, I Nakagawa
1Institute of Immunological Science, Department of Veterinary Clinical Sciences, Hokkaido University, Sapporo, Japan.
Abstract:
We studied the role of CD28/CTLA4 costimulatory T-cell activation pathway on the pathogenesis of MRL/lpr mice. Administration of CTLA4IgG from day 0 significantly inhibited autoantibody production such as anti-double-stranded DNA antibody and rheumatoid factor. In addition, end-organ diseases in kidney, salivary gland, and liver were significantly improved. Improvement of pathologic findings coincided with a significant improvement in survival. At 350 days of age, 90% of mice treated with CTLA4IgG from day 0 were still alive, compared with none of mice treated with hIgG. As expected, activation of conventional T cells was significantly inhibited after CTLA4IgG treatment. However, lung disease that was characterized by perivascular accumulation and interstitial infiltration of lymphocytes and macrophages was not inhibited. Even after CTLA4IgG treatment from day 0, pathologic findings of lung disease were not improved. Additionally, the expression of activation markers such as B7-1, B7-2, CD71, ICAM1, and LFA1 on Mac1+ fraction in both spleen and lung and the concentration of TNFalpha in bronchoalveolar lavage fluid were not significantly suppressed. These results demonstrated that lung disease was independent of the CD28/CTLA4-B7 pathway. Thus, this study emphasizes the differential dependence of the CD28/CTLA4-B7 pathway in development of diseases in MRL/lpr mice.
Insights
The CD28/CTLA4-B7 pathway significantly impacts autoimmune disease in MRL/lpr mice, inhibiting autoantibodies and improving organ damage. However, lung disease in these mice is independent of this pathway.
Area of Science:
- Immunology
- Autoimmunity
- Pathogenesis
Background:
- The CD28/CTLA4 costimulatory pathway plays a crucial role in T-cell activation and immune regulation.
- MRL/lpr mice are a model for systemic lupus erythematosus (SLE), exhibiting autoimmune diseases including autoantibody production and organ damage.
Purpose of the Study:
- To investigate the role of the CD28/CTLA4-B7 costimulatory pathway in the pathogenesis of autoimmune diseases in MRL/lpr mice.
- To determine if targeting this pathway could ameliorate disease manifestations, including lung pathology.
Main Methods:
- MRL/lpr mice were treated with CTLA4IgG or human IgG (hIgG) from day 0.
- Autoantibody production (anti-dsDNA, RF), end-organ damage (kidney, salivary gland, liver), survival rates, T-cell activation markers, and lung disease pathology were assessed.
- Expression of activation markers (B7-1, B7-2, CD71, ICAM1, LFA1) and TNF-alpha in lung tissue and bronchoalveolar lavage fluid were analyzed.
Main Results:
- CTLA4IgG treatment significantly inhibited autoantibody production and improved kidney, salivary gland, and liver pathology, leading to enhanced survival.
- Conventional T-cell activation was significantly inhibited by CTLA4IgG.
- Lung disease, characterized by perivascular lymphocyte and macrophage infiltration, was not improved by CTLA4IgG treatment.
- Activation markers and TNF-alpha levels in the lung remained unchanged, indicating pathway independence.
Conclusions:
- The CD28/CTLA4-B7 pathway is critical for the development of systemic autoimmune diseases in MRL/lpr mice, but not for lung-specific pathology.
- Lung disease in MRL/lpr mice is independent of the CD28/CTLA4-B7 costimulatory pathway.
- These findings highlight the differential dependence of various autoimmune manifestations on specific immune pathways.
