Abstract
Duchenne muscular dystrophy (DMD) is a genetic disease that results in the death of affected boys by early adulthood. The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, the mdx mouse has been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in the mdx mouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in the mdx mouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared.
Highlights
Duchenne muscular dystrophy (DMD) is a lethal, Xchromosome muscle wasting disease affecting approximately one in 3,500 boys [1, 2]
Since we are interested in following the role of the immune system during disease progression, we use a simplistic description of the development of damaged tissue while we model the cell interaction during the buildup of the adaptive immune response in more detail
Immune response is known to play a key role in exacerbating the disease in DMD patients and mdx mice
Summary
Duchenne muscular dystrophy (DMD) is a lethal, Xchromosome muscle wasting disease affecting approximately one in 3,500 boys [1, 2]. T-cells and macrophages are classically thought to be responsible for triggering and orchestrating the immune response, inducing target cell death, recognizing immune stimuli, and removing cellular debris Immunosuppressive therapy, such as treatment with glucocorticoids, improves muscle strength and prolongs ambulation in DMD patients but does not prevent disease progression [3, 12]. We constructed a mechanistic differential equations model as the first step toward building a comprehensive model of the immune response in DMD aiming to provide insight into the nature of the immune/inflammatory mechanisms contributing to DMD pathogenesis in the early disease stages Understanding these underlying mechanisms will provide a key tool to develop effective therapeutic approaches. The model suggests that CD8+ T-cells likely contribute to muscle damage and predicts two distinct modes for the long-term dynamics of the immune response
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