Modeling cyclic waves of circulating T cells in autoimmune diabetes
Modeling cyclic waves of circulating T cells in autoimmune diabetes
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DOI：
10.1137/060661144
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发表时间：
2007-01-01
影响因子：
1.9
通讯作者：
Edelstein-Keshet, Leah
中科院分区：
文献类型：
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作者：
Mahaffy, Joseph M.;Edelstein-Keshet, Leah
1型糖尿病（T1 D）是一种自身免疫性疾病，其中免疫细胞，特别是T淋巴细胞，靶向并杀死分泌胰岛素的胰腺β细胞。一旦这些β细胞中有足够大的一部分被破坏，就会导致血糖水平升高和糖尿病全面爆发。最近对动物，即非肥胖糖尿病（NOD）小鼠中T1 D的研究揭示了在糖尿病发作前数周，血液中循环的T细胞水平的大的周期性波动[J.D.特鲁多角Kelly-Smith，C. B。Verchere，J. F. Elliott，J. P. Dutz，D. T. Finegood、P. Santamaria和R. Tan，J. Clin. Invest.，111（2003），pp. 217-223]，但这些振荡的机制尚不清楚。我们在这里描述了一个数学模型的免疫反应，提出了一个可能的解释循环模式的行为。我们发现，当T细胞的激活是自身抗原水平的增加函数时，可以发生类似于实验观察到的周期，而记忆细胞的产生则随着该水平的下降而下降。我们的模型扩展了以前关于T1 D中T细胞动力学的理论工作[A. F. M. Maree，P. Santamaria，and L. Edelstein-Keshet，国际免疫学，18（2006），pp. 1067-1077]，并导致有趣的非线性动力学，包括霍普夫和同宿分岔在生物合理的制度的参数。该模型导致了对周期的以下解释：高速率的β细胞死亡和相应的自身抗原升高，关闭了记忆细胞的生产，导致活化T细胞群体的缺口。一旦肽被非特异性机制清除，记忆池就会更新，从而产生循环行为。
Type 1 diabetes (T1D) is an autoimmune disease in which immune cells, notably T lymphocytes, target and kill the insulin-secreting pancreatic beta cells. Elevated blood-sugar levels and full-blown diabetes result once a large enough fraction of these beta cells has been destroyed. Recent investigation of T1D in animals, namely nonobese diabetic ( NOD) mice, has revealed large cyclic fluctuations in the levels of T cells circulating in the blood, weeks before the onset of diabetes [J. D. Trudeau, C. Kelly-Smith, C. B. Verchere, J. F. Elliott, J. P. Dutz, D. T. Finegood, P. Santamaria, and R. Tan, J. Clin. Invest., 111 (2003), pp. 217-223], but the mechanism for these oscillations is unclear. We here describe a mathematical model for the immune response that suggests a possible explanation for the cyclic pattern of behavior. We show that cycles similar to those observed experimentally can occur when activation of T cells is an increasing function of self-antigen level, whereas the production of memory cells declines with that level. Our model extends previous theoretical work on T-cell dynamics in T1D [A. F. M. Maree, P. Santamaria, and L. Edelstein-Keshet, Int. Immunol., 18 ( 2006), pp. 1067-1077], and leads to interesting nonlinear dynamics, including Hopf and homoclinic bifurcations in biologically reasonable regimes of parameters. The model leads to the following explanation for cycles: High rates of beta-cell death, and corresponding elevation of self-antigen, shut off memory-cell production, leading to a gap in the population of activated T cells. Once peptide has been cleared by nonspecific mechanisms, the memory pool is renewed, and the cyclic behavior results.