Modeling dynamic changes in type 1 diabetes progression: quantifying beta-cell variation after the appearance of islet-specific autoimmune responses.
Type 1 diabetes (T1DM) is a chronic autoimmune disease with a long prodrome, which is characterized by dysfunction and ultimately destruction of pancreatic beta-cells. Because of the limited access to pancreatic tissue and pancreatic lymph nodes during the normoglycemic phase of the disease, little is known about the dynamics involved in the chain of events leading to the clinical onset of the disease in humans. In particular, during T1DM progression there is limited information about temporal fluctuations of immunologic abnormalities and their effect on pancreatic beta-cell function and mass. Therefore, our understanding of the pathoetiology of T1DM relies almost entirely on studies in animal models of this disease. In an effort to elucidate important mechanisms that may play a critical role in the progression to overt disease, we propose a mathematical model that takes into account the dynamics of functional and dysfunctional beta-cells, regulatory T cells, and pathogenic T cells. The model assumes that all individuals carrying susceptible HLA haplotypes will develop variable degrees of T1DM-related immunologic abnormalities. The results provide information about the concentrations and ratios of pathogenic T cells and regulatory T cells, the timing in which beta-cells become dysfunctional, and how certain kinetic parameters affect the progression to T1DM. Our model is able to describe changes in the ratio of pathogenic T cells and regulatory T cells after the appearance of islet antibodies in the pancreas. Finally, we discuss the robustness of the model and its ability to assist experimentalists in designing studies to test complicated theories about the disease.
Nelson
Patrick
P
University of Michigan, Department of Mathematics, Center for Computational Medicine and Bioinformatics, 100 Washtenaw Ave, Ann Arbor, MI 48109-2218, USA. pwn@umich.edu
Smith
Noah
N
Ciupe
Stanca
S
Zou
Weiping
W
Omenn
Gilbert S
GS
Pietropaolo
Massimo
M
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055641:Mathematical Concepts; D051379:Mice; D018448:Models, Immunological; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
D001323:Autoantibodies; D007328:Insulin; C024211:islet cell antibody; D005947:Glucose