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Modelling the onset of Type 1 diabetes: Can impaired macrophage phagocytosis make the difference between health and disease?

Maree, A.F.M., Kublik, R., Finegood, D.T. and Edelstein-Keshet, L. 2006. Modelling the onset of Type 1 diabetes: Can impaired macrophage phagocytosis make the difference between health and disease? Philosophical Transactions A: Mathematical, Physical and Engineering Sciences 364 (1842) , pp. 1267-1282. 10.1098/rsta.2006.1769

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Abstract

A wave of apoptosis (programmed cell death) occurs normally in pancreatic β-cells of newborn mice. We previously showed that macrophages from non-obese diabetic (NOD) mice become activated more slowly and engulf apoptotic cells at a lower rate than macrophages from control (Balb/c) mice. It has been hypothesized that this low clearance could result in secondary necrosis, escalating inflammation and self-antigen presentation that later triggers autoimmune, Type 1 diabetes (T1D). We here investigate whether this hypothesis could offer a reasonable and parsimonious explanation for onset of T1D in NOD mice. We quantify variants of the Copenhagen model (Freiesleben De Blasio et al. 1999 Diabetes48, 1677), based on parameters from NOD and Balb/c experimental data. We show that the original Copenhagen model fails to explain observed phenomena within a reasonable range of parameter values, predicting an unrealistic all-or-none disease occurrence for both strains. However, if we take into account that, in general, activated macrophages produce harmful cytokines only when engulfing necrotic (but not apoptotic) cells, then the revised model becomes qualitatively and quantitatively reasonable. Further, we show that known differences between NOD and Balb/c mouse macrophage kinetics are large enough to account for the fact that an apoptotic wave can trigger escalating inflammatory response in NOD, but not Balb/c mice. In Balb/c mice, macrophages clear the apoptotic wave so efficiently, that chronic inflammation is prevented.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Biosciences
Publisher: Royal Society, The
ISSN: 1364-503X
Last Modified: 18 Feb 2019 09:00
URI: https://orca.cardiff.ac.uk/id/eprint/119507

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