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Modelling the onset of Type 1 diabetes: can impaired macrophage phagocytosis make the difference between health and disease?
- Source :
- Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences. 364:1267-1282
- Publication Year :
- 2006
- Publisher :
- The Royal Society, 2006.
-
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 theCopenhagen model(Freiesleben De Blasioet al. 1999Diabetes48, 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 cytokinesonlywhen 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.
- Subjects :
- Programmed cell death
Necrosis
General Mathematics
Phagocytosis
General Physics and Astronomy
Apoptosis
Inflammation
Cell Communication
Nod
Biology
Islets of Langerhans
Mice
medicine
Animals
Computer Simulation
NOD mice
Type 1 diabetes
Models, Immunological
General Engineering
Macrophage Activation
medicine.disease
Disease Models, Animal
Diabetes Mellitus, Type 1
Immunology
Cytokines
medicine.symptom
Subjects
Details
- ISSN :
- 14712962 and 1364503X
- Volume :
- 364
- Database :
- OpenAIRE
- Journal :
- Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences
- Accession number :
- edsair.doi.dedup.....e2c13ad8f48238033cd3a1cfa0b06468