title: Modelling the onset of Type 1 diabetes: can impaired macrophage phagocytosis make the difference between health and disease?
abstract: A wave of apoptosis (programmed cell death) occurs normally in pancreatic beta-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 Diabetes 48, 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.
authors.affiliation: Theoretical Biology/Bioinformatics, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands. a.f.m.maree@bio.uu.nl
authors.forename: Athanasius F M
authors.initials: AF
authors.lastname: Marée
authors.forename: Richard
authors.initials: R
authors.lastname: Kublik
authors.forename: Diane T
authors.initials: DT
authors.lastname: Finegood
authors.forename: Leah
authors.initials: L
authors.lastname: Edelstein-Keshet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D003198:Computer Simulation; D016207:Cytokines / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004195:Disease Models, Animal; D007515:Islets of Langerhans / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology*; D051379:Mice; D018448:Models, Immunological; D010587:Phagocytosis / Q000276:immunology*
chemical_list: D016207:Cytokines