Modeling immune complex-mediated autoimmune inflammation.
A number of autoimmune diseases are thought to feature a particular type of self-sustaining inflammation, caused by the deposition of immune complexes (IC) in the inflamed tissue and a consequent activation of local effector cells. The persistence of this inflammation is due to a positive feedback loop, where autoantigen particles released as part of the tissue damage caused by the inflammation stimulate autoreactive B cells, leading to the formation of further immune complexes and their subsequent deposition. We present a mathematical model for the exploration of IC-mediated autoimmune inflammation and its clinical implications. We characterize the possible differences between normal individuals and those susceptible to such inflammation, and show that both random perturbations and bifurcations can lead to disease onset. Our model explains how defects in the mechanisms responsible for cellular debris clearance contribute to the development of disease, in agreement with empirical evidence. Moreover, we show that parameters governing the dynamics of immune complexes, such as their clearance rate, have an even stronger effect in determining the behavior of the system. We demonstrate the existence of hysteresis, implying that once IC-mediated autoimmune inflammation is triggered, its long-term suppression may be difficult to achieve. Our results can serve to guide the development of novel therapies to autoimmune diseases involving this type of inflammation.
Arazi
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Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel. arnon.arazi@live.biu.ac.il
Neumann
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AU
D000465:Algorithms; D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology* / Q000628:therapy; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation; D005246:Feedback; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000276:immunology*; D018448:Models, Immunological
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens