title: A mathematical model of immune activation with a unified self-nonself concept.
abstract: The adaptive immune system reacts against pathogenic nonself, whereas it normally remains tolerant to self. The initiation of an immune response requires a critical antigen(Ag)-stimulation and a critical number of Ag-specific T cells. Autoreactive T cells are not completely deleted by thymic selection and partially present in the periphery of healthy individuals that respond in certain physiological conditions. A number of experimental and theoretical models are based on the concept that structural differences discriminate self from nonself. In this article, we establish a mathematical model for immune activation in which self and nonself are not distinguished. The model considers the dynamic interplay of conventional T cells, regulatory T cells (Tregs), and IL-2 molecules and shows that the renewal rate ratio of resting Tregs to naïve T cells as well as the proliferation rate of activated T cells determine the probability of immune stimulation. The actual initiation of an immune response, however, relies on the absolute renewal rate of naïve T cells. This result suggests that thymic selection reduces the probability of autoimmunity by increasing the Ag-stimulation threshold of self reaction which is established by selection of a low number of low-avidity autoreactive T cells balanced with a proper number of Tregs. The stability analysis of the ordinary differential equation model reveals three different possible immune reactions depending on critical levels of Ag-stimulation: a subcritical stimulation, a threshold stimulation inducing a proper immune response, and an overcritical stimulation leading to chronic co-existence of Ag and immune activity. The model exhibits oscillatory solutions in the case of persistent but moderate Ag-stimulation, while the system returns to the homeostatic state upon Ag clearance. In this unifying concept, self and nonself appear as a result of shifted Ag-stimulation thresholds which delineate these three regimes of immune activation.
authors.affiliation: Department of Systems Immunology, Helmholtz Centre for Infection Research , Braunschweig , Germany.
authors.forename: Sahamoddin
authors.initials: S
authors.lastname: Khailaie
authors.affiliation: CIPCE, School of Electrical and Computer Engineering, College of Engineering, University of Tehran , Tehran , Iran.
authors.forename: Fariba
authors.initials: F
authors.lastname: Bahrami
authors.affiliation: Neuroscience Research Centre and Department of Physiology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences , Tehran , Iran.
authors.forename: Mahyar
authors.initials: M
authors.lastname: Janahmadi
authors.affiliation: Department of Experimental Immunology, Helmholtz Centre for Infection Research , Braunschweig , Germany.
authors.forename: Pedro
authors.initials: P
authors.lastname: Milanez-Almeida
authors.affiliation: Department of Experimental Immunology, Helmholtz Centre for Infection Research , Braunschweig , Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
authors.affiliation: Department of Systems Immunology, Helmholtz Centre for Infection Research , Braunschweig , Germany ; Bio Centre for Life Science, Technische Universität Braunschweig , Braunschweig , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer-Hermann
keywords: autoimmunity; autoreactive T cells; central tolerance; immune activation; peripheral tolerance; regulatory T cells