Bifurcations and multistability in a model of cytokine-mediated autoimmunity

This paper investigates the dynamics of immune response and autoimmunity with particular emphasis on the role of regulatory T cells (Tregs), T cells with different activation thresholds, and cytokines in mediating T cell activity. Analysis of the steady states yields parameter regions corresponding to regimes of normal clearance of viral infection, chronic infection, or autoimmune behavior, and the boundaries of stability and bifurcations of relevant steady states are found in terms of system parameters. Numerical simulations are performed to illustrate different dynamical scenarios, and to identify basins of attraction of different steady states and periodic solutions, highlighting the important role played by the initial conditions in determining the outcome of immune interactions

Time-delayed model of autoimmune dynamics

Among various environmental factors associated with triggering or exacerbating autoimmune response, an important role is played by infections. A breakdown of immune tolerance as a byproduct of immune response against these infections is one of the major causes of autoimmune disease. In this paper we analyse the dynamics of immune response with particular emphasis on the role of time delays characterising the infection and the immune response, as well as on interactions between different types of T cells and cytokines that mediate their behaviour. Stability analysis of the model provides insights into how different model parameters affect the dynamics. Numerical stability analysis and simulations are performed to identify basins of attraction of different dynamical states, and to illustrate the behaviour of the model in different regime

Low doses of ionizing radiation induce immune-stimulatory responses in isolated human primary monocytes

The health effects arising from exposure to low doses of ionizing radiation are of particular concern, mainly due to the increased application of diagnostic and therapeutic X-ray modalities. The mechanisms behind the cell and tissue responses to low doses remain to be elucidated. Accumulating evidence suggests that low doses of ionizing radiation induce activation of the immune response; however, the processes involved have yet to be adequately investigated. Monocytes are key players in the induction of an immune response. Within the context of this study, we investigated the activation of toll-like receptors (TLRs), mitogen-activated protein kinases (MAPKs) and NF-B signaling in isolated human primary monocytes in response to low doses (0.05 and 0.1 Gy) and a high dose (1 Gy) of ionizing radiation. Using quantitative RT-PCR and ELISA techniques, our results showed a positive regulation of TLR signaling in response to low doses but a less significant response at high doses. This activation was demonstrated via the activation of TLR signaling molecules (HMGB1, TLR4, TLR9, MyD88 and IRAK1). Furthermore, and in contrast to the high dose, the low doses showed increased phosphorylation levels of the protein IB, and therefore positive signaling of the NF-B pathway. This result denotes pro-survival and pro-inflammatory responses. Additionally, MAPKs were activated in response to 0.05 Gy, while 0.1 and 1 Gy showed a downregulatory trend that may be related to activation of the PF4 gene. On the other hand, there was highly significant involvement of activated p53 and damaged genes in response to high but not low doses. In conclusion, this study addressed the need to re-evaluate health risks arising from exposure to low doses of ionizing radiation, particularly in view of the accumulating evidence reporting inflammatory and oncogenic consequences from these exposures

HSP: Bystander Antigen in Atopic Diseases?

Over the last years insight in the complex interactions between innate and adaptive immunity in the regulation of an inflammatory response has increased enormously. This has revived the interest in stress proteins; proteins that are expressed during cell stress. As these proteins can attract and trigger an immunological response they can act as important mediators in this interaction. In this respect, of special interest are proteins that may act as modulators of both innate and adaptive immunity. Heat shock proteins (HSPs) are stress proteins that have these, and more, characteristics. More than two decades of studies on HSPs has revealed that they are part of intrinsic, “natural” mechanisms that steer inflammation. This has provoked comprehensive explorations of the role of HSPs in various human inflammatory diseases. Most studies have focused on classical autoimmune diseases. This has led to the development of clinical studies with HSPs that have shown promise in Phase II/III clinical trials. Remarkably, only very little is yet known of the role of HSPs in atopic diseases. In allergic disease a number of studies have investigated the possibility that allergen-specific regulatory T cell (Treg) function is defective in individuals with allergic diseases. This raises the question whether methods can be identified to improve the Treg repertoire. Studies from other inflammatory diseases have suggested HSPs may have such a beneficial effect on the T cell repertoire. Based on the immune mechanisms of atopic diseases, in this review we will argue that, as in other human inflammatory conditions, understanding immunity to HSPs is likely also relevant for atopic diseases. Specifically, we will discuss why certain HSPs such as HSP60 connect the immune response to environmental antigens with regulation of the inflammatory response. Thus they provide a molecular link that may eventually even help to better understand the immune pathological basis of the hygiene hypothesis

Autoimmune Consequences of Histone Deimination during Neutrophil Activation

Tolerance blocks the expression of autoantibodies, whereas autoimmunity promotes it. How tolerance breaks and autoantibody production begins, thus, are crucial questions for the understanding and treatment of autoimmune diseases. Evidence implicates cell death and autoantigen modifications in the initiation of autoimmune reactions. One form of neutrophil cell death deserves attention because it occurs as a consequence of neutrophil activation, requires the post-translational modification of histones and results in the extracellular release of chromatin. The extracellular chromatin incorporates histones in which arginines have been converted to citrullines by peptidylarginine deiminase IV (PAD4) creating structures that capture or trap bacterial pathogens. Neutrophil extracellular traps (NETs), as these structures are known, generate an extracellular complex of deiminated histones and bacterial cell adjuvants. The complex of bacterial antigens and deiminated chromatin may be internalized by host phagocytes during inflammatory conditions, as arise during bacterial infections or chronic autoinflammatory disorders. The uptake and processing of deiminated chromatin together with bacterial adjuvants by phagocytes may induce the presentation of modified histone epitopes and co-stimulation, thus yielding a powerful stimulus to break tolerance. To test the hypothesis that NETs can lead to autoimmunity, we measured autoantibodies to deiminated histones in human autoimmune disorders. We detected autoantibodies to deiminated histones in Felty\u27s syndrome (FS) patients, whereas autoantibodies from Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) patients did not distinguish deiminated from non-deiminated histones. FS autoantibodies colocalized with deiminated histone H3 in LPS-treated neutrophils suggesting activated neutrophils as the source of autoantigens. In addition, we identified and characterized deimination of linker histone H1 and found rare autoantibodies to deiminated H1 in SLE and Sjogren\u27s syndrome patients. We also studied sera of autoimmune lupus prone mice to determine if they would recognize deiminated histones and found that deimination represses binding of murine lupus autoantibodies to histones. The inability of immunoglobin from sera of lupus mice to recognize deiminated histones suggests the presence of effective tolerance to NET components released during innate neutrophil response to infections. Our finding of antibodies to deiminated histones in Felty\u27s syndrome supports the idea that tolerance to deiminated histones is compromised only in exceptional circumstances. Understanding the tolerance mechanism to deiminated histones and how they are compromised in patients could be useful to design strategies for the prevention and treatment of many autoimmune disorders

Biological Modulation of the Treg:Teff Ratio: From Immunosuppression to Immunoactivation

T cell-mediated immunomodulation can be, in simple terms, defined as altering the normal Treg:Teff ratio. Immunosuppression skews the net Treg:Teff ratio toward the ‘tolerogenic’ Treg component, while immunoactivation skews the response toward the ‘proinflammatory’ Teff component. In the treatment of autoimmune diseases, achieving an immunosuppressive state is a desirable goal in order to prevent ongoing injury by activated Teff cells. In contrast, an innate, or induced, immunosuppressive state can be deleterious and prevent pathogen-induced disease while allow for the progression of cancer. Indeed, a current goal of cancer therapy is attenuating an existing endogenous immunosuppressive state that prevents effective T cell-mediated immunorecognition of cancer cells. Thus, the biological modulation of the Treg:Teff ratio provides a unique approach for treating both autoimmune diseases and cancers. Using a biomanufacturing system, miRNA-enriched immunotherapeutic has been generated that either induce (TA1) or overcome (IA1) an immunosuppressive state. As will be shown, these therapeutics show efficacy both in vitro and in vivo in the prevention of autoimmune Type 1 diabetes and in enhancing the ability of resting immune cells to recognize and inhibit cancer cell growth. The successful development of these cost-effective, and easily biomanufactured, secretome-based therapeutics may prove useful in treating both autoimmune diseases and cancer

Doctor of Philosophy

dissertationA fundamental challenge for the immune system is the distinction between self and nonself, or infected and uninfected. Autoimmune disease arises when the immune response mounts an immune response against the hosts tissues. Via a mathematical model, we show that the immune system can distinguish self from nonself via the interaction of T-cells and and dendritic cells (DCs) and explain how autoimmunity is avoided in most people most of the time. The NOD mouse develops Type 1 diabetes, an autoimmune disease, spontaneously with an incidence of about 80% in females. The progression of Type 1 diabetes may be either accelerated or delayed by viral infection. We first create a mathematical model to understand the factors that affect progression in uninfected mice and how it may be interrupted via certain treatments. We categorize which types of viral infection should accelerate Type 1 diabetes or delay. We find that the timing of infection is important, as well as the cell type infected

IL-15 augments TCR-induced CD4⁺ T cell expansion in vitro by inhibiting the suppressive function of CD25High CD4⁺ T cells

Due to its critical role in NK cell differentiation and CD8(+) T cell homeostasis, the importance of IL-15 is more firmly established for cytolytic effectors of the immune system than for CD4(+) T cells. The increased levels of IL-15 found in several CD4(+) T cell-driven (auto-) immune diseases prompted us to examine how IL-15 influences murine CD4(+) T cell responses to low dose TCR-stimulation in vitro. We show that IL-15 exerts growth factor activity on both CD4(+) and CD8+ T cells in a TCR-dependent and Cyclosporin A-sensitive manner. In CD4(+) T cells, IL-15 augmented initial IL-2-dependent expansion and once IL-15R alpha was upregulated, IL-15 sustained the TCR-induced expression of IL-2/15R beta, supporting proliferation independently of secreted IL-2. Moreover, IL-15 counteracts CD4(+) T cell suppression by a gradually expanding CD25(High)CD4(+) T cell subset that expresses Foxp3 and originates from CD4(+)CD25(+) Tregs. These in vitro data suggest that IL-15 may dramatically strengthen the T cell response to suboptimal TCR-triggering by overcoming an activation threshold set by Treg that might create a risk for autoimmune pathology

Regulatory T Cells Are Dispensable for Tolerance to RBC Antigens

Autoimmune hemolytic anemia (AIHA) occurs when pathogenic autoantibodies against red blood cell (RBC) antigens are generated. Whilst the basic disease pathology of AIHA is well studied, the underlying mechanism(s) behind the failure in tolerance to RBC autoantigens are poorly understood. Thus, to investigate the tolerance mechanisms required for the establishment and maintenance of tolerance to RBC antigens, we developed a novel murine model. With this model, we evaluated the role of regulatory T cells (Tregs) in tolerance to RBC-specific antigens. Herein, we show that neither sustained depletion of Tregs nor immunization with RBC-specific proteins in conjunction with Treg depletion led to RBC-specific autoantibody generation. Thus, these studies demonstrate that Tregs are not required to prevent autoantibodies to RBCs and suggest that other tolerance mechanisms are likely involved