Modelling and finite time stability analysis of psoriasis pathogenesis

A new systems model of psoriasis is presented and analysed from the perspective of control theory. Cytokines are treated as actuators to the plant model that govern the cell population under the reasonable assumption that cytokine dynamics are faster than the cell population dynamics. The analysis of various equilibria is undertaken based on singular perturbation theory. Finite time stability and stabilisation has been studied in various engineering applications where the principal paradigm uses non-Lipschitz functions of the states. A comprehensive study of the finite time stability properties of the proposed psoriasis dynamics is carried out. It is demonstrated that the dynamics are finite time convergent to certain equilibrium points rather than asymptotically or exponentially convergent. This feature of finite time convergence motivates the development of a modi?ed version of the Michaelis-Menten function, frequently used in biology. This framework is used to model cytokines as fast finite time actuators

Role of subnetworks mediated by TNF α, IL-23/IL-17 and IL-15 in a network involved in the pathogenesis of psoriasis

Psoriasis is a chronic inflammatory skin disease clinically characterized by the appearance of red colored, well-demarcated plaques with thickened skin and with silvery scales. Recent studies have established the involvement of a complex signalling network of interactions between cytokines, immune cells and skin cells called keratinocytes. Keratinocytes form the cells of the outermost layer of the skin (epidermis). Visible plaques in psoriasis are developed due to the fast proliferation and unusual differentiation of keratinocyte cells. Despite that, the exact mechanism of the appearance of these plaques in the cytokine-immune cell network is not clear. A mathematical model embodying interactions between key immune cells believed to be involved in psoriasis, keratinocytes and relevant cytokines has been developed. The complex network formed of these interactions poses several challenges. Here, we choose to study subnetworks of this complex network and initially focus on interactions involving TNFα, IL-23/IL-17, and IL-15. These are chosen based on known evidence of their therapeutic efficacy. In addition, we explore the role of IL-15 in the pathogenesis of psoriasis and its potential as a future drug target for a novel treatment option. We perform steady state analyses for these subnetworks and demonstrate that the interactions between cells, driven by cytokines could cause the emergence of a psoriasis state (hyper-proliferation of keratinocytes) when levels of TNFα, IL-23/IL-17 or IL-15 are increased. The model results explain and support the clinical potentiality of anti-cytokine treatments. Interestingly, our results suggest different dynamic scenarios underpin the pathogenesis of psoriasis, depending upon the dominant cytokines of subnetworks. We observed that the increase in the level of IL-23/IL-17 and IL-15 could lead to psoriasis via a bistable route, whereas an increase in the level of TNFα would lead to a monotonic and gradual disease progression. Further, we demonstrate how this insight, bistability, could be exploited to improve the current therapies and develop novel treatment strategies for psoriasis

Linking quantitative radiology to molecular mechanism for improved vascular disease therapy selection and follow-up

Objective: Therapeutic advancements in atherosclerotic cardiovascular disease have improved the prevention of ischemic stroke and myocardial infarction. However, diagnostic methods for atherosclerotic plaque phenotyping to aid individualized therapy are lacking. In this thesis, we aimed to elucidate plaque biology through the analysis of computed-tomography angiography (CTA) with sufficient sensitivity and specificity to capture the differentiated drivers of the disease. We then aimed to use such data to calibrate a systems biology model of atherosclerosis with adequate granularity to be clinically relevant. Such development may be possible with computational modeling, but given, the multifactorial biology of atherosclerosis, modeling must be based on complete biological networks that capture protein-protein interactions estimated to drive disease progression. Approach and Results: We employed machine intelligence using CTA paired with a molecular assay to determine cohort-level associations and individual patient predictions. Examples of predicted transcripts included ion transporters, cytokine receptors, and a number of microRNAs. Pathway analyses elucidated enrichment of several biological processes relevant to atherosclerosis and plaque pathophysiology. The ability of the models to predict plaque gene expression from CTAs was demonstrated using sequestered patients with transcriptomes of corresponding lesions. We further performed a case study exploring the relationship between biomechanical quantities and plaque morphology, indicating the ability to determine stress and strain from tissue characteristics. Further, we used a uniquely constituted plaque proteomic dataset to create a comprehensive systems biology disease model, which was finally used to simulate responses to different drug categories in individual patients. Individual patient response was simulated for intensive lipid-lowering, anti-inflammatory drugs, anti-diabetic, and combination therapy. Plaque tissue was collected from 18 patients with 6735 proteins at two locations per patient. 113 pathways were identified and included in the systems biology model of endothelial cells, vascular smooth muscle cells, macrophages, lymphocytes, and the integrated intima, altogether spanning 4411 proteins, demonstrating a range of 39-96% plaque instability. Simulations of drug responses varied in patients with initially unstable lesions from high (20%, on combination therapy) to marginal improvement, whereas patients with initially stable plaques showed generally less improvement, but importantly, variation across patients. Conclusion: The results of this thesis show that atherosclerotic plaque phenotyping by multi-scale image analysis of conventional CTA can elucidate the molecular signatures that reflect atherosclerosis. We further showed that calibrated system biology models may be used to simulate drug response in terms of atherosclerotic plaque instability at the individual level, providing a potential strategy for improved personalized management of patients with cardiovascular disease. These results hold promise for optimized and personalized therapy in the prevention of myocardial infarction and ischemic stroke, which warrants further investigations in larger cohorts

The Impact of Clinical Application Protocols for Multiple Topical Products on Drug Delivery to the Skin

In the treatment of inflammatory skin conditions patients are often prescribed more than one topical product: a topical corticosteroid (TCS), an emollient and a topical antibiotic in cases of clinically infected skin. Despite widespread prescribing, there exists a remarkable lack of consensus between healthcare bodies on the optimum application protocol for the products, with recommendations made on the basis of clinical ‘expert’ opinion rather than evidence-based findings. Thus, the aim of this thesis was to evaluate the impact of clinical application protocols on the in vitro percutaneous absorption and skin retention of TCSs and topical antibiotics. A two component model was initially employed where the model TCSs (Elocon cream and Dermovate cream) were applied before or after six emollients, with a five or thirty minute interval. The Aron mix, a tailored extemporaneous therapy, was subsequently investigated to confirm whether the trends observed with TCSs and emollients were applicable to further complex mixtures of a topical antibiotic (Fucidin cream) and a TCS (Diprosone cream) substantially diluted in an emollient base (Diprobase cream). The findings demonstrated that applying multiple topical products to the skin can induce rapid formulation changes in situ or indeed in the extemporaneously prepared Aron mix, resulting in an altered performance of the medicinal products in a formulation specific manner. Mixing of the TCSs or topical antibiotic with an emollient dissimilar to the product base resulted in a multitude of effects including alterations in drug and solvent thermodynamic activities, rapid drug crystallisation and emollient excipients acting with penetration enhancing effects. Complementary drug stability investigations of the extemporaneous Aron mix did not support the typically recommended shelf life for the product (two weeks to one month), with significant decreases in drug content evident after seven days. In disagreement with clinical recommendations for TCSs and emollients, allowing up to thirty minutes between product applications was not sufficient to mitigate emollient effects on TCS drug delivery to the skin. Furthermore, application of the TCS after the emollient largely decreases drug delivery to the skin up to 4.4 fold compared to the TCS alone, findings which counter the clinical opinion that application of a TCS to well moisturised skin can increase drug delivery. Overall, the work presented in this thesis delivers a body of evidence previously unreported to suggest that applying multiple topical products to the skin at similar times may significantly alter the critical quality attributes of the product(s) to unpredictable extents and upon further investigation, these findings will support the advancement of conclusive clinical guidance

Dynamics of a network mediated by IL-36 and involved in the pathogenesis of psoriasis

The pathogenesis of the inflammatory, chronic, and common skin disease psoriasis involves immune cells, skin cells (keratinocytes), and the cytokines they secrete. Hyperproliferation and abnormal differentiation of keratinocytes are hallmarks of the disease. The roles of cytokines such as TNFα, IL-15, IL-17, and IL-23 in psoriasis have been studied through mathematical/computational models as well as experiments. However, the role of proinflammatory cytokine IL-36 in the onset and progression of psoriasis is still elusive. To explore the role of IL-36, we construct a network embodying indirect cell–cell interactions of a few immune and skin cells mediated by IL-36 based on existing knowledge. We also develop a mathematical model for the network and perform a global sensitivity analysis. Our results suggest that the model is most sensitive to a parameter that represents the level of cytokine IL-36. In addition, a steady-state analysis of the model suggests that an increase in the level of IL-36 could lead to the hyperproliferation of keratinocytes and, thus, psoriasis. Our analysis also highlights that the plaque formation and progression of psoriasis could occur through either a gradual or a switch-like increase in the keratinocyte population. We propose that the switch-like increase would be due to a bistable behavior of the network toward either a psoriatic or healthy state and could be used as a novel treatment strategy

Somatic evolution in healthy and chronically inflamed colon and skin

The human body is made up of trillions of cells which cooperate to reproduce their genetic material. While all the cells are a part of a whole, each is also an individual and will selfishly give rise to a clonal expansion of cells within a tissue given the chance, even to the detriment of the organism. This thesis discusses the evolutionary forces acting on cells within the body, specifically on epithelial cells in the colon and skin. After a general introduction of the evolutionary forces acting on normal cells and the methods used to study them, Chapter 2 focuses specifically on genetic drift within the colon, where clones expand through the process of crypt fission. I apply a statistical framework called Approximate Bayesian Computation to estimate the crypt fission rate in the normal colon and in individuals with Familial adenomatous polyposis (FAP). I estimate the rate of crypt fission to be one every 27 years in the normal colon and one every 13 years in (FAP). In Chapter 3, I describe somatic evolution in the colon under conditions of chronic inflam- mation. I used whole-genome sequencing of individual colonic crypts from patients with inflammatory bowel disease (IBD) to show that the IBD-colon is characterized by a higher mutation burden and larger clonal expansions than the healthy colon. I also show that muta- tions in immune-related genes, including PIGR, ZC3H12A and genes in the interleuking 17 and toll-like receptor pathways, are under positive selection in the colons of IBD patients and may contribute to the disease pathogenesis. In Chapter 4, I focus on the skin. I performed whole-exome sequencing of microbiopsies of epidermis from patients with psoriasis, a second chronic inflammatory disease. In contrast to IBD, I did not find increased mutation burden and clonal spread in psoriasis, except when the skin had been treated with psoralens + UVA (PUVA) phototreatment. The selection landscape of psoriatic skin resembles that of normal skin, and mutations in NOTCH1, FAT1, TP53, PPM1D and NOTCH2 are positively selected. ZFP36L2 was the only gene found to be enriched in mutations that has not been previously reported in normal skin, but it is as yet uncertain if selection of ZFP36L2 mutant cells is a feature specific to psoriatic skin or not. Finally, Chapter 5 discusses my findings in the broader context of cancer and complex-trait genomics. I discuss how a causal relationship between somatic evolution and non-neoplastic diseases may be established and the different ways somatic evolution may affect disease progression for good or ill. I further discuss how to design a study to search for germline determinants of somatic evolution and the need for developing methods to enable such studies to be conducted at scale.Wellcome Trus

Skin Tissue Models

Skin Tissue Models provides a translational link for biomedical researchers on the interdisciplinary approaches to skin regeneration. As the skin is the largest organ in the body, engineered substitutes have critical medical application to patients with disease and injury - from burn wounds and surgical scars, to vitiligo, psoriasis and even plastic surgery. This volume offers readers preliminary description of the normal structure and function of mammalian skin, exposure to clinical problems and disease, coverage of potential therapeutic molecules and testing, skin substitutes, models as study platforms of skin biology and emerging technologies. The editors have created a table of contents which frames the relevance of skin tissue models for researchers as platforms to study skin biology and therapeutic approaches for different skin diseases, for clinicians as tissue substitutes, and for cosmetic and pharmaceutical industries as alternative test substrates that can replace animal models. Offers descriptions of the normal structure/function of mammalian skin, exposure to clinical problems, and more Presents coverage of skin diseases (cancer, genodermatoses, vitiligo and psoriasis) that extends to clinical requirements and skin diseases in vitro models Addresses legal requirements and ethical concerns in drugs and cosmetics in vitro testing Edited and authored by internationally renowned group of researchers, presenting the broadest coverage possible. © 2018 Elsevier Inc. All rights reserved.(undefined)info:eu-repo/semantics/publishedVersio

From practice to theory: computational studies on fluorescence detection and laser therapy in dermatology

Computational studies on light‐tissue interactions in medical treatment and diagnosis have offered deeper insights in the processes underlying laser treatments and fluorescence measurements. I apply this approach in the study of fluorescence detection and of laser therapy. First, I investigate three methods of fluorescence detection and the reported contrast between healthy skin and malignant tissue. I varied the concentration of haemoglobin in the target, the concentration of melanin in the epidermis, the scattering of light in the skin, the depth at which the target is located in the skin, the width of the target, the thickness of the target, the concentration of photosensitizer in the target, and the concentration of photosensitizer in the skin. My findings confirm previous clinical studies in that the auto‐fluorescence corrected fluorescence detection method generally shows a higher contrast than the other methods. The results support earlier clinical studies and are in accordance with expert experience. Second, I study laser therapy for psoriasis. In a series of simulations, I analyse three types of pulsed dye laser systems and one IPL system. The investigated biological effects are heat shock proteins, hyperthermic tissue damage and vasoconstriction of the microvasculature. The changes in the skin concern blood volume, blood oxygenation and scattering in the epidermis. The calculations show that there are some notable differences in the effect changes in the composition of psoriatic tissue has on the efficacy of laser and IPL therapy. Still, Inter‐device variance was more prominent than intra‐geometry variance. My study adds to the understanding of fluorescence detection of keratinocyte skin cancers, as well as that of laser therapy for psoriasis. Additionally, it offers potential avenues for increasing the efficacy and efficiency of these therapies

MAIT cells and the microbiome

Mucosal associated invariant T (MAIT) cells are innate-like T lymphocytes, strikingly enriched at mucosal surfaces and characterized by a semi-invariant αβ T cell receptor (TCR) recognizing microbial derived intermediates of riboflavin synthesis presented by the MHC-Ib molecule MR1. At barrier sites MAIT cells occupy a prime position for interaction with commensal microorganisms, comprising the microbiota. The microbiota is a rich source of riboflavin derived antigens required in early life to promote intra-thymic MAIT cell development and sustain a life-long population of tissue resident cells. A symbiotic relationship is thought to be maintained in health whereby microbes promote maturation and homeostasis, and in turn MAIT cells can engage a TCR-dependent “tissue repair” program in the presence of commensal organisms conducive to sustaining barrier function and integrity of the microbial community. MAIT cell activation can be induced in a MR1-TCR dependent manner or through MR1-TCR independent mechanisms via pro-inflammatory cytokines interleukin (IL)-12/-15/-18 and type I interferon. MAIT cells provide immunity against bacterial, fungal and viral pathogens. However, MAIT cells may have deleterious effects through insufficient or exacerbated effector activity and have been implicated in autoimmune, inflammatory and allergic conditions in which microbial dysbiosis is a shared feature. In this review we summarize the current knowledge on the role of the microbiota in the development and maintenance of circulating and tissue resident MAIT cells. We also explore how microbial dysbiosis, alongside changes in intestinal permeability and imbalance between pro- and anti-inflammatory components of the immune response are together involved in the potential pathogenicity of MAIT cells. Whilst there have been significant improvements in our understanding of how the microbiota shapes MAIT cell function, human data are relatively lacking, and it remains unknown if MAIT cells can conversely influence the composition of the microbiota. We speculate whether, in a human population, differences in microbiomes might account for the heterogeneity observed in MAIT cell frequency across mucosal sites or between individuals, and response to therapies targeting T cells. Moreover, we speculate whether manipulation of the microbiota, or harnessing MAIT cell ligands within the gut or disease-specific sites could offer novel therapeutic strategies