Immune signatures in chronic inflammatory diseases:Focus on metabolism and IL-6

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory rheumatic diseases that may develop with aging. GCA is one of the most common forms of vasculitis affecting large- and medium-sized blood vessels in elderly patients. Histologically, inflamed arteries of patients with GCA show infiltration of CD4+ T-cells and macrophages, but the pathogenesis of GCA is not yet fully understood. In this thesis, we first explored macrophage heterogeneity and their varying functions in GCA pathogenesis. Next, we studied markers of cellular metabolism and reported their role in vascular imaging and assisting in the diagnosis and monitoring of disease activity. A negative association between glucose and lipid metabolism, and the risk of developing GCA has been reported in population-based registry and cohort studies. As the data on this relation were limited, we further studied the metabolic features and prevalence of comorbidities in treatment-naïve patients with GCA and PMR, and compared these data with those of the population-based Dutch Lifelines cohort. We demonstrated metabolic disturbances in treatment-naïve GCA patients, suggesting the potential of metabolic factors as biomarkers. Glucocorticoids (GCs) are the mainstay for GCA treatment. Prolonged GC treatment is associated with GC-related adverse events. Here, we unveiled an increase in comorbidities and an unhealthy metabolic profile with GC treatment, indicating the need for prednisone-sparing targeted treatment in patients with GCA. One of the proven GC-sparing drugs is Tocilizumab, a drug that blocks the IL-6 receptor. Unfortunately, Tocilizumab is only effective in half of the patients. Therefore, we analyzed downstream interleukin-6 (IL-6) signalling in GCA patients in order to identify patients who will benefit from treatment with tocilizumab from those who will not benefit. The discoveries in this thesis demonstrate the crucial involvement of metabolism and the IL-6 signalling pathway in the progression of GCA and introduce a new perspective for diagnostic tools and therapeutic strategies in GCA

Evidence for increased interferon type I activity in CD8+ T cells in giant cell arteritis patients

INTRODUCTION: Giant cell arteritis (GCA) is a vasculitis of the medium- and large-sized arteries. Interferon type I (IFN-I) is increasingly recognized as a key player in autoimmune diseases and might be involved in GCA pathogenesis, however evidence is limited. IFN-I activates Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways, leading to increased expression of interferon stimulated genes. In this study, IFN-I activity in GCA is explored, focusing on CD8+ T cells.METHODS: Expression of phospho-STAT (pSTAT) 1, 3 and 5 was investigated in IFN-α-stimulated peripheral mononuclear cells (PBMCs) gated separately for CD8+ T cells of patients with GCA (n=18), healthy controls (HC, n=15) and infection controls (n=11) by Phosphoflow method combined with fluorescent cell barcoding technique. Furthermore, IFN-I induced myxovirus-resistance protein A (MxA) and CD8+ T cell expression was investigated by immunohistochemistry in temporal artery biopsies (TAB) of GCA patients (n=20) and mimics (n=20), and in aorta tissue of GCA (n=8) and atherosclerosis patients (n=14).RESULTS: pSTAT1 expression was increased in IFN-α stimulated CD8+ T cells from GCA patients, whereas no difference was observed in pSTAT3 and pSTAT5 expression. MxA was present in TABs of 13/20 GCA patients compared to 2/20 mimics and in 8/8 GCA+ compared to 13/14 GCA- aorta tissues. MxA location partially co-localized with CD8+T cells.CONCLUSIONS: Our results provide evidence for increased IFN-I activity in CD8+ T cells of GCA patients, both systemically and locally. These findings warrant further investigation regarding IFN-I induced biomarkers and IFN-I related novel therapeutic options in GCA.</p

Functionally Heterogenous Macrophage Subsets in the Pathogenesis of Giant Cell Arteritis:Novel Targets for Disease Monitoring and Treatment

Giant cell arteritis (GCA) is a granulomatous large-vessel vasculitis that affects adults above 50 years of age. In GCA, circulating monocytes are recruited to the inflamed arteries. With cues from the vascular microenvironment, they differentiate into macrophages and play important roles in the pathogenesis of GCA via pro-inflammatory cytokine production and vascular remodeling. However, a deeper understanding of macrophage heterogeneity in GCA pathogenesis is needed to assist the development of novel diagnostic tools and targeted therapies. Here, we review the current knowledge on macrophage heterogeneity and diverse functions of macrophage subsets in the pathogenesis of GCA. We next discuss the possibility to exploit their heterogeneity as a source of novel biomarkers and as targets for nuclear imaging. Finally, we discuss novel macrophage-targeted therapies and future directions for targeting these cells in GCA

Metabolic features and glucocorticoid-induced comorbidities in patients with giant cell arteritis and polymyalgia rheumatica in a Dutch and Danish cohort

OBJECTIVES: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are age-associated inflammatory diseases that frequently overlap. Both diseases require long-term treatment with glucocorticoids (GCs), often associated with comorbidities. Previous population-based cohort studies reported that an unhealthier metabolic profile might prevent the development of GCA. Here, we report metabolic features before start of treatment and during treatment in patients with GCA and PMR. METHODS: In the Dutch GCA/PMR/SENEX (GPS) cohort, we analysed metabolic features and prevalence of comorbidities (type 2 diabetes, hypercholesterolaemia, hypertension, obesity and cataract) in treatment-naïve patients with GCA (n=50) and PMR (n=42), and compared those with the population-based Lifelines cohort (n=91). To compare our findings in the GPS cohort, we included data from patients with GCA (n=52) and PMR (n=25) from the Aarhus cohort. Laboratory measurements, comorbidities and GC use were recorded for up to 5 years in the GPS cohort. RESULTS: Glycated haemoglobin levels tended to be higher in treatment-naïve patients with GCA, whereas high-density lipoprotein, low-density lipoprotein and cholesterol levels were lower compared with the Lifelines population. Data from the Aarhus cohort were aligned with the findings obtained in the GPS cohort. Presence of comorbidities at baseline did not predict long-term GC requirement. The incidence of diabetes, obesity and cataract among patients with GCA increased upon initiation of GC treatment. CONCLUSION: Data from the GCA and PMR cohorts imply a metabolic dysregulation in treatment-naïve patients with GCA, but not in patients with PMR. Treatment with GCs led to the rise of comorbidities and an unhealthier metabolic profile, stressing the need for prednisone-sparing targeted treatment in these vulnerable patients

Plasma Pyruvate Kinase M2 as a marker of vascular inflammation in Giant Cell Arteritis

OBJECTIVES: Giant Cell Arteritis (GCA) is a large vessel vasculitis in which metabolically active immune cells play an important role. GCA diagnosis is based on CRP/ESR and temporal artery biopsies (TABs), in combination with [18F]FDG-PET/CT relying on enhanced glucose uptake by glycolytic macrophages. Here, we studied circulating Pyruvate Kinase M2 (PKM2), a glycolytic enzyme, as a possible systemic marker of vessel wall inflammation in GCA. METHODS: Immunohistochemical detection of PKM2 was performed on inflamed (n = 12) and non-inflamed (n = 4) TABs from GCA patients and non-GCA (n = 9) patients. Dimeric PKM2 levels were assessed in plasma of GCA patients (n = 44), age-matched healthy controls (HC, n = 41), metastatic melanoma patients (n = 7) and infection controls (n = 11). CRP, ESR and macrophage markers calprotectin and YKL-40 were correlated with plasma PKM2 levels. To detect the cellular source of plasma PKM2 in tissue, double immunofluorescence staining was performed on inflamed GCA TABs. [18F]FDG-PET scans of 23 GCA patients were analyzed and maximum standard uptake values (SUVmax) and target to background ratios (TBR) were calculated. RESULTS: PKM2 is abundantly expressed in TABs of GCA patients. Dimeric PKM2 plasma levels were elevated in GCA and correlated with CRP, ESR, calprotectin, and YKL-40 levels. Elevated plasma PKM2 levels were downmodulated by GC-treatment. PKM2 was detected in both macrophages and T cells at the site of vascular inflammation. Circulating PKM2 levels correlated with average TBR PET scores. CONCLUSION: Elevated plasma PKM2 levels reflect active vessel inflammation in GCA and may assist in disease diagnosis and in disease monitoring

Functionally Heterogenous Macrophage Subsets in the Pathogenesis of Giant Cell Arteritis: Novel Targets for Disease Monitoring and Treatment

Giant cell arteritis (GCA) is a granulomatous large-vessel vasculitis that affects adults above 50 years of age. In GCA, circulating monocytes are recruited to the inflamed arteries. With cues from the vascular microenvironment, they differentiate into macrophages and play important roles in the pathogenesis of GCA via pro-inflammatory cytokine production and vascular remodeling. However, a deeper understanding of macrophage heterogeneity in GCA pathogenesis is needed to assist the development of novel diagnostic tools and targeted therapies. Here, we review the current knowledge on macrophage heterogeneity and diverse functions of macrophage subsets in the pathogenesis of GCA. We next discuss the possibility to exploit their heterogeneity as a source of novel biomarkers and as targets for nuclear imaging. Finally, we discuss novel macrophage-targeted therapies and future directions for targeting these cells in GCA

Akademik kütüphanelerde aşinalık durumunun ve işaret türlerinin yön bulmaya etkisi : Bilkent Üniversitesi Kütüphanesinde bir çalışma

Cataloged from PDF version of article.Thesis (M.S.): Bilkent University, Department of Interior Architecture and Environmental Design, İhsan Doğramacı Bilkent University, 2016.Includes bibliographical references (leaves 78-86).The purpose of the study is to investigate the relationship between utilized signage types, familiarity and confidence in respondents’ cognitive maps in academic libraries. Besides, it is to understand the influence of utilized signs on wayfinding performance. The experiment was administered in Bilkent University Library. Seventy one non-architecture university students from Bilkent University participated in the study, which was conducted in two parts. The first part was a library tour which involved reaching two target rooms. The second part utilized a questionnaire which inquired about respondents’ familiarity, confidence in their cognitive maps and signage. The study found that although newcomers had higher number of wrong turns and time spent to reach destination points, there was no difference in hesitation. As in other types of spaces, wrong turns and time spent decreased with increasing familiarity.by İdil Esen Duran.M.S