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T Helper 17 Cell Activation in Response to Candida Albicans in Autoimmune Polyendocrine Syndrome Type 1

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T Helper 17 Cell Activation in Response to Candida Albicans in Autoimmune Polyendocrine Syndrome Type 1 T helper 17 cell activation in response to Candida albicans in autoimmune polyendocrine syndrome type 1 Iulia Karlsson Degree project in biology, Master of science (2 years), 2010 Examensarbete i biologi 45 hp till masterexamen, 2010 Biology Education Centre and Biology Education Centre and Department of Medical Sciences, Uppsala University, Uppsala University Supervisor: As. Prof. Anna Lobell Table of Contents Abbreviations.........................................................................................................................2 Abstract..................................................................................................................................3 Introduction Autoimmune polyendocrine syndrome type 1 .....................................................................4 Chronic mucocutaneous candidiasis....................................................................................4 Th17 cells...........................................................................................................................5 Previous findings................................................................................................................5 Hypothesis and goals ..........................................................................................................6 Methods Cell purification..................................................................................................................7 Cell culture.........................................................................................................................7 Intracellular cytokine staining.............................................................................................7 ELISpot..............................................................................................................................7 Real-time RT-PCR .............................................................................................................8 Statistical analyses..............................................................................................................8 Results Population of rare Th17 cells abtained by flow cytometry without ionomycin pre- stimulation ...................................................................................................................9 C. albicans increased the amount of IL-17A + cells in controls and APS-1 patients..............9 Blocking of IL-1β and IL-6 cytokines did not modify Th17 reactivity.................................9 IL-17A contribution to pathogenesis.................................................................................10 The exacerbated Th17 cell reactivity in APS-1 is C. albicans -specific ..............................10 Treg cells number and Foxp3 mRNA expression were not affected by C. albicans stimulation, both in APS-1 patients and in controls......................................................10 Upregulated IFN-γ mRNA after stimulation with C. albicans ..........................................10 IL-1β and IL-6 mRNA levels vere not elevated by C. albicans stimulation ......................11 Discussion............................................................................................................................12 References............................................................................................................................14 Figures 1-7 ...........................................................................................................................16 Acknowledgements ..............................................................................................................23 1 Abbreviations AIRE autoimmune regulator APECED autoimmune polyendocrinopathy candidiasis ectodermal dystrophy APS-1 autoimmune polyendocrine syndrome type 1 CMC chronic mucocutaneous candidiasis FACS fluorescence-activated cell sorting HCA human Candida albicans PBMCs peripheral blood mononuclear cells PGN peptidoglycan TGF tumor growth factor 2 Abstract Rare autosomal recessive disorder - autoimmune polyendocrine syndrome type 1 (APS-1), also known as autoimmune polyendocrine candidiasis ectodermal dystrophy (APECED) - is caused by mutation in the autoimmune regulator gene and characterised by chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and adrenal failure. CMC is C. albicans -caused infection that occurs in 100% of APS-1 patients, most often coming as initial symtpom and setting on very early in patient’s life. Patients in a constant need of antifungal drugs are most often on a life-long drug treatment, which creates a major risk to become colonized with drug-resistant strains. The main risk factors that predispose to such severe opportunistic infection are defects of cell-mediated immunity, including dysregulated Th-cell reactivity. Th17 cells are thought to be involved in several autoimmune and inflammatory conditions and could probably contribute to the pathogenesis of CMC in APS-1 as well. We studied Th17 reactivity ex vivo in response to C. albicans and other antigens in four APS-1 patients and sex- and age-matched healthy controls. After 3 days of stimulation we could detect C. albicans-specific enlargement of Th17-cell fraction, increase in IL-17A mRNA expression and a dramatic increase of IL-17A cytokine production ( p < 0.05) in peripheral blood mononuclear cells (PBMCs) purified from APS-1 patients. In healthy controls the changes in corresponding cell population, mRNA and protein expression were significantly smaller compared to APS-1, suggesting an important role for Th17 cells and IL-17A in chronic mucocutaneous candidiasis accompanying APS-1. 3 Introduction Autoimmune polyendocrine syndrome type 1 (APS-1) Autoimmunity is a state of an organism when its immune system attacks self matter. It is the result of a complex interaction between genetic and environmental factors, most of which have not been identified (Burek and Talor 2009). In human autoimmune diseases (as a group), a large number of antibodies and T cells directed against functional cell structures (e.g. nucleic acids, nuclear molecules, receptors) can be found. Autoantibodies and autoimmune T cells can also be present in other clinical conditions, such as cancer or acute tissue damage, as well as in individuals with no clinical manifestations of a disease. In order to avoid autoimmune conditions, B and T cells must bypass multiple checkpoint mechanisms during their maturation, and the failure of both central and peripheral tolerance mechanisms is favouring the development of autoimmunity. In APS-1, one mechanism of central tolerance – negative selection – is impaired, which allows self-reactive thymocytes to escape clonal deletion and cause substantial damage to tissues and organs of the body. Several genes expressed by medullary thymic epithelial cells are important for maintenance of self-tolerance, and autoimmune regulator ( AIRE ) is shown to be one of them (Peterson, Org et al. 2008). Aire-deficient (Aire 0/0 ) mice demonstrate a role for Aire in negative selection of T cells in the thymus (Anderson, Venanzi et al. 2005) through activating the expression of peripheral tissue-specific antigens. Additional roles for Aire in negative selection have also been reported (Mathis and Benoist 2007). Mutations in AIRE gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED; also known as APS-1), which is a rare monogenic recessive disorder characterized by autoimmune processes localized at endocrine glands and caused by the presence of autoantibodies and T helper (Th)-cells specific for multiple self antigens (Peterson, Org et al. 2008). Several endocrine glands and other organs may be destroyed or damaged by the patient’s immune system (Rautemaa, Hietanen et al. 2007). Most commonly, patients with APS-1 have chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and Addison’s disease, although the range of clinical features varies among the patients (Perheentupa 2006). Chronic mucocutaneous candidiasis (CMC) CMC in APS-1 patients is caused by Candida albicans ( C. albicans) infection, including localised invasion of the mucosa that can lead to oral and oesophageal squamous cell carcinoma (Rautemaa, Hietanen et al. 2007). The molecular basis of the increased susceptibility to CMC in APS-1 patients is still poorly understood. C. albicans is a dimorphic organism capable of colonizing, infecting and persisting on mucosal surfaces. It is a human commensal fungus that under certain circumstances can invade mucosa through a phenotype switch from yeast to hyphal form, and may seek to induce a protective host immune response to permit its own survival (Romani 1999). Among 4 the fungal pathogens, Candida spp. are the most predominant causes of invasive infections and C. albicans is the most common causative species of candidaemia (Shao, Huang et al. 2007). In adult immune-competent individuals, immune defence against fungal infections is achieved through a cooperative effort of the innate and adaptive immune systems. When infectious fungi can breach early lines of defence, generation of a dominant Th1-cell response mediated by interleukin-12 (IL-12) will ensue. Through production of the signature cytokine interferon- gamma (IFN-γ) and providing help for opsonizing antibodies, Th1 cells can optimally activate phagocytes at cites of infection. Dendritic cells producing IL-10 and T regulatoty (T reg ) cells activated by this cytokine are needed to provide a proper coordination and regulation
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