Introduction: The main aim of this PhD thesis was to gain further insight into the pathogenetic mechanisms of giant cell arteritis (GCA) and to relate these to arterial ultrasound (nowadays the test of choice in the diagnosis of giant cell vasculitis). In the studies carried out as part of this PhD, we examined the expression of microRNAs (miRNAs) in temporal arteries (TA) of patients and their target genes. We phenotyped and quantified immune cells constituting the inflammatory infiltrate in temporal artery biopsies (TAB) from GCA patients and correlated the histopathological data obtained with miRNA expression. In addition, we evaluated the correlation between TA ultrasound (US) findings and, histopathological data and the expression of selected miRNAs on the other hand.
Methods: In the first part of the study, we evaluated the expression of 28 miRNAs in TAB specimens from 30 patients with histologically confirmed disease and compared the results with the expression of miRNAs in TAB specimens from 16 patients without histologically confirmed disease and 22 subjects without GCA. In the second part of the study, we quantitatively assessed histological changes in temporal arteries of patients with GCA using histopathological and immunohistochemical techniques. In the third part of the study, we examined how findings on US examination of the TA correlated with histopathological changes of the TA and with miRNA expression.
Results: The miRNA expression study revealed aberrant (more than twofold) elevated or decreased expression of 28 miRNAs. Aberrantly expressed miRNAs are involved in pathogenetic mechanisms involved in arterial remodelling and regulation of the immune response. In a study of the association between histopathological characteristics of the infiltrate and miRNA expression, we found that the inflammatory cell infiltrate consisted predominantly of CD3+, CD4+, CD8+ T lymphocytes, CD68+ macrophages, accompanied by increased expression of cytoplasmic nuclear factor of activated T cells 1 (NFATC). We showed that altered expression of selected miRNAs could be associated with infiltration of the vascular wall by lymphocytes and macrophages and activation of T lymphocytes. In a study of the association of histopathological, epigenetic, clinical and imaging data, we found a strong correlation between the presence of halo sign and the thickness of the intima-media complex with the intensity of the inflammatory infiltrate, the altered miRNA expression profile, the change in clinical appearance of TA and pain in the masticatory muscles.
Conclusions: Identification of miRNA expression profiles in the temporal artery wall of GCA patients, potentially involved in the regulation of inflammatory infiltration, immune response and smooth muscle cell phenotype, provides new insights into the complex pathogenesis of GCA. We showed that altered expression of selected miRNAs could be associated with infiltration of the vascular wall by lymphocytes and macrophages and activation of T lymphocytes, which upregulated NFATC expression in the TAB of GCA patients. Our study provides insight into the correlation of ultrasound examination parameters with the histopathological, epigenetic, clinical and laboratory features of vascular lesions found in GCA patients.
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