Abstract
ObjectivesThe aim of this study was to quantitatively assess distinct immune cell subsets comprising inflammatory infiltrate in temporal artery biopsies (TABs) from patients with giant cell arteritis (GCA), and to link the obtained histopathological data with expression profiles of immune-related microRNAs (miRNAs).MethodsThe study included 68 formalin-fixed, paraffin-embedded TABs from treatment-naïve patients, including 30 histologically positive GCA and 16 negative GCA TABs, and 22 control non-GCA TABs. Quantitative assessment of histological parameters was performed using histopathological and immunohistochemical techniques. miRNA expression analysis was performed by quantitative real-time PCR.ResultsIntense transmural mononuclear inflammatory infiltrates in TAB-positive GCA arteries were predominantly composed of CD3+, CD4+ and CD8+ T lymphocytes, and CD68+ macrophages, accompanied by a strong nuclear overexpression of the nuclear factor of activated T cells, cytoplasmic 1 (NFATC) in the lymphocyte infiltrate fraction. Furthermore, TAB-positive GCA arteries were characterized by significant overexpression of nine pro-inflammatory miRNAs (miR-132-3p/-142-3p/-142-5p/-155-5p/-210-3p/-212-3p/-326/-342-5p/-511-5p) and a significant under-expression of six regulatory immune-related miRNAs (miR-30a-5p/-30b-5p/-30c-5p/-30d-5p/-30e-5p/-124-3p), whose expression levels significantly associated with most evaluated histopathological parameters. Notably, we revealed miR-132-3p/-142-3p/-142-5p/-155-5p/-212-3p/-511-5p as major promoters of arterial inflammation and miR-30a-5p/-30c-5p/-30d-5p as putative regulators of NFATC signaling in TAB-positive GCA arteries.ConclusionOverall, we demonstrated that an altered arterial tissue-specific pro-inflammatory miRNA signature favors enhanced T cell-driven inflammation and macrophage activity in TAB-positive GCA arteries. Moreover, dysregulation of several immune-related miRNAs seems to contribute crucially to GCA pathogenesis, through impairing their regulatory activity towards T cell-mediated immune responses driven by the calcineurin (CaN)/NFAT signaling pathway, indicating their therapeutic, diagnostic and prognostic potential.
Highlights
Giant cell arteritis (GCA) is a systemic vasculitis affecting largeand medium-sized arteries, especially the extracranial branches of the carotid artery and the aorta [1]
Intense transmural mononuclear inflammatory infiltrates in temporal artery biopsies (TABs)-positive GCA arteries were predominantly composed of CD3+, CD4+ and CD8+ T lymphocytes, and CD68+ macrophages, accompanied by a strong nuclear overexpression of the nuclear factor of activated T cells, cytoplasmic 1 (NFATC) in the lymphocyte infiltrate fraction
TAB-positive GCA arteries were characterized by significant overexpression of nine pro-inflammatory miRNAs and a significant under-expression of six regulatory immune-related miRNAs, whose expression levels significantly associated with most evaluated histopathological parameters
Summary
Giant cell arteritis (GCA) is a systemic vasculitis affecting largeand medium-sized arteries, especially the extracranial branches of the carotid artery and the aorta [1]. Histopathological changes in temporal artery biopsies (TABs) from GCA patients include a transmural, frequently granulomatous mononuclear inflammatory cell infiltrate, disruption of the internal elastic lamina and intimal thickening [2, 4]. There are no data on the temporal relationship between the composition and intensity of the TAB inflammatory infiltrate, duration of GCA and elevated levels of systemic inflammatory mediators and signs of inflammation in GCA patients, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), acute phase serum amyloid A protein (A-SAA), peripheral blood thrombocytes, hemoglobin and fibrinogen [3, 5, 13]. The current concept of GCA pathogenesis suggests the initial activation of the vasa vasorum and resident vascular dendritic cells in the adventitia of the affected arteries, followed by infiltration, activation and differentiation of CD4+ T cells into IFN-g-secreting Th1 and IL-17-secreting Th17 cells
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