Project description:Background Giant cell arteritis (GCA) is a prevalent, intractable, granulomatous, large-vessel vasculitis. The pathologic features include destruction of the tunica media, infiltrating macrophages and multinucleated giant cells (MNGCs), immune responses associated with CD4+ T cells, accumulation of myofibroblasts, and hypertrophy of the intima. Objectives The molecular pathology of GCA has largely remained elusive, while the morphological features are well defined. We aimed to identify key molecules associated with the pathogenesis of GCA. Method Arterial lesions were obtained through temporal artery biopsy from 16 patients, including those diagnosed as GCA and not. The obtained samples underwent genome-wide gene expression profiling. The resulting data were examined to reveal specific pathways and genes, and some of the molecules were followed up by immunohistochemistry. Results GCA lesions had a distinguishing pattern of gene expression, including enrichment of immune cells and phagocytic pathways related to microglia and osteoclasts. We found MMP12 (macrophage elastase), HLA-DRA, phagocytosis- and osteoclast-associated molecules in infiltrating macrophages and MNGCs. We also found LRRC15-expressing cells in the tunica intima, suggesting a myofibroblast subpopulation that suppresses cytotoxic CD8+ T cells. These molecules were often upregulated in other granulomatous diseases affecting not only arteries but also lymph nodes. Conclusion Infiltrating macrophages and MNGCs expressed molecules that contribute to the pathogenetic features of GCA, including degradation of the tunica medium, induction of immune responses, and accumulation of myofibroblasts. The extended list of key molecules provides a solid baseline of elucidating the pathogenesis of GCA and developing therapeutic strategies.
Project description:To identify the key coding genes underlying the biomarkers and pathways associated with giant cell arteritis (GCA), we performed in situ spatial profiling of molecules involved in the temporal arteries of GCA patients and controls
Project description:This study used the NanoString GeoMx Digital Spatial Profiler (DSP) platform to spatially profile gene expression in temporal artery biopsy tissue from patients with giant cell arteritis (GCA), taken at the time of diagnosis. Tissue sections were hybridised with the Human Whole Transcriptome Atlas panel and segmented to isolate immune-enriched (CD45⁺) and full-tissue regions across anatomical layers (adventitia, media, intima). Gene expression data were stratified according to clinical trajectory, comparing patients who later achieved sustained remission (SR) under glucocorticoid monotherapy with those who relapsed or failed to remit (non-remission, NR). Non-GCA controls (C) were also included for comparisons. Data from two sequencing batches were merged and normalised using DESeq2 for downstream analysis. This submission includes: (1) unnormalised digital counts and segment metadata; (2) normalised processed data and associated metadata; and (3) clinical information to aid re-analysis.
Project description:Spatial profiling of temporal artery biopsies from patients with giant cell arteritis using NanoString GeoMx Whole Transcriptome Atlas
Project description:Formalin-fixed, paraffin-embedded (FFPE) temporal artery sections from GCA subjects were stained for VZV antigen. Samples testing positive (VZV+) and negative (VZV-) from both GCA and control subjects without GCA were analyzed by targeted RNA sequencing of the whole-human transcriptome (BioSpyder TempO-Seq™).
Project description:Vasculitis is characterized by the inflammation of blood vessels. In patients with giant cell arteritis (GCA) large- to medium-sized vessels are affected. Single-cell RNA sequencing was performed on GCA patients and healthy controls (HC) to study the transcriptome of peripheral blood mononuclear cells of patients and controls.
Project description:Temporal artery biopsy (TAB) is currently the gold standard procedure to diagnose giant cell arteritis. Despite low sensitivity, TAB is routinely performed even if a clinical diagnosis has already been made. The objective of this study was to determine the usefulness of TAB for giant cell arteritis management.MethodsWe performed a systematic review to identify studies that compared steroid treatment between TAB+ and TAB- patients. EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched from inception until April 4, 2020. Titles, abstracts, and full texts were reviewed by two independent reviewers and conflicts resolved by consensus. Studies reporting TAB result and steroid treatment were included. Information pertaining to steroid treatment was compared between TAB+ and TAB- groups. Steroid duration was compared by grouping patients in a less than 6 month group, a 6-24 month group, and a more than 24 month group.ResultsAn estimated 5288 abstracts were screened and 13 studies involving 1355 patients were included. Rate of prebiopsy steroid treatment was higher in TAB+ patients compared with TAB- patients [93% versus 63% (P < 0.001)]. The TAB+ group was more likely to be started on steroids prebiopsy [28% versus 8% (P < 0.001)]. TAB+ and TAB- patients had similar steroid duration for all groups [<6-month group 17% versus 19% (P-0.596), the 6-24-month group 16% versus 19% (P-0.596), and the >24-month group 66% versus 63% (P-0.642)].ConclusionTAB results have minimal impact on treatment, and the utility should be reconsidered when a clinical diagnosis of giant cell arteritis is possible.