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: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.
Project description:Background: Kawasaki Disease (KD) is a childhood illness of suspected infectious etiology that causes medium-sized muscular arteritis, most critically affecting the coronary arteries. No single diagnostic test exists, hampering early diagnosis and treatment. Approximately 25% of untreated patients develop coronary artery disease, and children who are treated with intravenous gammaglobulin but do not respond are also at high risk. Subacute/chronic arteritis and luminal myofibroblastic proliferation are the pathologic processes occurring in KD CA after the second week of illness, when neutrophilic necrotizing arteritis has subsided. The specific dysregulated immune pathways contributing to subacute/chronic arteritis have been unknown, hampering the development of effective immunomodulatory therapies for patients not responding to intravenous gammaglobulin therapy. Methods and Results: Deep RNA sequencing was performed on KD (n=8) and childhood control (n=7) coronary artery tissues, revealing 1074 differentially expressed mRNAs. Molecular pathways involving T helper cell, cytotoxic T lymphocyte, dendritic cells, and antigen presentation were the most significantly dysregulated. There was significant upregulation of immunoglobulin and type I interferon-stimulated genes. 80 upregulated extracellular genes encoding secreted proteins are candidate biomarkers of KD arteritis. Conclusions: The immune transcriptional profile in KD coronary artery tissues is primarily T helper and cytotoxic lymphocyte-mediated, and has features of an antiviral immune response such as type I interferon-stimulated gene expression. This first report of the KD coronary artery transcriptome identifies specific dysregulated immune response pathways that can inform the development of new therapies for and biomarkers of KD arteritis, and provide direction for future etiologic studies.
Project description:PurposeTo determine the positive yield (utility rate) of temporal artery biopsy (TAB) in patients with suspected giant cell arteritis (GCA).Study designSystematic review (CRD42017078508) and meta-regression.Materials and methodsAll articles concerning TAB for suspected GCA with English language abstracts from 1998 to 2017 were retrieved. Articles were excluded if they exclusively reported positive TAB, or only cases of known GCA. Where available, the pre-specified predictors of age, sex, vision symptoms, jaw claudication, duration of steroid treatment prior to TAB, specimen length, bilateral TAB, and use of ultrasound/MRI (imaging) were recorded for meta-regression.ResultsOne hundred and thirteen articles met eligibility criteria. The I 2 was 92%, and with such high heterogeneity, meta-analysis is unsuitable. The median yield of TAB was 0.25 (95% confidence interval 0.21 to 0.27), with interquartile range 0.17 to 0.34. On univariate meta-regression age (coefficient 0.012, p = 0.025) was the only statistically significant patient factor associated with TAB yield.ConclusionsSystematic review revealed high heterogeneity in the yield of TAB. The median utility rate of 25% and its interquartile range provides a benchmark for decisions regarding the under/overutilization of TAB and aids in the evaluation of non-invasive alternatives for the investigation of GCA.