Longitudinal expression profiling of CD4+ and CD8+ cells in patients with active to quiescent giant cell arteritis

Elisabeth De Smit, Samuel W. Lukowski, Lisa Anderson, Anne Senabouth, Kaisar Dauyey, Sharon Song, Bruce Wyse, Lawrie Wheeler, Christine Y. Chen, Khoa Cao, Amy Wong Ten Yuen, Neil Shuey, Linda Clarke, Isabel Lopez Sanchez, Sandy S.C. Hung, Alice Pébay, David A. Mackey, Matthew A. Brown, Alex W. Hewitt, Joseph E. Powell

Research output: Contribution to journalArticle

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Abstract

Background: Giant cell arteritis (GCA) is the most common form of vasculitis affecting elderly people. It is one of the few true ophthalmic emergencies but symptoms and signs are variable thereby making it a challenging disease to diagnose. A temporal artery biopsy is the gold standard to confirm GCA, but there are currently no specific biochemical markers to aid diagnosis. We aimed to identify a less invasive method to confirm the diagnosis of GCA, as well as to ascertain clinically relevant predictive biomarkers by studying the transcriptome of purified peripheral CD4+ and CD8+ T lymphocytes in patients with GCA. Methods: We recruited 16 patients with histological evidence of GCA at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia, and aimed to collect blood samples at six time points: acute phase, 2-3 weeks, 6-8 weeks, 3 months, 6 months and 12 months after clinical diagnosis. CD4+ and CD8+ T-cells were positively selected at each time point through magnetic-assisted cell sorting. RNA was extracted from all 195 collected samples for subsequent RNA sequencing. The expression profiles of patients were compared to those of 16 age-matched controls. Results: Over the 12-month study period, polynomial modelling analyses identified 179 and 4 statistically significant transcripts with altered expression profiles (FDR < 0.05) between cases and controls in CD4+ and CD8+ populations, respectively. In CD8+ cells, two transcripts remained differentially expressed after 12 months; SGTB, associated with neuronal apoptosis, and FCGR3A, associatied with Takayasu arteritis. We detected genes that correlate with both symptoms and biochemical markers used for predicting long-term prognosis. 15 genes were shared across 3 phenotypes in CD4 and 16 across CD8 cells. In CD8, IL32 was common to 5 phenotypes including Polymyalgia Rheumatica, bilateral blindness and death within 12 months. Conclusions: This is the first longitudinal gene expression study undertaken to identify robust transcriptomic biomarkers of GCA. Our results show cell type-specific transcript expression profiles, novel gene-phenotype associations, and uncover important biological pathways for this disease. In the acute phase, the gene-phenotype relationships we have identified could provide insight to potential disease severity and as such guide in initiating appropriate patient management.

Original languageEnglish
Article number61
JournalBMC Medical Genomics
Volume11
Issue number1
DOIs
Publication statusPublished - 23 Jul 2018

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Giant Cell Arteritis
Biomarkers
Phenotype
Transcriptome
Genes
Polymyalgia Rheumatica
RNA Sequence Analysis
T-Lymphocytes
Temporal Arteries
Takayasu Arteritis
Blindness
Vasculitis
Signs and Symptoms
Ear
Emergencies
RNA
Apoptosis
Biopsy
Gene Expression
Population

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De Smit, E., Lukowski, S. W., Anderson, L., Senabouth, A., Dauyey, K., Song, S., ... Powell, J. E. (2018). Longitudinal expression profiling of CD4+ and CD8+ cells in patients with active to quiescent giant cell arteritis. BMC Medical Genomics, 11(1), [61]. https://doi.org/10.1186/s12920-018-0376-4
De Smit, Elisabeth ; Lukowski, Samuel W. ; Anderson, Lisa ; Senabouth, Anne ; Dauyey, Kaisar ; Song, Sharon ; Wyse, Bruce ; Wheeler, Lawrie ; Chen, Christine Y. ; Cao, Khoa ; Wong Ten Yuen, Amy ; Shuey, Neil ; Clarke, Linda ; Lopez Sanchez, Isabel ; Hung, Sandy S.C. ; Pébay, Alice ; Mackey, David A. ; Brown, Matthew A. ; Hewitt, Alex W. ; Powell, Joseph E. / Longitudinal expression profiling of CD4+ and CD8+ cells in patients with active to quiescent giant cell arteritis. In: BMC Medical Genomics. 2018 ; Vol. 11, No. 1.
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abstract = "Background: Giant cell arteritis (GCA) is the most common form of vasculitis affecting elderly people. It is one of the few true ophthalmic emergencies but symptoms and signs are variable thereby making it a challenging disease to diagnose. A temporal artery biopsy is the gold standard to confirm GCA, but there are currently no specific biochemical markers to aid diagnosis. We aimed to identify a less invasive method to confirm the diagnosis of GCA, as well as to ascertain clinically relevant predictive biomarkers by studying the transcriptome of purified peripheral CD4+ and CD8+ T lymphocytes in patients with GCA. Methods: We recruited 16 patients with histological evidence of GCA at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia, and aimed to collect blood samples at six time points: acute phase, 2-3 weeks, 6-8 weeks, 3 months, 6 months and 12 months after clinical diagnosis. CD4+ and CD8+ T-cells were positively selected at each time point through magnetic-assisted cell sorting. RNA was extracted from all 195 collected samples for subsequent RNA sequencing. The expression profiles of patients were compared to those of 16 age-matched controls. Results: Over the 12-month study period, polynomial modelling analyses identified 179 and 4 statistically significant transcripts with altered expression profiles (FDR < 0.05) between cases and controls in CD4+ and CD8+ populations, respectively. In CD8+ cells, two transcripts remained differentially expressed after 12 months; SGTB, associated with neuronal apoptosis, and FCGR3A, associatied with Takayasu arteritis. We detected genes that correlate with both symptoms and biochemical markers used for predicting long-term prognosis. 15 genes were shared across 3 phenotypes in CD4 and 16 across CD8 cells. In CD8, IL32 was common to 5 phenotypes including Polymyalgia Rheumatica, bilateral blindness and death within 12 months. Conclusions: This is the first longitudinal gene expression study undertaken to identify robust transcriptomic biomarkers of GCA. Our results show cell type-specific transcript expression profiles, novel gene-phenotype associations, and uncover important biological pathways for this disease. In the acute phase, the gene-phenotype relationships we have identified could provide insight to potential disease severity and as such guide in initiating appropriate patient management.",
keywords = "CD4 & CD8 T lymphocytes, Disease biomarkers, Expression profiling, Giant cell arteritis, Magnetic-assisted cell sorting, RNA sequencing, Transcriptome",
author = "{De Smit}, Elisabeth and Lukowski, {Samuel W.} and Lisa Anderson and Anne Senabouth and Kaisar Dauyey and Sharon Song and Bruce Wyse and Lawrie Wheeler and Chen, {Christine Y.} and Khoa Cao and {Wong Ten Yuen}, Amy and Neil Shuey and Linda Clarke and {Lopez Sanchez}, Isabel and Hung, {Sandy S.C.} and Alice P{\'e}bay and Mackey, {David A.} and Brown, {Matthew A.} and Hewitt, {Alex W.} and Powell, {Joseph E.}",
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De Smit, E, Lukowski, SW, Anderson, L, Senabouth, A, Dauyey, K, Song, S, Wyse, B, Wheeler, L, Chen, CY, Cao, K, Wong Ten Yuen, A, Shuey, N, Clarke, L, Lopez Sanchez, I, Hung, SSC, Pébay, A, Mackey, DA, Brown, MA, Hewitt, AW & Powell, JE 2018, 'Longitudinal expression profiling of CD4+ and CD8+ cells in patients with active to quiescent giant cell arteritis' BMC Medical Genomics, vol. 11, no. 1, 61. https://doi.org/10.1186/s12920-018-0376-4

Longitudinal expression profiling of CD4+ and CD8+ cells in patients with active to quiescent giant cell arteritis. / De Smit, Elisabeth; Lukowski, Samuel W.; Anderson, Lisa; Senabouth, Anne; Dauyey, Kaisar; Song, Sharon; Wyse, Bruce; Wheeler, Lawrie; Chen, Christine Y.; Cao, Khoa; Wong Ten Yuen, Amy; Shuey, Neil; Clarke, Linda; Lopez Sanchez, Isabel; Hung, Sandy S.C.; Pébay, Alice; Mackey, David A.; Brown, Matthew A.; Hewitt, Alex W.; Powell, Joseph E.

In: BMC Medical Genomics, Vol. 11, No. 1, 61, 23.07.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Longitudinal expression profiling of CD4+ and CD8+ cells in patients with active to quiescent giant cell arteritis

AU - De Smit, Elisabeth

AU - Lukowski, Samuel W.

AU - Anderson, Lisa

AU - Senabouth, Anne

AU - Dauyey, Kaisar

AU - Song, Sharon

AU - Wyse, Bruce

AU - Wheeler, Lawrie

AU - Chen, Christine Y.

AU - Cao, Khoa

AU - Wong Ten Yuen, Amy

AU - Shuey, Neil

AU - Clarke, Linda

AU - Lopez Sanchez, Isabel

AU - Hung, Sandy S.C.

AU - Pébay, Alice

AU - Mackey, David A.

AU - Brown, Matthew A.

AU - Hewitt, Alex W.

AU - Powell, Joseph E.

PY - 2018/7/23

Y1 - 2018/7/23

N2 - Background: Giant cell arteritis (GCA) is the most common form of vasculitis affecting elderly people. It is one of the few true ophthalmic emergencies but symptoms and signs are variable thereby making it a challenging disease to diagnose. A temporal artery biopsy is the gold standard to confirm GCA, but there are currently no specific biochemical markers to aid diagnosis. We aimed to identify a less invasive method to confirm the diagnosis of GCA, as well as to ascertain clinically relevant predictive biomarkers by studying the transcriptome of purified peripheral CD4+ and CD8+ T lymphocytes in patients with GCA. Methods: We recruited 16 patients with histological evidence of GCA at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia, and aimed to collect blood samples at six time points: acute phase, 2-3 weeks, 6-8 weeks, 3 months, 6 months and 12 months after clinical diagnosis. CD4+ and CD8+ T-cells were positively selected at each time point through magnetic-assisted cell sorting. RNA was extracted from all 195 collected samples for subsequent RNA sequencing. The expression profiles of patients were compared to those of 16 age-matched controls. Results: Over the 12-month study period, polynomial modelling analyses identified 179 and 4 statistically significant transcripts with altered expression profiles (FDR < 0.05) between cases and controls in CD4+ and CD8+ populations, respectively. In CD8+ cells, two transcripts remained differentially expressed after 12 months; SGTB, associated with neuronal apoptosis, and FCGR3A, associatied with Takayasu arteritis. We detected genes that correlate with both symptoms and biochemical markers used for predicting long-term prognosis. 15 genes were shared across 3 phenotypes in CD4 and 16 across CD8 cells. In CD8, IL32 was common to 5 phenotypes including Polymyalgia Rheumatica, bilateral blindness and death within 12 months. Conclusions: This is the first longitudinal gene expression study undertaken to identify robust transcriptomic biomarkers of GCA. Our results show cell type-specific transcript expression profiles, novel gene-phenotype associations, and uncover important biological pathways for this disease. In the acute phase, the gene-phenotype relationships we have identified could provide insight to potential disease severity and as such guide in initiating appropriate patient management.

AB - Background: Giant cell arteritis (GCA) is the most common form of vasculitis affecting elderly people. It is one of the few true ophthalmic emergencies but symptoms and signs are variable thereby making it a challenging disease to diagnose. A temporal artery biopsy is the gold standard to confirm GCA, but there are currently no specific biochemical markers to aid diagnosis. We aimed to identify a less invasive method to confirm the diagnosis of GCA, as well as to ascertain clinically relevant predictive biomarkers by studying the transcriptome of purified peripheral CD4+ and CD8+ T lymphocytes in patients with GCA. Methods: We recruited 16 patients with histological evidence of GCA at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia, and aimed to collect blood samples at six time points: acute phase, 2-3 weeks, 6-8 weeks, 3 months, 6 months and 12 months after clinical diagnosis. CD4+ and CD8+ T-cells were positively selected at each time point through magnetic-assisted cell sorting. RNA was extracted from all 195 collected samples for subsequent RNA sequencing. The expression profiles of patients were compared to those of 16 age-matched controls. Results: Over the 12-month study period, polynomial modelling analyses identified 179 and 4 statistically significant transcripts with altered expression profiles (FDR < 0.05) between cases and controls in CD4+ and CD8+ populations, respectively. In CD8+ cells, two transcripts remained differentially expressed after 12 months; SGTB, associated with neuronal apoptosis, and FCGR3A, associatied with Takayasu arteritis. We detected genes that correlate with both symptoms and biochemical markers used for predicting long-term prognosis. 15 genes were shared across 3 phenotypes in CD4 and 16 across CD8 cells. In CD8, IL32 was common to 5 phenotypes including Polymyalgia Rheumatica, bilateral blindness and death within 12 months. Conclusions: This is the first longitudinal gene expression study undertaken to identify robust transcriptomic biomarkers of GCA. Our results show cell type-specific transcript expression profiles, novel gene-phenotype associations, and uncover important biological pathways for this disease. In the acute phase, the gene-phenotype relationships we have identified could provide insight to potential disease severity and as such guide in initiating appropriate patient management.

KW - CD4 & CD8 T lymphocytes

KW - Disease biomarkers

KW - Expression profiling

KW - Giant cell arteritis

KW - Magnetic-assisted cell sorting

KW - RNA sequencing

KW - Transcriptome

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DO - 10.1186/s12920-018-0376-4

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