Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients

Hadijat Kubura M. Makinde; Julia L.M. Dunn; Gaurav Gadhvi; Mary Carns; Kathleen Aren; Anh H. Chung; Lutfiyya N. Muhammad; Jing Song; Carla M. Cuda; Salina Dominguez; John E. Pandolfino; Jane E. Dematte D'Amico; G. Scott Budinger; Shervin Assassi; Tracy M. Frech; Dinesh Khanna; Alex Shaeffer; Harris Perlman; Monique Hinchcliff; Deborah R. Winter

doi:10.1002/art.42380

Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients

Hadijat Kubura M. Makinde, Julia L.M. Dunn, Gaurav Gadhvi, Mary Carns, Kathleen Aren, Anh H. Chung, Lutfiyya N. Muhammad, Jing Song, Carla M. Cuda, Salina Dominguez, John E. Pandolfino, Jane E. Dematte D'Amico, G. Scott Budinger, Shervin Assassi, Tracy M. Frech, Dinesh Khanna, Alex Shaeffer, Harris Perlman^*, Monique Hinchcliff^*, Deborah R. Winter^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Objective: Patients with diffuse cutaneous systemic sclerosis (dcSSc) display a complex clinical phenotype. Transcriptional profiling of whole blood or tissue from patients are affected by changes in cellular composition that drive gene expression and an inability to detect minority cell populations. We undertook this study to focus on the 2 main subtypes of circulating monocytes, classical monocytes (CMs) and nonclassical monocytes (NCMs) as a biomarker of SSc disease severity. Methods: SSc patients were recruited from the Prospective Registry for Early Systemic Sclerosis. Clinical data were collected, as well as peripheral blood for isolation of CMs and NCMs. Age-, sex-, and race-matched healthy volunteers were recruited as controls. Bulk macrophages were isolated from the skin in a separate cohort. All samples were assayed by RNA sequencing (RNA-seq). Results: We used an unbiased approach to cluster patients into 3 groups (groups A–C) based on the transcriptional signatures of CMs relative to controls. Each group maintained their characteristic transcriptional signature in NCMs. Genes up-regulated in group C demonstrated the highest expression compared to the other groups in SSc skin macrophages, relative to controls. Patients from groups B and C exhibited worse lung function than group A, although there was no difference in SSc skin disease at baseline, relative to controls. We validated our approach by applying our group classifications to published bulk monocyte RNA-seq data from SSc patients, and we found that patients without skin disease were most likely to be classified as group A. Conclusion: We are the first to show that transcriptional signatures of CMs and NCMs can be used to unbiasedly stratify SSc patients and correlate with disease activity outcome measures.

Original language	English (US)
Pages (from-to)	595-608
Number of pages	14
Journal	Arthritis and Rheumatology
Volume	75
Issue number	4
DOIs	https://doi.org/10.1002/art.42380
State	Published - Apr 2023

Funding

We thank the Northwestern University Lurie Cancer Center Flow Cytometry Core Facility, which is supported by NCI Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We also thank the Next Generation Sequencing Core, the Division of Pulmonary and Critical Care and Rheumatology Sequencing Core, NUCATS Biostatistics and Collaboration Center at Northwestern University, Northwestern University Core Center for Clinical Research in the Division of Rheumatology (project no. 5P30AR072579), and Northwestern University Skin Biology and Diseases Resource‐based Center (project no. 5P30AR075049). This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster on QUEST, which is jointly supported by the Feinberg School of Medicine, the Office of the Provost, the Office for Research, and Northwestern Information Technology. In addition, this work was made possible by a grant from the Northwestern Digestive Health Foundation and gifts from Joe and Nives Rizza and the Todd and Renee Schilling Charitable Fund. We thank the Northwestern University Lurie Cancer Center Flow Cytometry Core Facility, which is supported by NCI Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We also thank the Next Generation Sequencing Core, the Division of Pulmonary and Critical Care and Rheumatology Sequencing Core, NUCATS Biostatistics and Collaboration Center at Northwestern University, Northwestern University Core Center for Clinical Research in the Division of Rheumatology (project no. 5P30AR072579), and Northwestern University Skin Biology and Diseases Resource-based Center (project no. 5P30AR075049). This research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster on QUEST, which is jointly supported by the Feinberg School of Medicine, the Office of the Provost, the Office for Research, and Northwestern Information Technology. In addition, this work was made possible by a grant from the Northwestern Digestive Health Foundation and gifts from Joe and Nives Rizza and the Todd and Renee Schilling Charitable Fund.

ASJC Scopus subject areas

Immunology and Allergy
Rheumatology
Immunology

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Cite this

Makinde, H. K. M., Dunn, J. L. M., Gadhvi, G., Carns, M., Aren, K., Chung, A. H., Muhammad, L. N., Song, J., Cuda, C. M., Dominguez, S., Pandolfino, J. E., Dematte D'Amico, J. E., Budinger, G. S., Assassi, S., Frech, T. M., Khanna, D., Shaeffer, A., Perlman, H., Hinchcliff, M., & Winter, D. R. (2023). Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients. Arthritis and Rheumatology, 75(4), 595-608. https://doi.org/10.1002/art.42380

@article{a83b6578bf3b42d9a1249cab8057cdeb,

title = "Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients",

abstract = "Objective: Patients with diffuse cutaneous systemic sclerosis (dcSSc) display a complex clinical phenotype. Transcriptional profiling of whole blood or tissue from patients are affected by changes in cellular composition that drive gene expression and an inability to detect minority cell populations. We undertook this study to focus on the 2 main subtypes of circulating monocytes, classical monocytes (CMs) and nonclassical monocytes (NCMs) as a biomarker of SSc disease severity. Methods: SSc patients were recruited from the Prospective Registry for Early Systemic Sclerosis. Clinical data were collected, as well as peripheral blood for isolation of CMs and NCMs. Age-, sex-, and race-matched healthy volunteers were recruited as controls. Bulk macrophages were isolated from the skin in a separate cohort. All samples were assayed by RNA sequencing (RNA-seq). Results: We used an unbiased approach to cluster patients into 3 groups (groups A–C) based on the transcriptional signatures of CMs relative to controls. Each group maintained their characteristic transcriptional signature in NCMs. Genes up-regulated in group C demonstrated the highest expression compared to the other groups in SSc skin macrophages, relative to controls. Patients from groups B and C exhibited worse lung function than group A, although there was no difference in SSc skin disease at baseline, relative to controls. We validated our approach by applying our group classifications to published bulk monocyte RNA-seq data from SSc patients, and we found that patients without skin disease were most likely to be classified as group A. Conclusion: We are the first to show that transcriptional signatures of CMs and NCMs can be used to unbiasedly stratify SSc patients and correlate with disease activity outcome measures.",

author = "Makinde, {Hadijat Kubura M.} and Dunn, {Julia L.M.} and Gaurav Gadhvi and Mary Carns and Kathleen Aren and Chung, {Anh H.} and Muhammad, {Lutfiyya N.} and Jing Song and Cuda, {Carla M.} and Salina Dominguez and Pandolfino, {John E.} and {Dematte D'Amico}, {Jane E.} and Budinger, {G. Scott} and Shervin Assassi and Frech, {Tracy M.} and Dinesh Khanna and Alex Shaeffer and Harris Perlman and Monique Hinchcliff and Winter, {Deborah R.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.",

year = "2023",

month = apr,

doi = "10.1002/art.42380",

language = "English (US)",

volume = "75",

pages = "595--608",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

publisher = "John Wiley and Sons Ltd",

number = "4",

}

Makinde, HKM, Dunn, JLM, Gadhvi, G, Carns, M, Aren, K, Chung, AH, Muhammad, LN, Song, J, Cuda, CM, Dominguez, S, Pandolfino, JE , Dematte D'Amico, JE , Budinger, GS, Assassi, S, Frech, TM, Khanna, D, Shaeffer, A, Perlman, H, Hinchcliff, M & Winter, DR 2023, 'Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients', Arthritis and Rheumatology, vol. 75, no. 4, pp. 595-608. https://doi.org/10.1002/art.42380

TY - JOUR

T1 - Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients

AU - Makinde, Hadijat Kubura M.

AU - Dunn, Julia L.M.

AU - Gadhvi, Gaurav

AU - Carns, Mary

AU - Aren, Kathleen

AU - Chung, Anh H.

AU - Muhammad, Lutfiyya N.

AU - Song, Jing

AU - Cuda, Carla M.

AU - Dominguez, Salina

AU - Pandolfino, John E.

AU - Dematte D'Amico, Jane E.

AU - Budinger, G. Scott

AU - Assassi, Shervin

AU - Frech, Tracy M.

AU - Khanna, Dinesh

AU - Shaeffer, Alex

AU - Perlman, Harris

AU - Hinchcliff, Monique

AU - Winter, Deborah R.

PY - 2023/4

Y1 - 2023/4

N2 - Objective: Patients with diffuse cutaneous systemic sclerosis (dcSSc) display a complex clinical phenotype. Transcriptional profiling of whole blood or tissue from patients are affected by changes in cellular composition that drive gene expression and an inability to detect minority cell populations. We undertook this study to focus on the 2 main subtypes of circulating monocytes, classical monocytes (CMs) and nonclassical monocytes (NCMs) as a biomarker of SSc disease severity. Methods: SSc patients were recruited from the Prospective Registry for Early Systemic Sclerosis. Clinical data were collected, as well as peripheral blood for isolation of CMs and NCMs. Age-, sex-, and race-matched healthy volunteers were recruited as controls. Bulk macrophages were isolated from the skin in a separate cohort. All samples were assayed by RNA sequencing (RNA-seq). Results: We used an unbiased approach to cluster patients into 3 groups (groups A–C) based on the transcriptional signatures of CMs relative to controls. Each group maintained their characteristic transcriptional signature in NCMs. Genes up-regulated in group C demonstrated the highest expression compared to the other groups in SSc skin macrophages, relative to controls. Patients from groups B and C exhibited worse lung function than group A, although there was no difference in SSc skin disease at baseline, relative to controls. We validated our approach by applying our group classifications to published bulk monocyte RNA-seq data from SSc patients, and we found that patients without skin disease were most likely to be classified as group A. Conclusion: We are the first to show that transcriptional signatures of CMs and NCMs can be used to unbiasedly stratify SSc patients and correlate with disease activity outcome measures.

AB - Objective: Patients with diffuse cutaneous systemic sclerosis (dcSSc) display a complex clinical phenotype. Transcriptional profiling of whole blood or tissue from patients are affected by changes in cellular composition that drive gene expression and an inability to detect minority cell populations. We undertook this study to focus on the 2 main subtypes of circulating monocytes, classical monocytes (CMs) and nonclassical monocytes (NCMs) as a biomarker of SSc disease severity. Methods: SSc patients were recruited from the Prospective Registry for Early Systemic Sclerosis. Clinical data were collected, as well as peripheral blood for isolation of CMs and NCMs. Age-, sex-, and race-matched healthy volunteers were recruited as controls. Bulk macrophages were isolated from the skin in a separate cohort. All samples were assayed by RNA sequencing (RNA-seq). Results: We used an unbiased approach to cluster patients into 3 groups (groups A–C) based on the transcriptional signatures of CMs relative to controls. Each group maintained their characteristic transcriptional signature in NCMs. Genes up-regulated in group C demonstrated the highest expression compared to the other groups in SSc skin macrophages, relative to controls. Patients from groups B and C exhibited worse lung function than group A, although there was no difference in SSc skin disease at baseline, relative to controls. We validated our approach by applying our group classifications to published bulk monocyte RNA-seq data from SSc patients, and we found that patients without skin disease were most likely to be classified as group A. Conclusion: We are the first to show that transcriptional signatures of CMs and NCMs can be used to unbiasedly stratify SSc patients and correlate with disease activity outcome measures.

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Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients

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