Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes

Fan Zhang; Anna Helena Jonsson; Aparna Nathan; Nghia Millard; Michelle Curtis; Qian Xiao; Maria Gutierrez-Arcelus; William Apruzzese; Gerald F. M. Watts; Dana Weisenfeld; Saba Nayar; Javier Rangel-Moreno; Nida Meednu; Kathryne E. Marks; Ian Mantel; Joyce B. Kang; Laurie Rumker; Joseph Mears; Kamil Slowikowski; Kathryn Weinand; Dana E. Orange; Laura Geraldino-Pardilla; Kevin D. Deane; Darren Tabechian; Arnoldas Ceponis; Gary S. Firestein; Mark Maybury; Ilfita Sahbudin; Ami Ben-Artzi; Arthur M. Mandelin II; Alessandra Nerviani; Myles J. Lewis; Felice Rivellese; Constantino Pitzalis; Laura B Hughes; Diane Horowitz; Edward DiCarlo; Ellen M. Gravallese; Brendan F. Boyce; Accelerating Medicines Partnership (AMP) RA/SLE Network; Larry W. Moreland; Susan M. Goodman; Harris Perlman; V. Michael Holers; Katherine P. Liao; Andrew Filer; Vivian P. Bykerk; Kevin Wei; Deepak A. Rao; Laura T. Donlin; Jennifer H. Anolik; Michael B. Brenner; Soumya Raychaudhuri

doi:10.1038/s41586-023-06708-y

Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes

Fan Zhang, Anna Helena Jonsson, Aparna Nathan, Nghia Millard, Michelle Curtis, Qian Xiao, Maria Gutierrez-Arcelus, William Apruzzese, Gerald F. M. Watts, Dana Weisenfeld, Saba Nayar, Javier Rangel-Moreno, Nida Meednu, Kathryne E. Marks, Ian Mantel, Joyce B. Kang, Laurie Rumker, Joseph Mears, Kamil Slowikowski, Kathryn WeinandDana E. Orange, Laura Geraldino-Pardilla, Kevin D. Deane, Darren Tabechian, Arnoldas Ceponis, Gary S. Firestein, Mark Maybury, Ilfita Sahbudin, Ami Ben-Artzi, Arthur M. Mandelin II, Alessandra Nerviani, Myles J. Lewis, Felice Rivellese, Constantino Pitzalis, Laura B Hughes, Diane Horowitz, Edward DiCarlo, Ellen M. Gravallese, Brendan F. Boyce, Accelerating Medicines Partnership (AMP) RA/SLE Network, Larry W. Moreland, Susan M. Goodman, Harris Perlman, V. Michael Holers, Katherine P. Liao, Andrew Filer, Vivian P. Bykerk, Kevin Wei, Deepak A. Rao, Laura T. Donlin, Jennifer H. Anolik, Michael B. Brenner, Soumya Raychaudhuri^*

^*Corresponding author for this work

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

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Abstract

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1, 2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.

Original language	English
Pages (from-to)	616-624
Number of pages	9
Journal	Nature
Volume	623
Issue number	7987
Early online date	8 Nov 2023
DOIs	https://doi.org/10.1038/s41586-023-06708-y
Publication status	Published - 16 Nov 2023

Bibliographical note

Acknowledgments:
This work was supported by the Accelerating Medicines Partnership® Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP® RA/SLE) Network. AMP is a public-private partnership (AbbVie, Arthritis Foundation, Bristol-Myers Squibb Company, Foundation for the National Institutes of Health, GlaxoSmithKline, Janssen Research and Development, LLC, Lupus Foundation of America, Lupus Research Alliance, Merck & Co., Inc., National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer, Inc., Rheumatology Research Foundation, Sanofi and Takeda Pharmaceuticals International, Inc.) created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. Funding was provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2- AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694 and UM2- AR067678). Accelerating Medicines Partnership and AMP are registered service marks of the US Department of Health and Human Services. This work was also supported by the PhRMA Foundation and the Arthritis National Research Foundation Award (to F.Z.); NIH NIAMS K08AR081412, Rheumatology Research Foundation Investigator Award, and Arthritis National Research Foundation Award (to A.H.J.); NIH NHGRI T32HG002295 and NIAMS T32AR007530 (to A. Nathan); NIH NIAMS K08AR077037, Rheumatology Research Foundation Innovative Research Award, and Burroughs Wellcome Fund Career Award in Medical Sciences (to K. Wei); NIH NIGMS T32GM007753 (to J.B.K.); NIH NIAMS R01078268 and NCATS UL1 TR001866 (to D.E.O.); NIH NIAID T32AR007258 (to K.S.); Research into Inflammatory Arthritis Centre Versus Arthritis (22072), IMI-RTCure (777357) and the NIHR Birmingham Biomedical Research Centre (BRC-1215-20009) (to A.F. and D.S.T.); NIH NIAMS K08AR072791 and Burroughs Wellcome Fund Career Award in Medical Sciences (to D.A.R.); NIH NIAID R01AI148435 (to L.T.D.); NIH NIAMS R21AR071670 and P30 AR069655 (to J.H.A.); NIH NIAMS R01AR073833 and R01AR073290 (to M.B.B.); NIH NHGRI U01HG009379 and NIAMS R01AR063759 (to S.R.). We especially acknowledge people in the AMP RA/SLE Network: A. Arazi, C. Berthier, J. Buyon, M. Dall’Era, A. Davidson, B. Diamond, A. Fava, J. Grossman, N. Hacohen, D. Hildeman, J. Hodgin, T. Hwang, M. Ishimori, K. Kalunian, D. Kamen, M. Kretzler, H. Maecker, R. Mao, M. McMahon, F. Payan-Schober, M. Petri, C. Putterman, D. Simmons, T. Tuschl, D. Wofsy and Steve Woodle.

Keywords

Humans
Arthritis, Rheumatoid/pathology
Synovial Membrane/pathology
Cytokines/metabolism
Inflammation/pathology

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10.1038/s41586-023-06708-yLicence: Creative Commons: Attribution (CC BY)

ZhangF2023DeconstructionFinal published version, 37.6 MBLicence: Creative Commons: Attribution (CC BY)

NIHR Biomedical Research Centre (BRC) - Core Theme
Barrett, T. (Co-Investigator), Adams, D. (Principal Investigator), Newsome, P. (Co-Investigator), Kyte, D. (Co-Investigator), Slade, A. (Co-Investigator) & Calvert, M. (Co-Investigator)
NIHR CENTRAL COMMISSIONING FACILITY
1/04/17 → 30/11/22
Project: Other Government Departments

Cite this

Zhang, F., Jonsson, A. H., Nathan, A., Millard, N., Curtis, M., Xiao, Q., Gutierrez-Arcelus, M., Apruzzese, W., Watts, G. F. M., Weisenfeld, D., Nayar, S., Rangel-Moreno, J., Meednu, N., Marks, K. E., Mantel, I., Kang, J. B., Rumker, L., Mears, J., Slowikowski, K., ... Raychaudhuri, S. (2023). Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes. Nature, 623(7987), 616-624. https://doi.org/10.1038/s41586-023-06708-y

@article{facb91d361e141f1a55c09febfa98e1f,

title = "Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes",

abstract = "Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1, 2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.",

keywords = "Humans, Arthritis, Rheumatoid/pathology, Synovial Membrane/pathology, Cytokines/metabolism, Inflammation/pathology",

author = "Fan Zhang and Jonsson, {Anna Helena} and Aparna Nathan and Nghia Millard and Michelle Curtis and Qian Xiao and Maria Gutierrez-Arcelus and William Apruzzese and Watts, {Gerald F. M.} and Dana Weisenfeld and Saba Nayar and Javier Rangel-Moreno and Nida Meednu and Marks, {Kathryne E.} and Ian Mantel and Kang, {Joyce B.} and Laurie Rumker and Joseph Mears and Kamil Slowikowski and Kathryn Weinand and Orange, {Dana E.} and Laura Geraldino-Pardilla and Deane, {Kevin D.} and Darren Tabechian and Arnoldas Ceponis and Firestein, {Gary S.} and Mark Maybury and Ilfita Sahbudin and Ami Ben-Artzi and {Mandelin II}, {Arthur M.} and Alessandra Nerviani and Lewis, {Myles J.} and Felice Rivellese and Constantino Pitzalis and Hughes, {Laura B} and Diane Horowitz and Edward DiCarlo and Gravallese, {Ellen M.} and Boyce, {Brendan F.} and {Accelerating Medicines Partnership (AMP) RA/SLE Network} and Moreland, {Larry W.} and Goodman, {Susan M.} and Harris Perlman and Holers, {V. Michael} and Liao, {Katherine P.} and Andrew Filer and Bykerk, {Vivian P.} and Kevin Wei and Rao, {Deepak A.} and Donlin, {Laura T.} and Anolik, {Jennifer H.} and Brenner, {Michael B.} and Soumya Raychaudhuri",

note = "Acknowledgments: This work was supported by the Accelerating Medicines Partnership{\textregistered} Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP{\textregistered} RA/SLE) Network. AMP is a public-private partnership (AbbVie, Arthritis Foundation, Bristol-Myers Squibb Company, Foundation for the National Institutes of Health, GlaxoSmithKline, Janssen Research and Development, LLC, Lupus Foundation of America, Lupus Research Alliance, Merck & Co., Inc., National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer, Inc., Rheumatology Research Foundation, Sanofi and Takeda Pharmaceuticals International, Inc.) created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. Funding was provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2- AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694 and UM2- AR067678). Accelerating Medicines Partnership and AMP are registered service marks of the US Department of Health and Human Services. This work was also supported by the PhRMA Foundation and the Arthritis National Research Foundation Award (to F.Z.); NIH NIAMS K08AR081412, Rheumatology Research Foundation Investigator Award, and Arthritis National Research Foundation Award (to A.H.J.); NIH NHGRI T32HG002295 and NIAMS T32AR007530 (to A. Nathan); NIH NIAMS K08AR077037, Rheumatology Research Foundation Innovative Research Award, and Burroughs Wellcome Fund Career Award in Medical Sciences (to K. Wei); NIH NIGMS T32GM007753 (to J.B.K.); NIH NIAMS R01078268 and NCATS UL1 TR001866 (to D.E.O.); NIH NIAID T32AR007258 (to K.S.); Research into Inflammatory Arthritis Centre Versus Arthritis (22072), IMI-RTCure (777357) and the NIHR Birmingham Biomedical Research Centre (BRC-1215-20009) (to A.F. and D.S.T.); NIH NIAMS K08AR072791 and Burroughs Wellcome Fund Career Award in Medical Sciences (to D.A.R.); NIH NIAID R01AI148435 (to L.T.D.); NIH NIAMS R21AR071670 and P30 AR069655 (to J.H.A.); NIH NIAMS R01AR073833 and R01AR073290 (to M.B.B.); NIH NHGRI U01HG009379 and NIAMS R01AR063759 (to S.R.). We especially acknowledge people in the AMP RA/SLE Network: A. Arazi, C. Berthier, J. Buyon, M. Dall{\textquoteright}Era, A. Davidson, B. Diamond, A. Fava, J. Grossman, N. Hacohen, D. Hildeman, J. Hodgin, T. Hwang, M. Ishimori, K. Kalunian, D. Kamen, M. Kretzler, H. Maecker, R. Mao, M. McMahon, F. Payan-Schober, M. Petri, C. Putterman, D. Simmons, T. Tuschl, D. Wofsy and Steve Woodle.",

year = "2023",

month = nov,

day = "16",

doi = "10.1038/s41586-023-06708-y",

language = "English",

volume = "623",

pages = "616--624",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7987",

}

Zhang, F, Jonsson, AH, Nathan, A, Millard, N, Curtis, M, Xiao, Q, Gutierrez-Arcelus, M, Apruzzese, W, Watts, GFM, Weisenfeld, D, Nayar, S, Rangel-Moreno, J, Meednu, N, Marks, KE, Mantel, I, Kang, JB, Rumker, L, Mears, J, Slowikowski, K, Weinand, K, Orange, DE, Geraldino-Pardilla, L, Deane, KD, Tabechian, D, Ceponis, A, Firestein, GS, Maybury, M, Sahbudin, I, Ben-Artzi, A, Mandelin II, AM, Nerviani, A, Lewis, MJ, Rivellese, F, Pitzalis, C, Hughes, LB, Horowitz, D, DiCarlo, E, Gravallese, EM, Boyce, BF, Accelerating Medicines Partnership (AMP) RA/SLE Network, Moreland, LW, Goodman, SM, Perlman, H, Holers, VM, Liao, KP, Filer, A, Bykerk, VP, Wei, K, Rao, DA, Donlin, LT, Anolik, JH, Brenner, MB & Raychaudhuri, S 2023, 'Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes', Nature, vol. 623, no. 7987, pp. 616-624. https://doi.org/10.1038/s41586-023-06708-y

TY - JOUR

T1 - Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes

AU - Zhang, Fan

AU - Jonsson, Anna Helena

AU - Nathan, Aparna

AU - Millard, Nghia

AU - Curtis, Michelle

AU - Xiao, Qian

AU - Gutierrez-Arcelus, Maria

AU - Apruzzese, William

AU - Watts, Gerald F. M.

AU - Weisenfeld, Dana

AU - Nayar, Saba

AU - Rangel-Moreno, Javier

AU - Meednu, Nida

AU - Marks, Kathryne E.

AU - Mantel, Ian

AU - Kang, Joyce B.

AU - Rumker, Laurie

AU - Mears, Joseph

AU - Slowikowski, Kamil

AU - Weinand, Kathryn

AU - Orange, Dana E.

AU - Geraldino-Pardilla, Laura

AU - Deane, Kevin D.

AU - Tabechian, Darren

AU - Ceponis, Arnoldas

AU - Firestein, Gary S.

AU - Maybury, Mark

AU - Sahbudin, Ilfita

AU - Ben-Artzi, Ami

AU - Mandelin II, Arthur M.

AU - Nerviani, Alessandra

AU - Lewis, Myles J.

AU - Rivellese, Felice

AU - Pitzalis, Constantino

AU - Hughes, Laura B

AU - Horowitz, Diane

AU - DiCarlo, Edward

AU - Gravallese, Ellen M.

AU - Boyce, Brendan F.

AU - Accelerating Medicines Partnership (AMP) RA/SLE Network

AU - Moreland, Larry W.

AU - Goodman, Susan M.

AU - Perlman, Harris

AU - Holers, V. Michael

AU - Liao, Katherine P.

AU - Filer, Andrew

AU - Bykerk, Vivian P.

AU - Wei, Kevin

AU - Rao, Deepak A.

AU - Donlin, Laura T.

AU - Anolik, Jennifer H.

AU - Brenner, Michael B.

AU - Raychaudhuri, Soumya

N1 - Acknowledgments: This work was supported by the Accelerating Medicines Partnership® Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP® RA/SLE) Network. AMP is a public-private partnership (AbbVie, Arthritis Foundation, Bristol-Myers Squibb Company, Foundation for the National Institutes of Health, GlaxoSmithKline, Janssen Research and Development, LLC, Lupus Foundation of America, Lupus Research Alliance, Merck & Co., Inc., National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer, Inc., Rheumatology Research Foundation, Sanofi and Takeda Pharmaceuticals International, Inc.) created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. Funding was provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2- AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694 and UM2- AR067678). Accelerating Medicines Partnership and AMP are registered service marks of the US Department of Health and Human Services. This work was also supported by the PhRMA Foundation and the Arthritis National Research Foundation Award (to F.Z.); NIH NIAMS K08AR081412, Rheumatology Research Foundation Investigator Award, and Arthritis National Research Foundation Award (to A.H.J.); NIH NHGRI T32HG002295 and NIAMS T32AR007530 (to A. Nathan); NIH NIAMS K08AR077037, Rheumatology Research Foundation Innovative Research Award, and Burroughs Wellcome Fund Career Award in Medical Sciences (to K. Wei); NIH NIGMS T32GM007753 (to J.B.K.); NIH NIAMS R01078268 and NCATS UL1 TR001866 (to D.E.O.); NIH NIAID T32AR007258 (to K.S.); Research into Inflammatory Arthritis Centre Versus Arthritis (22072), IMI-RTCure (777357) and the NIHR Birmingham Biomedical Research Centre (BRC-1215-20009) (to A.F. and D.S.T.); NIH NIAMS K08AR072791 and Burroughs Wellcome Fund Career Award in Medical Sciences (to D.A.R.); NIH NIAID R01AI148435 (to L.T.D.); NIH NIAMS R21AR071670 and P30 AR069655 (to J.H.A.); NIH NIAMS R01AR073833 and R01AR073290 (to M.B.B.); NIH NHGRI U01HG009379 and NIAMS R01AR063759 (to S.R.). We especially acknowledge people in the AMP RA/SLE Network: A. Arazi, C. Berthier, J. Buyon, M. Dall’Era, A. Davidson, B. Diamond, A. Fava, J. Grossman, N. Hacohen, D. Hildeman, J. Hodgin, T. Hwang, M. Ishimori, K. Kalunian, D. Kamen, M. Kretzler, H. Maecker, R. Mao, M. McMahon, F. Payan-Schober, M. Petri, C. Putterman, D. Simmons, T. Tuschl, D. Wofsy and Steve Woodle.

PY - 2023/11/16

Y1 - 2023/11/16

N2 - Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1, 2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.

AB - Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1, 2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.

KW - Humans

KW - Arthritis, Rheumatoid/pathology

KW - Synovial Membrane/pathology

KW - Cytokines/metabolism

KW - Inflammation/pathology

U2 - 10.1038/s41586-023-06708-y

DO - 10.1038/s41586-023-06708-y

M3 - Article

C2 - 37938773

SN - 0028-0836

VL - 623

SP - 616

EP - 624

JO - Nature

JF - Nature

IS - 7987

ER -

Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes

Abstract

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Keywords

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