Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium

Garrett Dunlap; Aaron Wagner; Nida Meednu; Ruoqiao Wang; Fan Zhang; Jabea Cyril Ekabe; Anna Helena Jonsson; Kevin Wei; Saori Sakaue; Aparna Nathan; Vivian P. Bykerk; Laura T. Donlin; Susan M. Goodman; Gary S. Firestein; David L. Boyle; V. Michael Holers; Larry W. Moreland; Darren Tabechian; Costantino Pitzalis; Andrew Filer; Soumya Raychaudhuri; Michael B. Brenner; Juilee Thakar; Andrew McDavid; Deepak A. Rao; Jennifer H. Anolik; Jennifer Albrecht; William Apruzzese; Jennifer L. Barnas; Joan M. Bathon; Ami Ben-Artzi; Brendan F. Boyce; S. Louis Bridges; Debbie Campbell; Hayley L. Carr; Arnold Ceponis; Adam Chicoine; Andrew Cordle; Michelle Curtis; Kevin D. Deane; Edward DiCarlo; Patrick Dunn; Lindsy Forbess; Laura Geraldino-Pardilla; Ellen M. Gravallese; Peter K. Gregersen; Joel M. Guthridge; Diane Horowitz; Laura B. Hughes; Kazuyoshi Ishigaki; Lionel B. Ivashkiv; Judith A. James; Joyce B. Kang; Gregory Keras; Ilya Korsunsky; Amit Lakhanpal; James A. Lederer; Yuhong Li; Zhihan J. Li; Katherine P. Liao; Holden Maecker; Arthur M. Mandelin; Ian Mantel; Mark Maybury; Mandy J. McGeachy; Joseph Mears; Alessandra Nerviani; Dana E. Orange; Harris Perlman; Javier Rangel-Moreno; Karim Raza; Yakir Reshef; Christopher Ritchlin; Felice Rivellese; William H. Robinson; Laurie Rumker; Ilfita Sahbudin; Karen Salomon-Escoto; Dagmar Scheel-Toellner; Jennifer A. Seifert; Anvita Singaraju; Melanie H. Smith; Paul J. Utz; Kathryn Weinand; Dana Weisenfeld; Michael H. Weisman; Qian Xiao; Zhu Zhu

doi:10.1038/s41467-024-49186-0

Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium

Garrett Dunlap, Aaron Wagner, Nida Meednu, Ruoqiao Wang, Fan Zhang, Jabea Cyril Ekabe, Anna Helena Jonsson, Kevin Wei, Saori Sakaue, Aparna Nathan, Vivian P. Bykerk, Laura T. Donlin, Susan M. Goodman, Gary S. Firestein, David L. Boyle, V. Michael Holers, Larry W. Moreland, Darren Tabechian, Costantino Pitzalis, Andrew FilerSoumya Raychaudhuri, Michael B. Brenner, Juilee Thakar, Andrew McDavid, Deepak A. Rao^*, Jennifer H. Anolik^*, Jennifer Albrecht, William Apruzzese, Jennifer L. Barnas, Joan M. Bathon, Ami Ben-Artzi, Brendan F. Boyce, S. Louis Bridges, Debbie Campbell, Hayley L. Carr, Arnold Ceponis, Adam Chicoine, Andrew Cordle, Michelle Curtis, Kevin D. Deane, Edward DiCarlo, Patrick Dunn, Lindsy Forbess, Laura Geraldino-Pardilla, Ellen M. Gravallese, Peter K. Gregersen, Joel M. Guthridge, Diane Horowitz, Laura B. Hughes, Kazuyoshi Ishigaki, Lionel B. Ivashkiv, Judith A. James, Joyce B. Kang, Gregory Keras, Ilya Korsunsky, Amit Lakhanpal, James A. Lederer, Yuhong Li, Zhihan J. Li, Katherine P. Liao, Holden Maecker, Arthur M. Mandelin, Ian Mantel, Mark Maybury, Mandy J. McGeachy, Joseph Mears, Alessandra Nerviani, Dana E. Orange, Harris Perlman, Javier Rangel-Moreno, Karim Raza, Yakir Reshef, Christopher Ritchlin, Felice Rivellese, William H. Robinson, Laurie Rumker, Ilfita Sahbudin, Karen Salomon-Escoto, Dagmar Scheel-Toellner, Jennifer A. Seifert, Anvita Singaraju, Melanie H. Smith, Paul J. Utz, Kathryn Weinand, Dana Weisenfeld, Michael H. Weisman, Qian Xiao, Zhu Zhu

^*Corresponding author for this work

Medicine, Rheumatology Division

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

9 Scopus citations

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.

Original language	English (US)
Article number	4991
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-49186-0
State	Published - Dec 2024

Funding

A.H.J. receives research support from Amgen unrelated to the submitted work. K.Wei received a sponsored-research agreement from Gilead Sciences, 10X Genomics, and served as a consultant for Mestag Therapeutics and Santa Ana Bio. S.M.G. reports research support from Novartis and is a consultant for UCB unrelated to this work. G.S.F reports receiving grant support from Eli Lilly. V.M.H. is a co-founder of Q32 Bio and previously received research support from Janssen and was a consultant for Celgene and BMS, outside the submitted work. A.F. reports personal fees from Abbvie, Roche, and Janssen and grant support from Roche, UCB, Nascient, Mestag, GlaxoSmithKline and Janssen unrelated to this work. M.B.B. is a founder of Mestag Therapeutics and a consultant for GlaxoSmithKline, 4FO Ventures, and Scailyte AG. S.R is a founder of Mestag Therapeutics, a scientific adviser for Janssen and Pfizer, and a consultant for Gilead and Rheos Medicines, D.A.R. reports sponsored research from Janssen, Merck, and Bristol-Myers Squibb unrelated to the current work, and reports personal fees from Pfizer, Janssen, Merck, Scipher Medicine, GlaxoSmithKline, and Bristol-Myers Squibb and is co-inventor on a patent using T peripheral helper cells as a biomarker of autoimmune diseases. A.M.M. is a promotional speaker for Abbie and Pfizer, have developed educational content and speak for the National Psoriasis Foundation, and served as a consultant for CVS Caremark which none of this is relevant to this study. The remaining authors declare no competing interests.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-024-49186-0

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Dunlap, G., Wagner, A., Meednu, N., Wang, R., Zhang, F., Ekabe, J. C., Jonsson, A. H., Wei, K., Sakaue, S., Nathan, A., Bykerk, V. P., Donlin, L. T., Goodman, S. M., Firestein, G. S., Boyle, D. L., Holers, V. M., Moreland, L. W., Tabechian, D., Pitzalis, C., ... Zhu, Z. (2024). Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium. Nature communications, 15(1), Article 4991. https://doi.org/10.1038/s41467-024-49186-0

@article{583a6a2533e44e119484d6fdbe8ad2c0,

title = "Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium",

abstract = "Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.",

author = "Garrett Dunlap and Aaron Wagner and Nida Meednu and Ruoqiao Wang and Fan Zhang and Ekabe, {Jabea Cyril} and Jonsson, {Anna Helena} and Kevin Wei and Saori Sakaue and Aparna Nathan and Bykerk, {Vivian P.} and Donlin, {Laura T.} and Goodman, {Susan M.} and Firestein, {Gary S.} and Boyle, {David L.} and Holers, {V. Michael} and Moreland, {Larry W.} and Darren Tabechian and Costantino Pitzalis and Andrew Filer and Soumya Raychaudhuri and Brenner, {Michael B.} and Juilee Thakar and Andrew McDavid and Rao, {Deepak A.} and Anolik, {Jennifer H.} and Jennifer Albrecht and William Apruzzese and Barnas, {Jennifer L.} and Bathon, {Joan M.} and Ami Ben-Artzi and Boyce, {Brendan F.} and Bridges, {S. Louis} and Debbie Campbell and Carr, {Hayley L.} and Arnold Ceponis and Adam Chicoine and Andrew Cordle and Michelle Curtis and Deane, {Kevin D.} and Edward DiCarlo and Patrick Dunn and Lindsy Forbess and Laura Geraldino-Pardilla and Gravallese, {Ellen M.} and Gregersen, {Peter K.} and Guthridge, {Joel M.} and Diane Horowitz and Hughes, {Laura B.} and Kazuyoshi Ishigaki and Ivashkiv, {Lionel B.} and James, {Judith A.} and Kang, {Joyce B.} and Gregory Keras and Ilya Korsunsky and Amit Lakhanpal and Lederer, {James A.} and Yuhong Li and Li, {Zhihan J.} and Liao, {Katherine P.} and Holden Maecker and Mandelin, {Arthur M.} and Ian Mantel and Mark Maybury and McGeachy, {Mandy J.} and Joseph Mears and Alessandra Nerviani and Orange, {Dana E.} and Harris Perlman and Javier Rangel-Moreno and Karim Raza and Yakir Reshef and Christopher Ritchlin and Felice Rivellese and Robinson, {William H.} and Laurie Rumker and Ilfita Sahbudin and Karen Salomon-Escoto and Dagmar Scheel-Toellner and Seifert, {Jennifer A.} and Anvita Singaraju and Smith, {Melanie H.} and Utz, {Paul J.} and Kathryn Weinand and Dana Weisenfeld and Weisman, {Michael H.} and Qian Xiao and Zhu Zhu",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-49186-0",

language = "English (US)",

volume = "15",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Dunlap, G, Wagner, A, Meednu, N, Wang, R, Zhang, F, Ekabe, JC, Jonsson, AH, Wei, K, Sakaue, S, Nathan, A, Bykerk, VP, Donlin, LT, Goodman, SM, Firestein, GS, Boyle, DL, Holers, VM, Moreland, LW, Tabechian, D, Pitzalis, C, Filer, A, Raychaudhuri, S, Brenner, MB, Thakar, J, McDavid, A, Rao, DA, Anolik, JH, Albrecht, J, Apruzzese, W, Barnas, JL, Bathon, JM, Ben-Artzi, A, Boyce, BF, Bridges, SL, Campbell, D, Carr, HL, Ceponis, A, Chicoine, A, Cordle, A, Curtis, M, Deane, KD, DiCarlo, E, Dunn, P, Forbess, L, Geraldino-Pardilla, L, Gravallese, EM, Gregersen, PK, Guthridge, JM, Horowitz, D, Hughes, LB, Ishigaki, K, Ivashkiv, LB, James, JA, Kang, JB, Keras, G, Korsunsky, I, Lakhanpal, A, Lederer, JA, Li, Y, Li, ZJ, Liao, KP, Maecker, H, Mandelin, AM, Mantel, I, Maybury, M, McGeachy, MJ, Mears, J, Nerviani, A, Orange, DE, Perlman, H, Rangel-Moreno, J, Raza, K, Reshef, Y, Ritchlin, C, Rivellese, F, Robinson, WH, Rumker, L, Sahbudin, I, Salomon-Escoto, K, Scheel-Toellner, D, Seifert, JA, Singaraju, A, Smith, MH, Utz, PJ, Weinand, K, Weisenfeld, D, Weisman, MH, Xiao, Q & Zhu, Z 2024, 'Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium', Nature communications, vol. 15, no. 1, 4991. https://doi.org/10.1038/s41467-024-49186-0

TY - JOUR

T1 - Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium

AU - Dunlap, Garrett

AU - Wagner, Aaron

AU - Meednu, Nida

AU - Wang, Ruoqiao

AU - Zhang, Fan

AU - Ekabe, Jabea Cyril

AU - Jonsson, Anna Helena

AU - Wei, Kevin

AU - Sakaue, Saori

AU - Nathan, Aparna

AU - Bykerk, Vivian P.

AU - Donlin, Laura T.

AU - Goodman, Susan M.

AU - Firestein, Gary S.

AU - Boyle, David L.

AU - Holers, V. Michael

AU - Moreland, Larry W.

AU - Tabechian, Darren

AU - Pitzalis, Costantino

AU - Filer, Andrew

AU - Raychaudhuri, Soumya

AU - Brenner, Michael B.

AU - Thakar, Juilee

AU - McDavid, Andrew

AU - Rao, Deepak A.

AU - Anolik, Jennifer H.

AU - Albrecht, Jennifer

AU - Apruzzese, William

AU - Barnas, Jennifer L.

AU - Bathon, Joan M.

AU - Ben-Artzi, Ami

AU - Boyce, Brendan F.

AU - Bridges, S. Louis

AU - Campbell, Debbie

AU - Carr, Hayley L.

AU - Ceponis, Arnold

AU - Chicoine, Adam

AU - Cordle, Andrew

AU - Curtis, Michelle

AU - Deane, Kevin D.

AU - DiCarlo, Edward

AU - Dunn, Patrick

AU - Forbess, Lindsy

AU - Geraldino-Pardilla, Laura

AU - Gravallese, Ellen M.

AU - Gregersen, Peter K.

AU - Guthridge, Joel M.

AU - Horowitz, Diane

AU - Hughes, Laura B.

AU - Ishigaki, Kazuyoshi

AU - Ivashkiv, Lionel B.

AU - James, Judith A.

AU - Kang, Joyce B.

AU - Keras, Gregory

AU - Korsunsky, Ilya

AU - Lakhanpal, Amit

AU - Lederer, James A.

AU - Li, Yuhong

AU - Li, Zhihan J.

AU - Liao, Katherine P.

AU - Maecker, Holden

AU - Mandelin, Arthur M.

AU - Mantel, Ian

AU - Maybury, Mark

AU - McGeachy, Mandy J.

AU - Mears, Joseph

AU - Nerviani, Alessandra

AU - Orange, Dana E.

AU - Perlman, Harris

AU - Rangel-Moreno, Javier

AU - Raza, Karim

AU - Reshef, Yakir

AU - Ritchlin, Christopher

AU - Rivellese, Felice

AU - Robinson, William H.

AU - Rumker, Laurie

AU - Sahbudin, Ilfita

AU - Salomon-Escoto, Karen

AU - Scheel-Toellner, Dagmar

AU - Seifert, Jennifer A.

AU - Singaraju, Anvita

AU - Smith, Melanie H.

AU - Utz, Paul J.

AU - Weinand, Kathryn

AU - Weisenfeld, Dana

AU - Weisman, Michael H.

AU - Xiao, Qian

AU - Zhu, Zhu

PY - 2024/12

Y1 - 2024/12

N2 - Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.

AB - Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.

UR - http://www.scopus.com/inward/record.url?scp=85195888359&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85195888359&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-49186-0

DO - 10.1038/s41467-024-49186-0

M3 - Article

C2 - 38862501

AN - SCOPUS:85195888359

SN - 2041-1723

VL - 15

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4991

ER -

Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium

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