Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+ T Lymphocyte Signature

Tiina Kelkka*, Paula Savola, Dipabarna Bhattacharya, Jani Huuhtanen, Tapio Lönnberg, Matti Kankainen, Kirsi Paalanen, Mikko Tyster, Maija Lepistö, Pekka Ellonen, Johannes Smolander, Samuli Eldfors, Bhagwan Yadav, Sofia Khan, Riitta Koivuniemi, Christopher Sjöwall, Laura L. Elo, Harri Lähdesmäki, Yuka Maeda, Hiroyashi NishikawaMarjatta Leirisalo-Repo, Tuulikki Sokka-Isler, Satu Mustjoki

*Corresponding author for this work

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Abstract

Rheumatoid arthritis (RA) is a complex autoimmune disease targeting synovial joints. Traditionally, RA is divided into seropositive (SP) and seronegative (SN) disease forms, the latter consisting of an array of unrelated diseases with joint involvement. Recently, we described a severe form of SN-RA that associates with characteristic joint destruction. Here, we sought biological characteristics to differentiate this rare but aggressive anti-citrullinated peptide antibody-negative destructive RA (CND-RA) from early seropositive (SP-RA) and seronegative rheumatoid arthritis (SN-RA). We also aimed to study cytotoxic CD8+ lymphocytes in autoimmune arthritis. CND-RA, SP-RA and SN-RA were compared to healthy controls to reveal differences in T-cell receptor beta (TCRβ) repertoire, cytokine levels and autoantibody repertoires. Whole-exome sequencing (WES) followed by single-cell RNA-sequencing (sc-RNA-seq) was performed to study somatic mutations in a clonally expanded CD8+ lymphocyte population in an index patient. A unique TCRβ signature was detected in CND-RA patients. In addition, CND-RA patients expressed higher levels of the bone destruction-associated TNFSF14 cytokine. Blood IgG repertoire from CND-RA patients recognized fewer endogenous proteins than SP-RA patients’ repertoires. Using WES, we detected a stable mutation profile in the clonally expanded CD8+ T-cell population characterized by cytotoxic gene expression signature discovered by sc-RNA-sequencing. Our results identify CND-RA as an independent RA subset and reveal a CND-RA specific TCR signature in the CD8+ lymphocytes. Improved classification of seronegative RA patients underlines the heterogeneity of RA and also, facilitates development of improved therapeutic options for the treatment resistant patients.

Original languageEnglish
Article number578848
Number of pages12
JournalFRONTIERS IN IMMUNOLOGY
Volume11
DOIs
Publication statusPublished - 19 Nov 2020
MoE publication typeA1 Journal article-refereed

Keywords

  • ACPA-negative
  • CD8+ lymphocyte
  • rheumatoid arthritis
  • seronegative
  • somatic mutation
  • T cell receptor

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