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

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

doi:10.3389/fimmu.2020.578848

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.

Highlights

Rheumatoid arthritis is a chronic autoimmune disease in which the patient’s own immune system targets the synovial tissue in joints
Antibody profiles were stable as paired samples from two SP-rheumatoid arthritis (RA) patients after 14- or 16-months follow-up resulted in highly comparable results (Figure 1A and Supplementary Figure 4)
When Seronegative RA (SN-RA) patients were compared to CCP-negative destructive (CND)-RA, we found a median of 30 clonotypes that were enriched to SN-RA, and seropositive RA (SP-RA) patients had 12 such clonotypes, suggesting dissimilarity between the CND-RA and other RA subtypes (Figure 2E)

Summary

Introduction

Rheumatoid arthritis is a chronic autoimmune disease in which the patient’s own immune system targets the synovial tissue in joints. According to the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA), seropositive RA (SP-RA) is characterized by the presence of anti-cyclic citrullinated peptide antibodies (ACPA) and/or rheumatoid factor (RF). We have recently provided a clinical description of an unusually severe form of SN-RA [3]. These patients are negative for the clinically used anti-cyclic citrullinated peptide 2 (CCP2) test, and the clinical manifestations include the progression of joint destruction despite active therapy. We named the cohort as CCP-negative destructive (CND) RA, and differently from the classical SP-RA, the destruction is predominantly localized in the wrists, ankles, and even in large joints [3]. The biomedical characteristics of this RA sub-type have not been studied before

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