TY - JOUR
T1 - Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+ T Lymphocyte Signature
AU - Kelkka, Tiina
AU - Savola, Paula
AU - Bhattacharya, Dipabarna
AU - Huuhtanen, Jani
AU - Lönnberg, Tapio
AU - Kankainen, Matti
AU - Paalanen, Kirsi
AU - Tyster, Mikko
AU - Lepistö, Maija
AU - Ellonen, Pekka
AU - Smolander, Johannes
AU - Eldfors, Samuli
AU - Yadav, Bhagwan
AU - Khan, Sofia
AU - Koivuniemi, Riitta
AU - Sjöwall, Christopher
AU - Elo, Laura L.
AU - Lähdesmäki, Harri
AU - Maeda, Yuka
AU - Nishikawa, Hiroyashi
AU - Leirisalo-Repo, Marjatta
AU - Sokka-Isler, Tuulikki
AU - Mustjoki, Satu
N1 - | openaire: EC/H2020/765937/EU//CINCHRON
| openaire: EC/H2020/862011/EU//STRATIFY
| openaire: EC/H2020/677943/EU//DynaOmics
| openaire: EC/H2020/675395/EU//ENLIGHT-TEN
PY - 2020/11/19
Y1 - 2020/11/19
N2 - 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.
AB - 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.
KW - ACPA-negative
KW - CD8+ lymphocyte
KW - rheumatoid arthritis
KW - seronegative
KW - somatic mutation
KW - T cell receptor
UR - http://www.scopus.com/inward/record.url?scp=85097291853&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2020.578848
DO - 10.3389/fimmu.2020.578848
M3 - Article
AN - SCOPUS:85097291853
VL - 11
JO - FRONTIERS IN IMMUNOLOGY
JF - FRONTIERS IN IMMUNOLOGY
SN - 1664-3224
M1 - 578848
ER -