Rheumatoid arthritis synovial tissue harbours dominant B-cell and plasma-cell clones associated with autoreactivity

• Published in: Annals of the rheumatic diseases Vol. 73; no. 4; pp. 756 - 762
• Main Authors: Doorenspleet, M E, Klarenbeek, P L, de Hair, M J H, van Schaik, B D C, Esveldt, R E E, van Kampen, A H C, Gerlag, D M, Musters, A, Baas, F, Tak, P P, de Vries, N
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.04.2014
• Subjects: Amino Acid Sequence; Antigens; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Autoimmunity - immunology; B-Lymphocytes - immunology; Binding sites; Bioinformatics; Biopsy; Clone Cells - immunology; Cloning; Complementarity Determining Regions - genetics; Complementarity Determining Regions - immunology; Disease; Female; Genes; Genotype & phenotype; Humans; Immunoglobulin Class Switching - immunology; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Variable Region - genetics; Immunoglobulins; Inflammation; Lymphocyte Activation - immunology; Lymphocytes; Male; Molecular Sequence Data; Pathogenesis; Patients; Plasma; Plasma Cells - immunology; Rheumatoid arthritis; Severity of Illness Index; Studies; Synovial Membrane - immunology; T cell receptors; Synovitis; B cells; Rheumatoid Arthritis; Early Rheumatoid Arthritis
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2012-202861

Objective To identify potential autoreactive B-cell and plasma-cell clones by quantitatively analysing the complete human B-cell receptor (BCR) repertoire in synovium and peripheral blood in early and established rheumatoid arthritis (RA). Methods The BCR repertoire was screened in synovium and blood of six patients with early RA (ERA) (<6 months) and six with established RA (ESRA) (>20 months). In two patients, the repertoires in different joints were compared. Repertoires were analysed by next-generation sequencing from mRNA, generating >10 000 BCR heavy-chain sequence reads per sample. For each clone, the degree of expansion was calculated as the percentage of the total number of reads encoding the specific clonal sequence. Clones with a frequency ≥0.5% were considered dominant. Results Multiple dominant clones were found in inflamed synovium but hardly any in blood. Within an individual patient, the same dominant clones were detected in different joints. The majority of the synovial clones were class-switched; however, the fraction of clones that expressed IgM was higher in ESRA than ERA patients. Dominant synovial clones showed autoreactive features: in ERA in particular the clones were enriched for immunoglobulin heavy chain gene segment V4–34 (IGHV4–34) and showed longer CDR3 lengths. Dominant synovial clones that did not encode IGHV4–34 also had longer CDR3s than peripheral blood. Conclusions In RA, the synovium forms a niche where expanded—potentially autoreactive—B cells and plasma cells reside. The inflamed target tissue, especially in the earliest phase of disease, seems to be the most promising compartment for studying autoreactive cells.