Background T-cells are thought to be key players in the initiation and progression of rheumatoid arthritis (RA). Earlier we showed that already at the seropositive “at risk” stage uninflamed synovial tissue contains T-cell infiltrates1. In another study we showed that inflamed synovium selectively harbours expanded T-cell clones that are hardly present in paired blood samples2.
Objectives Following up on these observations, we longitudinally investigated whether the same expanded T-cell clones found in the inflamed synovial tissue at onset of RA are already present in the synovium in the seropositive “at risk” stage.
Methods Fifty-five individuals without arthritis but seropositive for IgM rheumatoid factor and/or anti-citrullinated protein antibody (ACPA) were prospectively followed. In five aCCP+ individuals synovial biopsies and paired blood samples at inclusion (“at risk” stage) and after development of RA (ACR2010 criteria; mean time to arthritis 27 months (range 11.7–47.3)) were available for analysis. T-cell clones were identified by their unique TCRβ sequence using RNA-based next generation sequencing3. For each sample, 3570 TCRβ sequences were analysed. Clones with a frequency of ≥0.5% were arbitrarily considered as highly expanded clones (HECs). ANOVA and t-test were used for statistical analysis.
Results T-cell repertoires in “at risk” and RA synovium were similar (mean (± SD) number of clones 488±70 vs 567±204 respectively, p=0.46), number of HECs (37±7 vs 31±18, p=0.41) and the impact of HECs collectively on the TCR repertoire (mean 48% ± 13% vs 50% ± 20%, p=0.84). Interestingly, of the HECs present in the synovium at onset of arthritis 23% (±9%) were already present as HECs in the synovium at the seropositive “at risk” stage. This overlap was significantly higher than that with paired blood samples taken at the arthritis (3% ± 3%; p=0.01) or at the seropositive “at risk” stage (5% ± 7%; p=0.01; Figure 1a-c patient example; Figure 1d summary of results). Further characterization of the synovial CDR3 sequences (length, total charge, polar, aromatic and aliphatic side chains) showed no significant differences between RA HECs that were and those that were not expanded in the seropositive “at risk” stage.
Conclusions Many T-cell clones found in early RA synovial tissue are already present in the pre-clinical “at risk” phase. The resemblance in TCR repertoires indicates that the process leading to disease – at least at the T-cell level – constitutes a smooth development. These clones, being already present in the very early stage of this disease and persisting as dominant clones during contraction of active arthritis, form attractive candidates for further characterization.
de Hair MJ et al. Arthritis Rheum. 2014.
Klarenbeek PL et al. Ann Rheum Dis. 2012.
Klarenbeek PL et al. Immunol Lett. 2010.
Disclosure of Interest None declared