Background/Purpose:

Previous studies indicate that circulating antibodies may be detected in individuals who later develop rheumatoid arthritis (RA) years before onset, and T cells have been implicated in the pathogenesis of RA. The purpose of this study was to investigate peripheral blood T cell phenotypes before the onset of RA.

Methods: Incident cases of RA were identified among participants (n=30447) in a community based health survey, which was linked to local and national registers, followed by a structured review of the medical records. One control, matched for age, sex and year of inclusion in the health survey, was selected for each validated case. Peripheral blood cells from a subset of participants in the health survey had been frozen according to a specified protocol and stored at -140° C. Phenotypes of peripheral blood T cells were determined by direct immunofluorescence staining and multicolor flow cytometry. Th1 cells were defined as CD4+ IFN-g+ cells, Th2 cells as CD4+ IL-4+ cells, Th17 cells as CD4+ IL-17+ cells, and regulatory T cells (Tregs) as CD25+ FoxP3+ cells. Anti-CCP2 antibodies (Euro-Diagnostica; reference interval <20 U/L) were measured in sera collected at the same time as the cell samples. Analyses were stratified by time from inclusion in the health survey to RA diagnosis and by anti-CCP2 status.

Results: Peripheral blood cell samples were available from 78 matched pairs of pre-RA cases and controls (mean age 57 years, 82 % women). The median time from inclusion in the health survey to RA diagnosis in the cases was 6 years [interquartile range (IQR) 3-8; range 1-13]. Twelve pre-RA cases (15 %) were anti-CCP2 positive. There were no major differences in lymphocyte counts or the proportions of CD3+, CD4+ or CD8+ cells among lymphocytes between cases and controls. Pre-RA cases and controls had similar proportions of Th1, Th2 and Th17 cells in the CD4+ population. The distribution of Tregs was skewed among pre-RA cases, with a reduced number of cases with high Treg counts compared to controls [median 0.50 % of CD3+ cells (IQR 0.22-1.03) vs. median 0.49 % (IQR 0.32-1.91)], although the difference did not reach significance (p=0.18). This trend was more pronounced in the subset of anti-CCP negative cases included 1-6 years before RA diagnosis and their controls [median 0.51 % (IQR 0.21-1.27) vs. 0.80 % (IQR 0.41-2.86); p=0.15]. Pre-RA cases had significantly lower proportions of CD4+ CD28null cells compared to controls [median 1.58 % of CD4+ cells (IQR 1.18-2.99) vs. 2.24 % (IQR 1.33-3.97); p=0.047].  Anti-CCP positive cases tended to have lower counts of Th1 cells [median 24.2 % of CD4+ cells (IQR 14.8-51.2) vs. 47.7 % (IQR 19.1-73.9); p=0.15] compared to controls.

Conclusion: In this study of a unique resource, we did not find any major abnormalities in the peripheral blood T cell repertoire before the clinical onset of RA. Given the limited sample, we can’t exclude a downregulation of Tregs in anti-CCP negative pre-RA cases and a down-regulation of Th1 cells in anti-CCP positive cases. The lower levels of CD4+ CD28null cells in the pre-RA cases suggest that the demonstrated expansion of such cells in established RA is a consequence of chronic inflammation, rather than an inherent part of the immune phenotype of the disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-peripheral-blood-t-cell-repertoire-before-the-clinical-onset-of-rheumatoid-arthritis-a-study-of-incident-cases-and-controls/