Background Plasmacytoid dendritic cells (pDCs) primarily produce type 1 interferons but also present antigen. pDCs migrate towards inflammatory sites and, in established RA, are reduced in peripheral blood but increased in synovium. We questioned their role in early disease by studying circulating pDCs in early, drug-naïve RA patients.
Materials and methods Drug-naïve early RA patients and healthy controls were recruited. Peripheral blood flow cytometry identified pDCs (CD20-CD19-CD3-CD203-CD14-HLADR+CD1c-Cd11c-CD141-CD123+). Frequency was calculated (percentage of lymphocytes) and activation/co-stimulation molecule expression quantified. Some RA patients were sampled longitudinally. The whole blood interferon gene signature (IGS) was defined as the mean expression (RT-PCR) of MxA, IFI6, OAS1, ISG15 and IFI44L. pDCs were flow sorted and their transcriptome analysed by NanoString nCounter technology. Significance when p<0.05.
Results 44 early RA patients (median age 57 [33–84], male:female 3:4) and 30 healthy controls (median age 37 [23–62], male:female 3:2) were studied. pDC frequency was significantly reduced in early RA, most markedly in seropositive (n=25) patients where it associated with increased CCR7 expression. CD86, HLA-DR and CD40 expression was comparable between early RA and healthy controls with no effect of serostatus (univariate linear regression (age and sex corrected) and Mann-Whitney U tests). Longitudinal analysis of early RA patients (n=15) demonstrated significant reduction in CD86, HLA-DR and CD40 expression during the first 12 months of symptoms but no change in CCR7 expression or pDC frequency (Wilcoxon signed-rank tests). There was no significant association between the IGS and pDC frequency or phenotype (linear regression). The pDC transcriptome was examined in 8 early RA patients and 4 healthy controls (age and sex matched). Differentially expressed genes (R Core team 2016) and Ingenuity Pathway Analysis suggested increased proliferation and reduced apoptosis in early RA but no increased activation.
Conclusions This is the first detailed examination of pDCs in early RA. The reduced frequency at diagnosis, alongside a comparatively activated phenotype, suggests possible migration to the synovium of potential pathogenic relevance. Furthermore, transcriptomic analysis highlighted a possible expansion of pDCs in early RA, via enhanced proliferation and reduced death. Synovial analysis will be essential to identify a pDC contribution to RA pathogenesis.
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