Phenotypic and Transcriptomic Analysis of Peripheral Blood Plasmacytoid and Conventional Dendritic Cells in Early Drug Naïve Rheumatoid Arthritis.

Faye A H Cooles,Mariola S Kurowska-Stolarska,Iain Mcinnes,Catharien M U Hilkens,Andrew Skelton,John D Isaacs,Amy E Anderson,Arthur G Pratt

doi:10.3389/fimmu.2018.00755

Abstract

Dendritic cells (DCs) are key orchestrators of immune function. To date, rheumatoid arthritis (RA) researchers have predominantly focused on a potential pathogenic role for CD1c+ DCs. In contrast, CD141+ DCs and plasmacytoid DCs (pDCs) have not been systematically examined, at least in early RA. In established RA, the role of pDCs is ambiguous and, since disease duration and treatment both impact RA pathophysiology, we examined pDCs, and CD1c+ and CD141+ conventional DCs (cDCs), in early, drug-naïve RA (eRA) patients. We analyzed the frequency and phenotype of pDCs, CD1c+, and CD141+ DCs from eRA patients and compared findings with healthy controls. In parallel, we performed transcriptional analysis of >600 immunology-related genes (Nanostring) from peripheral blood pDCs, CD1c+ DCs, B cells, T cells, and monocytes. All DC subsets were reduced in eRA (n = 44) compared with healthy controls (n = 30) and, for pDCs, this was most marked in seropositive patients. CD141+ and CD1c+ DCs, but not pDCs, had a comparatively activated phenotype at baseline (increased CD86) and CD1c+ DC frequency inversely associated with disease activity. All DC frequencies remained static 12 months after initiation of immunomodulatory therapy despite a fall in activation markers (e.g., HLA-DR, CD40). There was no association between the whole blood interferon gene signature (IGS) and pDC or CD1c+ DC parameters but an inverse association between CD141+ DC frequency and IGS was noted. Furthermore, IFN-I and IFN-III mRNA transcripts were comparable between eRA pDC and other leukocyte subsets (B cells, CD4+, and CD8+ T cells and monocytes) with no obvious circulating cellular source of IFN-I or IFN-III. Transcriptomic analysis suggested increased pDC and CD1c+ DC proliferation in eRA; pDC differentially expressed genes also suggested enhanced tolerogenic function, whereas for CD1c+ DCs, pro-inflammatory transcripts were upregulated. This is the first detailed examination of DC subsets in eRA peripheral blood. Compared with CD1c+ DCs, pDCs are less activated and may be skewed toward tolerogenic functions. CD141+ DCs may be implicated in RA pathophysiology. Our findings justify further investigation of early RA DC biology.

Highlights

Dendritic cells (DCs) are professional antigen-presenting cells (APCs), which orchestrate immune responses
PDC, CD1c+, and CD141+ DC Peripheral Blood Frequency Is Reduced in Early rheumatoid arthritis (RA), Which Is Sustained Into Established Disease
All DC subsets had significantly reduced frequency in early RA compared with healthy controls (Figure 1A)

Summary

Introduction

Dendritic cells (DCs) are professional antigen-presenting cells (APCs), which orchestrate immune responses. DC receptors can sense danger, microbe, or cytokine signals, which, when triggered, drive DC maturation and activation This promotes migration to lymph nodes, further proinflammatory cytokine release, increased stability of the antigen–MHC complex, and upregulation of costimulatory molecules, such as CD40 and CD86. Some DCs, while retaining APC capacity, are resistant to maturationinducing signals and downregulate co-stimulatory molecule expression and pro-inflammatory cytokines while simultaneously upregulating the expression of inhibitory molecules and antiinflammatory cytokines [4, 5] These so-called regulatory or tolerogenic DCs promote T cell anergy and regulatory T cell (Treg) generation and are being explored as a potential therapy in autoimmune disease [6,7,8,9,10,11]

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