Myeloid Dendritic Cells Are Enriched in Lymph Node Tissue of Early Rheumatoid Arthritis Patients but not in At Risk Individuals

Abstract

Lymph nodes (LNs) are highly organized structures where specific immune responses are initiated by dendritic cells (DCs). We investigated the frequency and distribution of human myeloid (mDCs) and plasmacytoid (pDCs) in LNs and blood during the earliest phases of rheumatoid arthritis (RA). We included 22 RA-risk individuals positive for IgM rheumatoid factor and/or anti-citrullinated protein antibodies, 16 biological-naïve RA patients and 8 healthy controls (HCs). DC subsets (CD1c+ mDCs and CD304+ pDCs) in LN tissue and paired peripheral blood were analyzed using flow cytometry and confocal microscopy. In blood of RA patients a significant decreased frequency of pDCs was found, with a similar trend for mDCs. In contrast, mDC frequencies were higher in RA compared with HCs and RA-risk individuals, especially in LN. Frequency of mDCs seemed higher in LNs compared to paired blood samples in all donors, while pDCs were higher in LNs only in RA patients. As expected, both mDCs and pDCs localized mainly in T-cell areas of LN tissue. In conclusion, compared with RA-risk individuals, mDCs and pDCs were enriched in the LN tissue of early-RA patients, while their frequency in RA-risk individuals was comparable to HCs. This may suggest that other antigen-presenting cells are responsible for initial breaks of tolerance, while mDCs and pDCs are involved in sustaining inflammation.

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“…We observed an increase in the percentage of pDCs and mDCs in RA patients, consistent with previous reports [ 38 , 39 ]. However, other study showed decreased of DCs in peripheral blood of RA [ 40 ]. It was reported that pre-DCs are expanded in the bone marrow of RA patients, the increase of pre-DCs in the bone marrow shall lead to the increase of DCs in the peripheral blood, which supports our results [ 41 ].…”

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“…For example, the DCs in the pancreatic lymph nodes of type I diabetes patients may have reduced tolerogenic function than those of healthy controls, and there were even differences in lymph node cell composition when correcting for sex and age ( 140 ). T cells, B cells, DCs, and other lymph node cells are also shown to be different in rheumatoid arthritis patients compared to healthy individuals ( 141 – 143 ). Furthermore, efferocytosis can be defective in patients with autoimmune diseases ( 144 , 145 ) or obese individuals ( 146 ), so for these patients nanoparticles that aim to exploit efferocytosis may not be as effective.…”

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“…Both dendritic cells (DCs) (25,26) as well as lymph node stromal cells (LNSC) (27,28) have the capacity to induce peripheral tolerance through presentation of peripheral tissue antigens (PTAs) to autoreactive T cells after which these cells undergo clonal deletion, differentiation into a regulatory T cell or become anergic. When studying DC subsets (CD1c + myeloid DCs and CD304 + plasmacytoid DCs) in LN tissue it appeared that frequencies are comparable between RA-risk individuals and healthy controls, but increased in RA patients (29). This may suggest that these DCs are involved in sustaining inflammation during established RA, or that other DC subsets or other antigen presenting cells (APCs) are responsible for the initial break in tolerance.…”