Dendritic Cells (DCs) in Rheumatoid Arthritis (RA): Progenitor Cells and Soluble Factors Contained in RA Synovial Fluid Yield a Subset of Myeloid DCs That Preferentially Activate Th1 Inflammatory-Type Responses

Abstract

There is evidence that mature dendritic cells (DCs) present in the rheumatoid arthritis (RA) joint mediate immunopathology in RA. In this study, we indicate that early myeloid progenitors for DCs and DC growth factors existing in RA synovial fluid (SF) are also likely participants in the RA disease process. A fraction of cells lacking markers associated with mature DCs or DC precursors and enriched in CD34negative myeloid progenitors was isolated from RA SF. These cells proliferated extensively when cultured in vitro with cytokines that promote the growth of myeloid DCs (GM-CSF/TNF/stem cell factor/IL-4) and, to a lesser degree, when cultured with monocyte/granulocyte-restricted growth factors (M-CSF/GM-CSF). Mature DCs derived from RA SF progenitors with CD14-DC cytokines known to be prevalent in the inflamed RA joint (GM-CSF/TNF/stem cell factor/IL-13) were potent stimulators of allogeneic T cells and inflammatory-type Th1 responses and included CD14-DC subtypes. Cell-free RA SF facilitated DC maturation from myeloid progenitors, providing direct evidence that the inflamed RA joint environment instructs DC growth. Enhanced development of CD14-derived DCs was correlated with the presence of soluble TNFR (p55), raising the possibility that soluble TNFR also regulate CD14-derived DC growth in vivo. SF from patients with osteoarthritis contained neither myeloid DC progenitors nor DC growth factors. The existence of DC progenitors and myeloid DC growth factors in RA SF supports the concept that RA SF may be a reservoir for joint-associated DCs and reveals a compelling mechanism for the amplification and perpetuation of DC-driven responses in the RA joint, including inflammatory-type Th1 responses.

Co‐stimulatory and adhesion molecules of dendritic cells in rheumatoid arthritis

“…DCs from control patients did not express such differentiation markers. We found a proportion of ST DCs in RA patients higher than previously reported [18,27], possibly due to our experimental design. The enhanced adhesion and co-stimulatory ability of SF and ST DCs may play an important role in the pathogenesis of the synovial immune response and its localization to the joint [43][44][45].…”

“…A large number of DCs is found in synovial effusions of patients with RA [15][16][17]. They comprise up to 5% SF mononuclear cells, compared to less than 1% of peripheral blood cells [18]. DCs are found in the SF of patients with other forms of inflammatory arthritis, but their number is significantly less than in RA and some data suggested that RA articular DCs present antigen more efficiently that those isolated from other sites [19].…”

Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming

“…4A). As previously noted by us (17), RASF contained CD86 ϩ DR ϩ DCs and CD14 dim DC precursors. CD91, the universal hspR (4) was highly coexpressed with CD14 (which can also bind hsp70 via the CD14 surface complex) (13,21).…”

Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis

“…However, osteoarthritic tissues contain similar numbers of progenitor cells, thus excluding inflammatory cytokines and chemokines as the only mechanisms that orchestrate recruitment. Progenitor cells have also been isolated from synovial fluid (34). Support for a reduction of the HPC pool in RA comes from studies describing reduced numbers of BM CD34ϩ cells and reduced recovery of CD34ϩ populations in RA patients undergoing BM transplantation (22,23).…”