Dendritic cells and the pathogenesis of rheumatoid arthritis

Thomas, Ranjeny; MacDonald, Kelli P. A.; Pettit, Allison R.; Cavanagh, Lois L.; Padmanabha, Jagadish; Zehntner, Simone P.

doi:10.1002/jlb.66.2.286

Cited by 103 publications

(100 citation statements)

References 86 publications

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“…APCs, such as macrophages and DCs, are abundant in the rheumatoid synovial tissues and by presenting autoantigens locally, they lead to amplification of systemic arthritogenic immune responses (49). Signaling via FLT3, expressed on DC progenitors and mature DCs, results in increased numbers of functional DCs and is required for their survival and activation (27).…”

Section: Discussionmentioning

confidence: 99%

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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“…These perivascular DCs were suggested to originate from blood-derived precursors that migrated through the activated endothelium and received differentiation signals, such as GM-CSF and IL-13, within the joint (reviewed in Ref. 38). It is thought that functional DC/T cell interaction can take place locally (39,40), and the perivascular region may act as a site for cell activation (41).…”

Section: Maturationmentioning

confidence: 99%

Collagen Induces Maturation of Human Monocyte-Derived Dendritic Cells by Signaling through Osteoclast-Associated Receptor

Schultz

Nitze

Zeuthen

et al. 2015

The Journal of Immunology

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Osteoclast-associated receptor (OSCAR) is widely expressed on human myeloid cells. Collagen types (Col)I, II, and III have been described as OSCAR ligands, and ColII peptides can induce costimulatory signaling in receptor activator for NF-κB–dependent osteoclastogenesis. In this study, we isolated collagen as an OSCAR-interacting protein from the membranes of murine osteoblasts. We have investigated a functional outcome of the OSCAR–collagen interaction in human monocyte-derived dendritic cells (DCs). OSCAR engagement by ColI/II-induced activation/maturation of DCs is characterized by upregulation of cell surface markers and secretion of cytokines. These collagen-matured DCs (Col-DCs) were efficient drivers of allogeneic and autologous naive T cell proliferation. The T cells expanded by Col-DCs secreted cytokines with no clear T cell polarization pattern. Global RNA profiling revealed that multiple proinflammatory mediators, including cytokines and cytokine receptors, components of the stable immune synapse (namely CD40, CD86, CD80, and ICAM-1), as well as components of TNF and TLR signaling, are transcriptional targets of OSCAR in DCs. Our findings indicate the existence of a novel pathway by which extracellular matrix proteins locally drive maturation of DCs during inflammatory conditions, for example, within synovial tissue of rheumatoid arthritis patients, where collagens become exposed during tissue remodeling and are thus accessible for interaction with infiltrating precursors of DCs.

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“…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]. DCs have also been detected in the ST, especially near dense lymphoid aggregates and high endothelial venules [20]. Synovial DCs migrate from the peripheral blood, presumably under the influence of a chemotactic gradient [21].…”

Section: Introductionmentioning

confidence: 99%

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

Bălănescu

Radu

Nat

et al. 2002

J Cellular Molecular Medi

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Dendritic cells (DCs) in the rheumatoid arthritis (RA) joint mediate the immunopathological process and act as a potent antigen presenting cell. We compared the expression of co‐stimulatory and adhesion molecules on DCs in RA patients versus controls with traumatic joint lesions and evalulated the correlation between the immunophenotypical presentation of DCs and the clinical status of the disease. Samples of peripheral venous blood, synovial fluid (SF) and synovial tissue (ST) were obtained from 10 patients with RA at the time of hip or knee replacement and from 9 control patients with knee arthroscopy for traumatic lesions. Clinical status was appreciated using the DAS28 score. Blood, SF and dissociated ST cell populations were separated by centrifugation and analyzed by flow cytometry. Cells phenotypes were identified using three‐color flow cytometry analysis for the following receptors HLA‐DR, CD80, CD83, CD86, CD11c, CD18, CD54, CD58, CD3, CD4, CD8, CD19, CD20, CD14, CD16, CD56. HLA‐DR molecules, co‐stimulatory receptors CD80, CD86, CD83 and adhesion molecules CD18, CD11c, CD54, CD58, were analyzed by two‐color immunofluorescence microscopy on ST serial sections. In patients with active RA (DAS28>5.1) we found a highly differentiated subpopulation of DCs in the ST and SF that expressed an activated phenotype (HLA‐DR, CD86+, CD80+, CD83+, CD11c+, CD54+, CD58+). No differences were found between circulating DCs from RA patients and control patients. Our data suggest an interrelationship between clinical outcome and the immunophenotypical presentation of DCs. Clinical active RA (DAS28>5.1) is associated with high incidence of activated DCs population in the ST and SF as demonstrated by expression of adhesion and co‐stimulatory molecules.

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Dendritic cells and the pathogenesis of rheumatoid arthritis

Cited by 103 publications

References 86 publications

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Collagen Induces Maturation of Human Monocyte-Derived Dendritic Cells by Signaling through Osteoclast-Associated Receptor

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

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