Rheumatoid Arthritis - Human Etiology and Pathogenesis

Today was the final day of the American College of Rheumatology's 2009 Scientific Meeting. Here are some of the study highlights from the finale.

Increased Proportions of CD4+CD25+CD127-FoxP3+ T Cells with Superior Suppressive Capacity Are Present in the Peripheral Blood of Early RA Patients Authors: García-Carmona Y, Benito-Miguel M, Balsa A, et al. Purpose: To assess "the frequency and function of CD4+CD25+CD127-FoxP3+ T cells in the peripheral blood of early RA patients."

Results: Researchers reported that "increased proportions of CD4+CD25+CD127-FoxP3+ T cells with superior suppressive capacity are present in the peripheral blood of early RA patients." However, the study authors noted that "this higher suppressive action is not able to overcome the increased Tresp IFN-γ and TNF-α secretion."

Gene Signatures That Predict Development of Arthritis Authors: Van Baarsen L, Bos WH, Rustenburg F, et al. Purpose: The aim of this study was "to identify molecular features that are associated with the development of RA in order to understand the pathophysiology of preclinical development and to assign predictive biomarkers."

Results: Results of this study implied that "IFN-mediated immunity, hematopoiesis and cell trafficking specify the processes relevant to progression to arthritis besides autoantibody positivity," and researchers reported that these findings "strongly suggest that gene signatures have predictive value for progression to arthritis, which will pave the way to preventive medicine."

Dendritic Cell-Derived Dopamine Induces IL-6-Th17 Axis in Rheumatoid Arthritis Authors: Nakano K, Yamaoka K, Saito K, Tanaka Y Purpose: "It is emerging that Th17 cells among various T cell subsets play important roles in the inflammatory processes including rheumatoid arthritis (RA). Although certain factors and immune cells such as dendritic cells (DCs) are known to be involved in the induction of Th17 cells in murine system, precise mechanisms in human diseases remain unclear. The neuron system is supposed to affect the immune system by releasing neurotransmitters and among them dopamine is a major one in the brain and the first catecholamine synthesized there. We found that DCs secrete dopamine and assessed the role of dopaminergic-signaling in the T cell differentiation and its involvement in the pathogenesis of RA using SCID mice co-implanted with synovium and cartilage from RA patients (SCID-HuRAg mice)."

Results: Findings of this study indicated that "DC is a major source of dopamine in RA synovium and that DC-derived dopamine induces IL-6 -Th17 axis, resulting in aggravation of RA."

CXCR3 Regulates the Invasive Properties of Synovial Fibroblasts Via Akt Signaling, Collagenase Activation and Actin Reorganization Authors: Laragione T, Mello A, Brenner M, et al. Purpose: The aim of this study was to test the following hypothesis: "The interaction between CXCL10 and CXCR3 plays a role in the regulation of FLS invasion and joint damage."

Results: This paper describes, for the first time, "a new autocrine/paracrine role for CXCL10 in the regulation of FLS invasion in arthritis, including RA." Researchers found that "Antibody neutralization and a small molecule inhibitor of the CXCL10 receptor, CXCR3, both in rats and human cells significantly reduced FLS invasion as well as key processes known to regulate cell invasion such as levels of phospho-Akt and MMP-1, and the polarized formation of lamellipodia," and note that their observations suggest "that the CXCL10-CXCR3 pathway is a promising new target for therapies aimed at reducing joint damage and pannus invasion and destruction in RA."

mTOR Regulates the Invasive Properties of Synovial Fibroblast Authors: Laragione T, Mello A, Amir K, Gulko PS Purpose: In this study, researchers use "Rapamycin, an inhibitor of mTOR, to assess the role of the ezrin-mTOR pathway on the invasive properties of FLS from DA rats with PIA and patients with RA."

Results: Researchers found that "Rapamycin significantly reduced FLS invasion in rat and human RA FLS through the suppression of ezrin-mediated mTOR signaling pathway," and note that "this is the first time that mTOR is implicated in the invasive properties of FLS." Their observations suggest that "rapamycin could have a role in RA therapy aimed at reducing the articular damage and erosive changes mediated by FLS."

Expression of Ang-1 and Engagement of Tie2 Is Related to Development of Persistent and Erosive Disease in Early Arthritis Patients Authors: van de Sande M, deLaunay D, van de Sande G, et al. Purpose: To investigate "the value of synovial tissue expression of Ang-1, Ang-2, Tie2 and active phosphorylated Tie2 (pTie2) in predicting outcome in early arthritis patients."

Results: This study "provides the first evidence that engagement of the Ang-1/Tie2 axis in synovial tissue is related to development of persistent and erosive disease," and consequently suggests that "targeting Ang-1 and Tie2 therapeutically may be useful in improving outcome in arthritis." Researchers mention that these markers may also be useful as biomarkers for predicting outc