In Seol Yoo

Functional Phenotype of Synovial Monocytes Modulating Inflammatory T-Cell Responses in Rheumatoid Arthritis (RA)

Monocytes function as crucial innate effectors in the pathogenesis of chronic inflammatory diseases, including autoimmunity, as well as in the inflammatory response against infectious pathogens. Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression. Although accumulating evidence suggests distinct functions of monocyte subsets in inflammatory conditions, their pathogenic roles in autoimmune diseases remain unclear. Thus, we investigated the phenotypic and functional characteristics of monocytes derived from synovial fluid and peripheral blood in RA patients in order to explore the pathogenic roles of these cells. In RA patients, CD14+CD16+, but not CD14dimCD16+, monocytes are predominantly expanded in synovial fluid and, to a lesser degree, in peripheral blood. Expression of co-signaling molecules of the B7 family, specifically CD80 and CD276, was markedly elevated on synovial monocytes, while peripheral monocytes of RA and healthy controls did not express these molecules without stimulation. To explore how synovial monocytes might gain these unique properties in the inflammatory milieu of the synovial fluid, peripheral monocytes were exposed to various stimuli. CD16 expression on CD14+ monocytes was clearly induced by TGF-β, although co-treatment with IL-1β, TNF-α, or IL-6 did not result in any additive effects. In contrast, TLR stimulation with LPS or zymosan significantly downregulated CD16 expression such that the CD14+CD16+ monocyte subset could not be identified. Furthermore, treatment of monocytes with IFN-γ resulted in the induction of CD80 and HLA-DR expression even in the presence of TGF-β. An in vitro assay clearly showed that synovial monocytes possess the unique capability to promote Th1 as well as Th17 responses of autologous peripheral CD4 memory T cells. Our findings suggest that the cytokine milieu of the synovial fluid shapes the unique features of synovial monocytes as well as their cardinal role in shaping inflammatory T-cell responses in RA.

T-helper 17 cells: the driving force of psoriasis and psoriatic arthritis.

There is growing evidence that two recently recognized, unique subsets of CD4+ T‐cells, T‐helper 17 cells (Th17) and CD4+ CD25+ regulatory T‐cells (Treg), may play important roles in the pathogenesis of psoriasis. This study sought to investigate the relationship between Th17 cells and psoriasis or psoriatic arthritis (PsA).

Regulatory B Cells Are Inversely Associated with Disease Activity in Rheumatoid Arthritis

Purpose The function of regulatory B lymphocytes is known to be abnormal in inflammatory diseases. However, a recent study indicates that IL-10+ B cells seem to be expanded in rheumatoid arthritis (RA). Therefore, the state of IL-10+ B cells in the peripheral blood from RA patients and healthy controls were investigated. Materials and Methods CD19+ cells in peripheral blood mononuclear cells were purified from blood samples of RA patients and age and gender-matched healthy controls, and stimulated with CD40 ligand and CpG for 48 hours. Then, intracellular IL-10 in CD19+ cells was analyzed using flow cytometry. Results There was no significant difference in the proportion of IL-10+ B cells between 10 RA patients and 10 healthy controls (RA, 0.300±0.07 vs. healthy control 0.459±0.07, p=0.114). The proportion of induced IL-10+ B cells to total B cells in RA patients was significantly higher than those in controls (RA, 4.44±3.44% vs. healthy control 2.44±1.64%, p=0.033). However, the proportion of IL-10+ B cells to total B cells correlated negatively with disease activity in RA patients (r=-0.398, p=0.040). Erythrocyte sedimentation rate or C-reactive protein or medication was not associated with the proportion of IL-10+ B cells. Conclusion The proportion of induced IL-10+ B cell increased in RA patients compared to healthy control, however, negatively correlated with disease activity in RA.

Prevalence of Pulmonary Arterial Hypertension in Korean Adult Patients with Systemic Sclerosis: Result of a Pilot Echocardiographic Screening Study

Background Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality among patients with systemic sclerosis (SSc). Early detection and prompt treatment of PAH associated with SSc (SSc-PAH) result in better prognosis. We conducted echocardiographic study to presume the prevalence of PAH in Korean adult SSc patients and to diagnose SSc-PAH in their early stages with right heart catheterization (RHC). Methods We performed free of charge echocardiographic study including 37 adult SSc patients at the Chungnam National University Hospital. The possibility of PAH is determined by the estimation of pulmonary arterial pressure by peak tricuspid regurgitation velocity of > 3.0 m/s. Patients with possible PAH were recommended to undergo RHC to confirm the diagnosis. Results In 37 patients, 8 patients were suspected with PAH. Among them, 6 patients agreed to be examined with RHC, and 4 were confirmed with PAH. The prevalence of possible PAH was 21.6% (8 of 37 patients), and that of confirmed PAH was 10.8% (4 of 37 patients). Four patients who were confirmed with SSc-PAH through RHC have been treated with specific pulmonary vasodilators and maintained stable. Conclusion Eight patients (21.6%) were possible PAH and 4 (10.8%) were diagnosed as SSc-PAH by RHC after the echocardiographic screening study of 37 adult SSc patients.

Preferential Induction of the T Cell Auxiliary Signaling Molecule B7-H3 on Synovial Monocytes in Rheumatoid Arthritis

B7-H3, a newly identified B7 family member, has functional duality as a co-stimulator and co-inhibitor that fine-tunes T cell-mediated immune responses. Given that B7-H3 expression on human monocytes and dendritic cells is enhanced by inflammatory cytokines, its potential inmmunoregulatory role at sites of inflammation has been suggested. Further, monocytes play crucial roles in the pathophysiology of various inflammatory disorders including autoimmune diseases; however, the immunological role of B7-H3 in rheumatoid arthritis (RA) has not been defined. Thus, we aimed to investigate the possible roles of monocyte B7-H3 in the pathogenesis of RA. Synovial monocytes, but not peripheral monocytes, in RA patients predominantly express surface B7-H3. The 4Ig isoform of B7-H3 is exclusively induced on the cell surface, whereas the 2Ig B7-H3 isoform is constitutively expressed in the intracytoplasmic region of both peripheral and synovial monocytes. B7-H3 knockdown experiments reveal that surface B7-H3 has an inhibitory effect on IFN-γ production in CD4 memory cells. Moreover, surface B7-H3 expression on synovial monocytes inversely correlates with RA clinical parameters. Our findings demonstrate that activation-induced B7-H3 expression on synovial monocytes has the potential to inhibit Th1-mediated immune responses and immunomodulatory roles affecting RA pathogenesis.

Serum and synovial fluid concentrations of cold-inducible RNA-binding protein in patients with rheumatoid arthritis

There is growing evidence that cold‐inducible RNA‐binding protein (CIRP) promotes inflammatory responses. This study investigated the relationship between CIRP and rheumatoid arthritis (RA).

PIM-1 kinase is a novel regulator of proinflammatory cytokine-mediated responses in rheumatoid arthritis fibroblast-like synoviocytes

Objectives This study investigated the expression of proviral-integration site for Moloney murine leukaemia virus (PIM) -1 kinase in RA synovium and RA fibroblast-like synoviocytes (FLSs) along with its impact on RA-FLS aggressiveness. Methods The expression of PIM kinases was assessed in synovial tissues by immunohistochemistry and double IF. After PIM-1 inhibition using either small-interfering RNA or the chemical inhibitor AZD1208, we performed proliferation and migration assays and measured the levels of MMPs and IL-6 released from RA-FLSs under stimulation with proinflammatory cytokines (TNF-α, S100A4 and IL-6/soluble IL-6 receptor). Additionally, PIM-1-associated downstream signalling pathways were analysed by immunoblotting. Results Three isoforms of PIM kinases were immunodetected in the synovial tissues from patients with RA or OA. Specifically, PIM-1 and PIM-3 were upregulated in RA synovium and PIM-1 was expressed in T cells, macrophages and FLSs. Additionally, upon stimulation of RA-FLSs with TNF-α, S100A4 and IL-6/sIL-6R, PIM-1 and PIM-3, but not PIM-2, were significantly inducible. Moreover, PIM-1 knockdown or AZD1208 treatment significantly suppressed basal or cytokine-induced proliferation and migration of RA-FLS and the secretion of MMPs from stimulated RA-FLSs. PIM-1 knockdown significantly affected the phosphorylation levels of extracellular signal-regulated kinase and cAMP responsive element binding protein in RA-FLSs. Conclusion PIM-1 was upregulated in RA synovial tissues and RA-FLSs and its inhibition significantly reduced the proliferation, migration and MMP production of RA-FLSs in vitro. These findings suggest PIM-1 as a novel regulator of the aggressive and invasive behaviour of RA-FLSs and indicate its potential as a target for RA treatment.

Intrinsic changes of left ventricular function in patients with Behçet disease and comparison according to systemic disease activity

Although cardiac manifestation of Behçet disease (BD) has been described in sporadic reports, its timely diagnosis remains difficult. The objective of this study was to describe early cardiac manifestations of BD. We also performed a comprehensive classification of systemic BD activity and compared their cardiac manifestations.

AB0088 Regulatory b cell is negatively associated with disease activity in rheumatoid arthritis

Background The regulatory function of B cells is beginning to be understood, and several subsets of regulatory B cells have been suggested. A recent study suggested that the human B cell secreting IL-10 may have a central role in the regulatory function in immune system. However, the roles of regulatory B cells secreting IL-10 (B10 cells) was not established in rheumatoid arthritis (RA) pathogenesis. Objectives To know the exact status of IL-10+ B cells, we investigated the induction of B10 cells in the RA patients and analyzed disease activity. Methods CD19+ cells in peripheral blood mononuclear cells were purified from blood samples of RA patients and age and sex matched healthy controls, and stimulated with CD40 ligand and CpG for 48 hours. Intracellular IL-10 was analyzed using flow cytometry. Results The proportion of IL-10+ B cells to total B cells in RA patients was significantly higher than those in controls (RA, 4.44% ± 3.44% vs. healthy control 2.44% ± 1.64%, p = 0.033). However, the proportion of IL-10+ B cells to total B cells was correlated negatively with disease activity (r = –0.398, p = 0.040). Although age was correlated with IL-10+ B cells positively (r = –0.525, p = 0.004), age was also correlated with disease activity (r = 0.409, p = 0.031) in RA patients in this study. In healthy controls, age was not correlated with IL-10+ B cells (r = 0.035, p = 0.895). Thus, the association could be attributed to disease activity. To evaluate the effect of soluble factors in serum, IL-10+ B cell was induced with adding patients’ serum. The proportion of IL-10+ B cells was increased with serum. However, there were no differences between active RA and inactive RA group. Conclusions The proportion of induced IL-10+ B cell increased in RA patients compared to healthy control and was negatively correlated with disease activity in rheumatoid arthritis. Adding active and inactive RA patients’ sera, the proportion of IL-10+ B cell did not different between two groups. Disclosure of Interest None Declared

AB0106 The relationship between anemia in rheumatoid arthritis and fgf-23

Background Rheumatoid arthritis (RA) is a chronic inflammatory disease that results in localized and generalized bone loss. Osteoporosis and anemia are one of the most common complications seen in patients with RA. Objectives The aim of this study was to identify the relationship between inflammation, hemoglobin, BMD loss and fibroblast growth factor (FGF)-23 that is a phosphaturic hormone. Methods This study included 42 patients with rheumatoid arthritis fulfilling the new American college of Rheumatology/European League Against Rheumatism diagnostic criteria for rheumatoid arthritis and 26 healthy volunteers as controls. All were subjected to a complete blood count, rheumatoid factor and/or anti-cyclic citru-llinated peptide antibody. The concentration of FGF-23 was measured by ELISA (Immuntopics Inc., CA USA). Dual-energy x-ray absorptiometry was used to measure bone mineral density (BMD) of the lumbar spine (L1-L4) at the time of recruitment. Results In comparison with control group, RA patients had elevated FGF-23 (p=0.041) and ESR (p<0.0001). In RA group, BMD (p=0.037), hemoglobin (p=0.004), and albumin (p<0.0001) were lower than control group. In both RA and Non-RA, ESR correlated negatively with BMD (r=-0.425, p=0.001), Hemoglobin (r=-0.473, p<0.0001), and albumin (r=-0.552, p<0.0001) and positively with FGF-23 (r=0.326, p=0.009). Also, Hemoglobin correlated negatively with FGF23 (r=-0.452, p<-0.0001) and positively with BMD(r=0.332, p=0.006). In only RA group, ESR correlated negatively with BMD (r=-0.43, p=0.005), hemoglobin (p=-0.426, p=0.005), and albumin (r=-0.489, p=0.001) but not correlated with FGF-23. However, Hemoglobin correlated negatively with FGF-23 (r=-0.442, p=0.003). Conclusions In this study, Hemoglobin rather than inflammation is a negative predictor of plasma FGF-23 that is a potent regulator of the vitamin D and phosphate metabolism. Therefore, the association between ESR, anemia, FGF-23, and BMD loss in RA suggests a pathway between disease activity and BMD loss. Disclosure of Interest None Declared