1α, 25-dihydroxyvitamin D3 suppresses differentiation, maturation and activation of dendritic cells from patients with systemic lupus erythematosus

BACKGROUND: Dendritic cells (DC), professional antigen presenting cells, are believed to play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). 1α, 25-dihydroxyvitamin D3 (VitD3), in addition to its effect on bone metabolism, has been increasingly recognised to have immunomodulatory effects. OBJECTIVE: To examine the effect of VitD3 on the differentiation, maturation, and activation of DCs in SLE patients. METHODS: CD14+ monocyte–derived DCs from SLE patients and age- and sex-matched controls were derived from growth medium cultured with IL-4, GM-CSF. Mature DCs were induced by addition of lipopolysaccharide and tumour necrosis factor-α in the presence or absence of VitD3 (1×10-10 M) and/or dexamethasone (1×10-6 M). The expression of CD1a, a DC marker and markers of maturation and co-stimulatory molecules such as CD80, CD86, CD40, HLA-DR and CD83 were examined by flow cytometry. After stimulation of DCs with CD40L for 24 hours, the production of pro-inflammatory cytokines including IL-12 and IL-6, were measured by ELISA kits. RESULTS: VitD3 suppresses differentiation of monocytes into DCs as showed by the decreased expression of CD1a (P<0.05). VitD3 inhibits the expression of maturation markers including CD86, CD40 and CD83 (P<0.05), but not CD80 and HLA-DR. This effect was more marked in SLE patients (n=14) than controls (n=9). In combination with dexamethasone, VitD3 displayed more potent immunosuppressive effect on DCs. Under the effect of VitD3, stimulated DCs produced less of IL-12 (3.1 vs 10.4 pg/mL, P=0.02) and IL-6 (216.0 vs 224.0 pg/mL, P=0.21) in SLE patients as well as controls (8.0 vs 36.6 μg/mL, P=0.01 for IL-12) and (380.7 vs 415.2 pg/mL, P=0.04 for IL-6). CONCLUSION: VitD3 is found to inhibit differentiation, maturation, and activation of DCs in vitro in both SLE patients and controls and may be considered as immunomodulatory agent in the treatment of SLE.published_or_final_versionThe 15th Medical Research Conference (15th MRC), Department of Medicine, University of Hong Kong, Hong Kong, 16 January 2010. In Hong Kong Medical Journal, 2010, v. 16 n. 1, suppl. 1, p. 57, abstract no. 9

The relation of cytokines of IL-17/IL-23 axis to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus

INTRODUCTION: Interleukin (IL)-17 is recently linked to the pathogenesis of systemic lupus erythematosus (SLE) but its relation to disease activity has not been well characterised. The objectives of this study were to examine the relation of serum cytokine levels from the IL-17/IL-23 axis (IL-17, IL-23) to Th1 (IL-12, IFN-γ), Th2 (IL-10, IL-6, IL-4) cytokines and disease activity in SLE patients. METHODS: Serum cytokines were measured by enzyme-linked immunosorbent assays. Disease activity was determined by SLE disease activity index (SLEDAI), anti-dsDNA antibody, C3 and C4 levels. RESULTS: Serum levels of IL-17, IL-10 and IFN-γ were higher in SLE patients (n=70) compared to age- and sexmatched controls (n=14) [P<0.001]. Higher serum IL-23 level was found in active lupus patients who had cutaneous manifestation (P=0.003) and serositis (P=0.03) compared to those who had not. Serum IL-17 was not different between patients who had active lupus nephritis (n=23), non-renal active lupus (n=13) and inactive disease (n=34) [P=0.23]. However, an inverse correlation between serum IL-17 with proteinuria was found among all SLE patients (r= –0.27, P=0.03). Serum IL-17 level was, otherwise, not related to SLEDAI, glomerular filtration rate, activity or chronicity score and ISN/RPS class among patients with active lupus nephritis and was not found to correlate with serum IFN-γ or IL-10. CONCLUSIONS: Elevated serum IL-23 was found in patients with inflammatory manifestations including cutaneous involvement and serositis. Serum IL-17 level was not shown to correlate with disease activity but demonstrated an inverse correlation with proteinuria suggesting urinary loss of IL-17 and its involvement in lupus renal pathology.published_or_final_versionThe 15th Medical Research Conference (15th MRC), Department of Medicine, University of Hong Kong, Hong Kong, 16 January 2010. In Hong Kong Medical Journal, 2010, v. 16 n. 1, suppl. 1, p. 45, abstract no. 7

CASCH: a tool for computer-aided scheduling

A software tool called Computer-Aided Scheduling (CASCH) for parallel processing on distributed-memory multiprocessors in a complete parallel programming environment is presented. A compiler automatically converts sequential applications into parallel codes to perform program parallelization. The parallel code that executes on a target machine is optimized by CASCH through proper scheduling and mapping.published_or_final_versio

Using genetic algorithm and TOPSIS for Xinanjiang model calibration with a single procedure

Author name used in this publication: Chun-Tian ChengAuthor name used in this publication: K. W. ChauAuthor name used in this publication: Xin-yu Wu2005-2006 > Academic research: refereed > Publication in refereed journalAccepted ManuscriptPublishe

Integration of pancreatic aggregates into BioSilk network to treat diabetes

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Cirmtuzumab inhibits Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia treated with ibrutinib.

Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival. In this study, we found that CLL cells of patients treated with ibrutinib had activated Rac1. Moreover, Wnt5a could induce Rac1 activation and enhance proliferation of CLL cells treated with ibrutinib at concentrations that were effective in completely inhibiting BTK and BCR-signaling. Wnt5a-induced Rac1 activation could be blocked by cirmtuzumab (UC-961), an anti-ROR1 mAb. We found that treatment with cirmtuzumab and ibrutinib was significantly more effective than treatment with either agent alone in clearing leukemia cells in vivo. This study indicates that cirmtuzumab may enhance the activity of ibrutinib in the treatment of patients with CLL or other ROR1+ B-cell malignancies

Diffuse large B-cell lymphoma of the central nervous system in mycophenolate mofetil-treated patients with systemic lupus erythematosus

We report the third case of primary lymphoma of the central nervous system (PCNSL) in a patient with systemic lupus erythematosus (SLE) given long-term mycophenolate mofetil (MMF). Our 43-year-old patient has a history of lupus nephritis and has been treated with MMF 500 mg/day in addition to azathioprine (AZA) for 8 years. She presented with subacute left-sided weakness. Magnetic resonance imaging revealed a gadoliniumenhancing mass in the right parietal region which was isointense on T2-weighted imaging. Brain biopsy revealed diffuse sheets of large lymphoid cells which demonstrated strong membranous expression of CD20 by immunohistochemistry and positive signal for Epstein Bar virus (EBV)–encoded RNA by in-situ hybridization study. Complete remission of PCNSL was achieved after discontinuation of MMF and administration of rituximab and whole brain radiotherapy. Patients with SLE are predisposed to development of lymphoma regardless of immunosuppressive use. One meta-analysis found that non-Hodgkin’s lymphoma was more common in SLE patients with a standardized incidence rate ranging from 5.2 to 44.4. However, the development of PCNSL secondary to immunosuppressive use is being increasingly recognised especially in MMF-treated renal transplant recipients with onset of PCNSL after a median of 14 months. It has also been described in some MMF-treated autoimmune conditions such as myasthenia gravis, dermatomyositis and relapsing polychondritis. Although AZA in combination with corticosteroids has been shown to predispose post-renal transplant patients to lymphoproliferative disease with a relative risk of 12.7, the association of AZA and EBV-related lymphoma is rare. The approach to management of this condition includes withdrawal of MMF and judicious use of future immunosuppressive agents.published_or_final_versionThe 15th Medical Research Conference (15th MRC), Department of Medicine, University of Hong Kong, Hong Kong, 16 January 2010. In Hong Kong Medical Journal, 2010, v. 16 n. 1, suppl. 1, p. 54, abstract no. 9

Genetic analysis of farmed and wild stocks of large yellow croaker Larimichthys crocea by using microsatellite markers

The large yellow croaker (Pseudosciaena crocea) is one of the most economically important mariculture fish species in China. In this study, the genetic diversity and relationship among a wild stock, four farmed stocks and a selectively bred strain of large yellow croaker were assessed by 14 microsatellite markers. A total of 108 different alleles were detected over all loci. The average number of allele per locus ranged from 5.57 to 7.93, with an average of 6.75; the observed and expected heterozygosity ranged from 0.572 to 0.665 and from 0.649 to 0.751, with an average of 0.621 and 0.694, respectively; the Shannon’s diversity index ranged from 1.34 to 1.64, with an average of 1.48. The selectively bred strain had the lowest genetic diversity; all farmed stocks showed a slight reduction of genetic variability contrasted with wild stock. All stocks suffered severe bottleneck. The pair-wise FST, the phylogenetic tree, the factor correspondence analysis and the model based clustering analysis revealed that, the Ningbo stock, which was from Zhejiang province, was different from the remaining stocks from Fujian province. This study suggested that (1) the farmed stocks were at relatively low level of genetic diversity compared with the wild stock; (2) samples from Ningbo investigated in this study have a distinct divergence with those from Fujian province; (3) there had emerged significant differentiation among farmed stocks.Key words: Pseudosciaena crocea, large yellow croaker, genetic structure, microsatellite markers