Aca 2013 Abstract Export Plenary Session: Plenary Session 1: Novel aspect of therapeutics of autoimmune diseases
THE EFFECT OF CXCL10 BLOCKADE IN C PROTEIN-INDUCED MYOSITIS
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- 111 ANTI-MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY IN PAEDIATRIC CNS DEMYELINATION DEFINES AN AUTOIMMUNE TREATMENT-RESPONSIVE INFLAMMATORY CNS DEMYELINATION REMINISCENT OF NMO SPECTRUM DISORDER.
- 112 A NON-INVASIVE PET/CT IMAGING PROCEDURE FOR DIAGNOSING ATHEROSCLEROTIC LESIONS: IMMUNOLOGIC TARGETING TO OXLDL/BETA2-GLYCOPROTEIN I IN THE WHHL RABBITS
- 113 FILAMENTOUS ANTIGEN-SPECIFIC THERAPY OF EAE VIA INTRANASAL DELIVERY OF PHAGE DISPLAYING A MYELIN IMMUNODOMINANT EPITOPE
- Plenary Session: Plenary Session 3: Genetics and Immunogenetics of autoimmune diseases 118 The pebbles of autoimmunity: genetic and autoantibodies in the complex mosaic of autoimmunity
- 119 Antiphospholipid syndrome; 30 years
- 120 From genetics to functional insights into the pathogenesis of rheumatoid arthritis
- 121 Aberrant Chromatin Modifications: The Epigenetics Mechanisms of Lupus
- Parallel Session: Parallel Session 7: Challenges in SLE 129 IMMUNOPATHOLOGICAL ROLES OF PATTERN-RECOGNITION RECEPTORS IN SYSTEMIC LUPUS ERYTHEMATOSUS
- 131 PLASMACYTOID DENDRITIC CELLS IN SLE PATHOGENESIS
110 THE EFFECT OF CXCL10 BLOCKADE IN C PROTEIN-INDUCED MYOSITIS J. Kim1, J. Choi2, S.H. Park3, S.H. Yang4, J.A. Park2, K. Shin2, E.Y. Lee2, E.B. Lee2, H. Kawachi5, H. Kohsaka6, Y.W. Song7 1Internal Medicine, Chungnam National University Hospital, Daejeon city, Korea 2Internal Medicine, Seoul National University College of Medicine, Seoul, Korea 3Pathology, Seoul National University College of Medicine, Seoul, Korea 4Kidney Research Institute, Seoul National University, Seoul, Korea 5Cell biology Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan 6Medicine and Rheumatology, Tokyo Medical and Dental University, Tokyo, Japan 7Internal Medicine, Seoul National Univerisity College of Medicine, Seoul, Korea Backgrounds and aims: CXCL10 (also called interferon-γ-inducible protein 10 [IP-10]) is a chemokine that plays a critical role in the infiltration of T cell in autoimmune disease. CXCL10 is reported to be expressed in muscle tissue of polymyositis. We investigated the role of CXCL10 and the effect of CXCL10 blockade in C protein-induced myositis, an animal model of polymyositis. Methods: C protein-induced myositis model was induced with human skeletal C protein fragment in 8-week-old female C57BL/6 mice. Immunohistochemistry was performed to detect CXCL10 and CXCR3, its receptor. CXCR3 in mouse splenocyte was investigated by flow cytometry and migration assay of mouse splenocyte was performed. Mice with C protein-induced myositis were treated with anti-CXCL10 antibody or control IgG 8 days after the induction of myositis every other day and the muscle inflammation was assessed 3 week after the induction. Results: Immunohistochemistry showed the expression of CXCL10 and CXCR3 in the muscle of C protein-induced myositis. Invading CD8+ T cell into myofiber expressed CXCR3. Moreover,IFN-γ+ cells were increased among CXCR3+CD8+ T cells compared to CXCR3-CD8+ T cells (CXCR3+CD8+ T cell, 28.0 ± 4.2% vs. CXCR3-CD8+ T cell, 9.5 ± 1.5%, p = 0.016). Migration of splenocyte was increased in response to CXCL10 (chemotactic index=1.91±0.45). Treatment with anti-CXCL10 antibody (n=10) showed less inflammation score in muscles than treatment with control IgG (n=10; median [range], anti IP-10, 0.75 [0.25-2.00] vs. control IgG, 1.43 [1.125-4.25], p=0.045). Conclusion: CXCL10 was expressed in the inflammation of C protein-induced myositis model and its blockade suppressed inflammation in muscle. 111 ANTI-MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY IN PAEDIATRIC CNS DEMYELINATION DEFINES AN AUTOIMMUNE TREATMENT-RESPONSIVE INFLAMMATORY CNS DEMYELINATION REMINISCENT OF NMO SPECTRUM DISORDER. R.C. Dale1, V. Merheb1, E. Tantsis1, R.Y.A. Kumaran1, F. Brilot1 1Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia Background and aims. Over the few last years, anti-human surface myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G antibody (MOG antibody) have been detected in approximately 20-40% of paediatric patients with first episode of CNS demyelination, but also in a few patients with Neuromyelitis Optica (NMO) spectrum disorder who are negative for NMO antibody. However, although the existence of this MOG antibody-positive paediatric subgroup is largely accepted and has been shown by multiple teams, the utility and the relevance of these antibodies are still unknown. We aimed to determine the importance of MOG antibody in paediatric patients with inflammatory CNS demyelination and whether MOG antibody could have pathogenic effect on oligodendrocyte physiology. Methods. We have performed detailed clinical phenotyping in a large Australian cohort of 75 retrospective and prospective children with CNS demyelination. We have measured MOG antibody using a flow cytometry lentivirus-transduced MOG-expressing cell line. Positivity for MOG antibody was defined as three standard deviations above the mean control value. We have compared antibody positive and negative patients. We also have tested the in vitro pathogenic potential of these antibodies using human oligodendrocytes. Results. We have found 40% of children positive for MOG antibody (30/75) and 0% in controls (0/22). MOG antibody-positive patients were more likely to be young, have acute disseminated encephalomyelitis, have bilateral optic neuritis (but not unilateral), have longitudinal extensive transverse myelitis, and have an elevated erythrocyte sedimentation rate. There was a strong correlation between MOG antibody positivity and bilateral optic neuritis, as well as between MOG antibody and erythrocyte sedimentation rate. In relapsing patients, intrathecal oligoclonal bands were only seen in MOG antibody-negative patients. Recent prospective relapsing MOG antibody- positive patients have been treated with steroids and mycophenolate. These patients were responsive to immune therapies, and levels of MOG antibody decreased with treatment. When we assessed the pathogenic potential of MOG antibody on live human oligodendrocytes, we observed a reduced MOG surface staining in otherwise healthy-looking cells, whereas live cells treated with control antibody displayed an undisturbed surface MOG expression. Conclusions. Overall our data suggest that there is emerging evidence that MOG antibody defines a separate autoimmune inflammatory disorder with a phenotype more reminiscent of NMO spectrum disorders and that MOG antibody might be pathogenic in these patients. 112 A NON-INVASIVE PET/CT IMAGING PROCEDURE FOR DIAGNOSING ATHEROSCLEROTIC LESIONS: IMMUNOLOGIC TARGETING TO OXLDL/BETA2-GLYCOPROTEIN I IN THE WHHL RABBITS T. Sasaki1, F. Takenaka1, Y. Matsunami2, H. Hirano3, S. Kita2, M. Eiji4 1Collaborative Research Center for Okayama Medical Innovation Center (OMIC), Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan 2IVD Development Department, Medical and Biological Laboratories Co Ltd, Ina, Japan 3Engineering Department, SHI Accelerator Service Ltd, Tokyo, Japan 4Department of Cell Chemistry, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama, Japan Background: Current in vivo diagnostic tools for detecting vulnerable plaques in preclinical and/or autoimmune atherosclerotic patients required a range of non-invasive imaging systems. We have demonstrated that oxidized LDL (oxLDL) form complexes with β2-glycoprotein I (oxLDL/β2GPI complexes) that function as a major pro-atherosclerotic/pro-thrombogenic autoantigen capable of triggering antiphospholipid antibodies. The aim of the study was to confirm the clinical utility of 64Cu-labeled single chain Fv of anti-oxLDL/β2GPI antibody (3H3-scFv) as a PET imaging probe for atherosclerotic lesions in the Watanabe heritable hyperlipidemic (WHHL) rabbits. Methods and Results: Twenty-four hours prior to obtaining PET/CT fusion images, 3H3-scFv labeled with 64Cu was intravenously injected into WHHL and control rabbits. The PET/CT fusion images demonstrated that aortic arches were clearly visualized only in WHHL but not control rabbits. Aortic arches and thoracic/abdominal arteries were positively stained with Sudan IV in WHHL but not control rabbits. After obtaining the PET/CT images, autoradiographic analyses and bio-distributional determination of 3H3-scFv were performed. Those results clearly revealed that 3H3-scFv was specific and preferentially accumulated in atherosclerotic plaques to provide an accurate imaging detection of the lesion. The bio-distribution analyses also quantitatively showed that the accumulation of 3H3-scFv was 1.37 to 2.81-fold greater in aortas of WHHL than control rabbits. Conclusions: Because of the similarity between the size of rabbit aortas and human coronary arteries, 3H3-scFv (an antibody variant lacking the Fc region) can be used as a probe suitable for in vivo clinical PET imaging of atherosclerosis with highly enough sensitivity and specificity. 113 FILAMENTOUS ANTIGEN-SPECIFIC THERAPY OF EAE VIA INTRANASAL DELIVERY OF PHAGE DISPLAYING A MYELIN IMMUNODOMINANT EPITOPE B. Solomon1 1Microbiology-Biotechnology, Tel-Aviv university, Tel-Aviv, Israel Backgound and aims The presence of anti-myelin antibodies in patients with early multiple sclerosis (MS) and in MS animal models led to renewed interest in a role for B cells, plasma cells and their products in the pathogenesis of the disease. Here we propose a novel strategy based on engineered filamentous phage in which its major coat protein was fused to the immunodominant epitope derived from the myelin oligodendrocyte glycoprotein (MOG 37-44). Filamentous phages are well-studied, both structurally and genetically. Their shape as a long fiber, 1000nm long and 6nm wide, enables penetration to the central nervous system via nasal administration. Methods: Experimental autoimmune encephalomyelitis (EAE) diseased mice (as a model of MS) intranasally treated with phage-MOG . Results The treated animal models showed improved clinical scores; reduction of antibodies against MOG; reduced proinflammatory cytokines, in particular monocyte chemoattractant protein 1 (MCP-1), interferon g (IFN-g) and IL-6; and prevented demyelinization, compared to untreated animals. Conclusions Brain delivery of MOG via filamentous phages suggests that the improved clinical effects obtained in EAE mice may be due to depletion of MOG autoantibodies in situ and/or stimulation of immune mechanisms towards induced tolerance in the periphery, indicating that the humoral immune system in MS would be a reasonable therapeutic option. Plenary Session: Plenary Session 3: Genetics and Immunogenetics of autoimmune diseases 118 The pebbles of autoimmunity: genetic and autoantibodies in the complex mosaic of autoimmunity C. Perricone1, N. Agmon-Levin2, F. Ceccarelli1, G. Valesini1, J.M. Anaya3, Y. Shoenfeld2 1Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Roma, Italy 2Sackler Faculty of Medicine Tel-Aviv University, The Zabludowicz Center for Autoimmune Diseases Sheba Medical Center, Tel-Aviv, Israel 3Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotà, Colombia Autoimmune diseases (ADs) are chronic conditions initiated by the loss of immunological tolerance to self-antigens. The pathogenic hypothesis comprises a complex interaction between genetic, environmental and hormonal factors that interact in an individual over time generating a dysregulation of the immune system leading to disease development. Several polymorphic genes contribute to the development of ADs. Furthermore, age and gender play a major role by influencing hormone levels that can represent the fulcrum unbalancing from susceptibility to protection. Evidences suggest that while all these steps occur, the susceptible individual develops autoantibodies over a long time lapse. Such autoantibody production is genetically determined and finally, their presence seems to determine the clinical presentation of ADs. The genetic predisposition to the developments of autoantibodies and toward the disease process may overlap. 119 Antiphospholipid syndrome; 30 years In 1983, Graham Hughes first described the concept of antiphospholipid syndrome (APS). The term APS refers to patients with arterial and/or venous thrombosis, pregnancy complications and circulating antibodies called Òantiphospholipid antibodiesÓ, appearing to make the blood far more sticky and liable to clot. In 1984, we described the enzyme-linked immunosorbent assay (ELISA) system which directly detected circulating aCL in patients with SLE who revealed biological false positive STS for syphilis. In 1990, three groups independently reported the necessity of a cofactor for the binding of autoimmune anticardiolipin antibodies (aCL) to the solid phase phospholipids. β2-glycoprotein I (β2GPI) was identified as this cofactor. In 1994,the epitope for aCL was shown to develop when β2GPI is adsorbed on polyoxygenated polystyrene plates. In 2000, we described antiprothrombin antibodies bind to prothrombin exposed to immobilized phosphatidylserine and established a phosphatidylserine dependent monoclonal antiprothrombin antibody. In 2004, a novel role of nicked β2GPI was identified in the negative feedback pathway of extrinsic fibrinolysis. Nicked β2GPI was found to bind angiostatin 4.5 and to attenuate its antiangiogenic property. In 2004, it was shown that the p38 MAPK pathway mediates induction of the tissue factor (TF) gene in stimulated with human monoclonal anti- β2GPI antibodies. Very recently, β2GPI was identified as a complement regulator. The cross-link between complement activation and prothrombotic status in patients with APS will be discussed. 120 From genetics to functional insights into the pathogenesis of rheumatoid arthritis K. Yamamoto1, A. Suzuki2, Y. Kochi2 1Department of Allergy and Rheumatology, Graduate School of Medicine The University of Tokyo, Tokyo, Japan 2Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences RIKEN, Yokohama, Japan The etiology and pathogenesis of rheumatoid arthritis (RA) are still unknown. Genome-wide association study (GWAS) has been conducted to identify RA associated genes. However, genetic study does not necessarily provide a direct conclusion. Therefore, information from GWAS should be used to understand the functional mechanisms of RA. For example, HLA-DR4 has been reported as the strongest genetic factor in RA. However, the precise mechanism of DR4 in RA pathogenesis has been unknown. We reported functional haplotypes of PADI4, encoding citrullinating enzyme peptidylargimine deiminase 4, are associated with RA. Our results imply that the RA susceptible PADI4 haplotype increases production of citrullinated peptides acting as auto-antigens. The function of PADI4 in inflammatory arthritis was further studied using knock-out mice. The knock-out mice exhibited decreased inflammatory joint lesions in collagen-induced arthritis, suggesting that PADI4 is actually involved in the pathogenesis of RA. We also reported a polymorphism that up-regulates the expression of Fc receptor-like 3 (FCRL3) gene. This polymorphism has recently been confirmed as predisposing for several different autoimmune diseases. FCRL3 is preferentially expressed on B cells. We found FCRL3 potentially inhibits BCR-mediated signaling. These results suggest that augmented inhibition of BCR-mediated signaling by FCRL3 alter the activation threshold and promote tolerance breakdown in B cells. We have further identified a polymorphism in the chemokine receptor CCR6 gene is associated with RA. CCR6 is a surface marker for Th17 cells, suggesting that CCR6 is critically involved in Th17-driven autoimmunity in RA.
In summary, aberrant chromatin modification plays a critical role in the development of lupus, and epigenetic-based therapies appear to hold promise for the treatment of lupus. Parallel Session: Parallel Session 7: Challenges in SLE 129 IMMUNOPATHOLOGICAL ROLES OF PATTERN-RECOGNITION RECEPTORS IN SYSTEMIC LUPUS ERYTHEMATOSUS C.K. Wong1, L.S. Tam2, S.L. Yu2, P.T.Y. Wong1, D.P. Chen1, E.K. Li2 1Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong China 2Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong China Background: Pattern recognition receptors (PRRs) including Toll-like receptors (TLR), NOD-like receptors (NLRs) and receptor for advanced glycation end products (RAGE) play import roles for the innate immunity against exogenous pathogens and endogenous damages. Methods: We investigated the expressions and functions of PRRs of PBMC in SLE patients using flow cytometry and immunoassays. Results: The aberrant expression of TLR and TLR-mediated release of inflammatory cytokines/chemokines was observed in SLE patients. Over-expression of intracytosolic NOD2 in monocytes of na•ve SLE patients treated with immunosuppressant exhibited positive association with longer disease duration. Immunosuppressive therapies could down-regulate the NOD2 expression in CD8+T lymphocytes, monocytes, myeloid and plasmacytoid dendritic cells in SLE patients which subsequently reduce IL-10 production, contributing towards the immunopathological mechanisms of SLE. Expression of full-length RAGE (flRAGE) was significantly increased in the monocytes of SLE patients, correlating with the plasma RAGE ligand high mobility group box (HMGB)1 levels. Plasma soluble (s)RAGE level negatively correlated with SLE disease activity. Plasma endogenous secretory RAGE (esRAGE) level was significantly lower in SLE patients with flare while esRAGE/sRAGE ratio negatively correlated with complement level. HMGB1 could moderately induce ex vivo inflammatory IL-6 production, resulting in transient activation of intracellular p38 MAPK, JNK and NF-κB in peripheral blood monocytes. Moreover, TLR9 ligand together with HMGB1 exhibited a synergistic effect on IL-6 and IL-12 secretions. Conclusion: The immunopathogenesis of SLE is related to the aberrant expression and function of PRRs and plasma sRAGE may serve as a potential biomarker for disease activity and future therapeutic target in SLE. 131 PLASMACYTOID DENDRITIC CELLS IN SLE PATHOGENESIS V. Chan1, S. Yan1, C.S. Lau1 1Medicine, University of Hong Kong, Hong Kong, Hong Kong China Plasmacytoid dendritic cells (pDCs) constitute a unique subset of cells which acquire many features of conventional dendritic cells (cDCs) upon activation. Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease affecting predominantly young females associated with significant morbidity and mortality. While cDCs likely contribute to SLE pathogenesis by breaking immune tolerance to self-antigens, pDCs are thought to play a major pathogenic role by virtue of its unique ability to produce large amount of type-I interferon upon nucleic acids stimulation through the toll-like receptors (TLRs)-7/9. We have previously observed a significant increase in the frequency of pDCs which show enhanced T cell stimulatory activity in SLE patients. Remarkably, bone marrow-derived pDCs from patients also exhibit activated phenotypes with higher expression of co-stimulatory molecules and induce a stronger T-cell proliferation. In the NZB/W F1 mouse model, we have similarly observed that bone marrow*derived pDCs from symptomatic F1 mice exhibit heightened up-regulation of co-stimulatory molecules upon TLR-7 stimulation when compared with pre-symptomatic animals. Functional abnormalities have also been found. In the study of regulatory mechanisms of pDC abnormality in lupus, microRNAs (miRNAs) expression analysis reveals that distinct miRNAs are differentially expressed by pDCs from lupus mice. On-going experiments are underway to correlate the perturbed miRNAs induction and the aberrant pDC functions in SLE using miRNA mimics and inhibitors. In summary, pDC functional abnormalities clearly contribute to SLE development and the study of regulatory miRNAs in lupus pDCs may reveal new potential therapeutic targets for clinical intervention. 133 THE ALARMIN FUNCTION OF IL-33/ST2 AXIS CONTRIBUTES TO ENDOTHELIAL CELL INJURY-MEDIATED PROINFLAMMATORY RESPONSE IN LUPUS NEPHRITIS T. Yi1, Y. Shui-Lian1, H. Can-Hui1, H. Wen-Hui1, W. Zhuo-Long1 1Department of Rheumatology, Guangzhou Medical University, Guangdong, China Background: "Alarmins" are prototypic endogenous pro-inflammatory factors are released from necotic cells and provoke local damage or systemic inflammation. Evidences are accumulating to support the inclusion of "Alarmins" as targets of autoreactivity as well as inducers in the pathogenesis of Systemic Lupus Erythematosus (SLE). Interleukin (IL)-33 is a novel member of the family of "Alarmins" because of its characteristics and functions in mediating host immune responses. We sought to determine the role of IL-33/ST2 axis in lupus pathogenesis. Objectives: (1) To determine whether IL-33 was present in renal glomerular endothelial cells; (2) To assess the functional and intracellular signal transuction mechanisms regulating the link between IL-33/ST2-mediated innate immunity and inflammation in CD4+ T cells-endothelial cells co-culture system of lupus patients. Preliminary results: Immunofluorescence (IF) for IL-33 in the kidney were performed in both MRLlpr lupus mice and C57BL/6J mice. On double staining for IL-33 and lectin, IL-33 was clearly seen in glomeruli and also in peritubular areas. To determine whether the IL-33 staining in glomeruli and peritubular areas was in endothelium, double IF staining for IL-33 and von Willebrand factor (vWF) was performed. IL-33 co-localized with vWF in glomeruli and in peritubular areas. The increased levels of IL-33 mRNA transcripts were detected in kidney of MRLlpr lupus mice compared with C57BL/6J mice. Expression of cell-surface ST2 was increased on the CD4+ T cells of lupus patients when compared with healthy controls. Serum sST2 level was significantly higher in SLE patients with flare than those without flare Download 1.13 Mb. Share with your friends:
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