Publications
142 results found
Murphy C-LM, Croca S, Artim-Esen B, et al., 2016, PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS WHO ARE ANTI-FACTOR XA IGG POSITIVE ARE LESS LIKELY TO HAVE ATHEROSCLEROTIC PLAQUE, Annual Meeting of the British-Society-for-Rheumatology, British-Health-Professionals-in-Rheumatology and the British-Society-for-Paediatric-and-Adolescent-Rheumatology (Rheumatology), Publisher: OXFORD UNIV PRESS, Pages: 166-166, ISSN: 1462-0324
McDonnell TCR, Pericleous C, Giles I, et al., 2016, THE ABILITY OF RECOMBINANT DOMAIN I OF BETA-2-GLYCOPROTEIN I TO INHIBIT THE LUPUS ANTICOAGULANT EFFECT OF IGG FROM PATIENTS WITH ANTI-PHOSPHOLIPID SYNDROME IS ENHANCED BY PEGYLATION, Annual Meeting of the British-Society-for-Rheumatology, British-Health-Professionals-in-Rheumatology and the British-Society-for-Paediatric-and-Adolescent-Rheumatology (Rheumatology), Publisher: OXFORD UNIV PRESS, Pages: 146-146, ISSN: 1462-0324
Bourke L, McCormick J, Taylor V, et al., 2015, Hydroxychloroquine protects against cardiac ischaemia/reperfusion injury In vivo via enhancement of ERK1/2 phosphorylation, PLoS ONE, Vol: 10, ISSN: 1932-6203
An increasing number of investigations including human studies demonstrate that pharmacological ischaemic preconditioning is a viable way to protect the heart from myocardial ischaemia/reperfusion (I/R) injury. This study investigated the role of hydroxychloroquine (HCQ) in the heart during I/R injury. In vitro and in vivo models of myocardial I/R injury were used to assess the effects of HCQ. It was found that HCQ was protective in neonatal rat cardiomyocytes through inhibition of apoptosis, measured by TUNEL and cleaved caspase-3. This protection in vitro was mediated through enhancement of ERK1/2 phosphorylation mediated by HCQ in a dose-dependent fashion. A decrease in infarct size was observed in an in vivo model of myocardial I/R injury in HCQ treated animals and furthermore this protection was blocked in the presence of the ERK1/2 inhibitor U0126. For the first time, we have shown that HCQ promotes a preconditioning like protection in an in vivo simulated rat myocardial I/R injury model. Moreover, it was shown that HCQ is protective via enhanced phosphorylation of the pro-survival kinase ERK1/2.
McDonnell T, Pericleous C, Laurine E, et al., 2015, Development of a high yield expression and purification system for Domain I of Beta-2-glycoprotein I for the treatment of APS, BMC Biotechnology, Vol: 15, ISSN: 1472-6750
BackgroundIn this paper we describe a novel method to achieve high yield bacterial expression of a small protein domain with considerable therapeutic potential; Domain I of Beta-2-glycoprotein I (β2GPI). β2GPI is intrinsic to the pathological progression of the Antiphospholipid Syndrome (APS). Patients develop autoantibodies targeting an epitope located on the N-terminal Domain I of β2GPI rendering this domain of interest as a possible therapeutic.ResultsThis new method of production of Domain I of β2GPI has increased the production yield by ~20 fold compared to previous methods in E.coli. This largely scalable, partially automated method produces 50–75 mg of pure, folded, active Domain I of β2GPI per litre of expression media.ConclusionThe application of this method may enable production of Domain I on sufficient scale to allow its use as a therapeutic.
Khawaja AA, Pericleous C, Ripoll VM, et al., 2015, Different Autoimmune Rheumatic Diease IgG Have Differential Effects upon Neutrophil Binding, Activation and Neutrophil Extracellular Trap Formation, Publisher: WILEY-BLACKWELL, ISSN: 2326-5191
Dias SS, Rodriguez-Garcia V, Hanh N, et al., 2015, Longer duration of B cell depletion is associated with better outcome, RHEUMATOLOGY, Vol: 54, Pages: 1876-1881, ISSN: 1462-0324
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- Citations: 19
Murphy C-L, Croca S, Artim-Esen B, et al., 2015, Patients with SLE Who Are Anti-Factor Xa IgG Positive Are Less Likely to Have Atherosclerotic Plaque, Publisher: WILEY-BLACKWELL, ISSN: 2326-5191
D'Souza A, Pericleous C, Leach O, et al., 2015, Different Patterns of Positivity for IgG Anti-Cardiolipin, Anti-Beta-2-Glycoprotein I and Anti-Domain I Antibodies within the First Year of Disease in 501 Patients with SLE - Associations with Different Clinical Outcomes, Publisher: WILEY-BLACKWELL, ISSN: 2326-5191
McDonnell T, Pericleous C, Ioannou Y, et al., 2015, Pegylated Recombinant Domain I of Beta-2-Glycoprotein I, a Potential Therapeutic Agent for Antiphospholipid Syndrome, Fully Retains Its Ability to Inhibit Binding of IgG or IgA Antibodies from Patients with APS to Beta-2-Glycoprotein I in Vitro, Publisher: WILEY-BLACKWELL, ISSN: 2326-5191
McDonnell T, Pericleous C, Giles I, et al., 2015, The Ability of Recombinant Domain I of Beta-2-Glycoprotein I to Inhibit Lupus Anticoagulant Effect of IgG from Patients with APS Is Enhanced By Pegylation, Publisher: WILEY-BLACKWELL, ISSN: 2326-5191
Raimondo MG, Pericleous C, Radziszewska A, et al., 2015, Oxidation of beta2-Glycoprotein I (beta2-GPI) Associates with the Presence of Antibodies to Domain I of beta2-GPI in Patients with the Antiphospholipid Syndrome but Is Not Affected By the Antibodies in Vivo in a Rat Model, Publisher: WILEY-BLACKWELL, ISSN: 2326-5191
Filippidou N, Krashias G, Pericleous C, et al., 2015, The association between IgM and IgG antibodies against cardiolipin, β2-glycoprotein I and Domain I of β2-glycoprotein I with disease profile in patients with multiple sclerosis, 31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 444-445, ISSN: 1352-4585
Raimondo MG, Pericleous C, Radziszewska A, et al., 2015, OXIDATION OF β<sub>2</sub>-GLYCOPROTEIN I IS STRONGLY ASSOCIATED WITH THE PRESENCE OF ANTI-DOMAIN I ANTIBODIES IN PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME, Publisher: BMJ PUBLISHING GROUP, Pages: 100-100, ISSN: 0003-4967
Poulton K, Ripoll VM, Pericleous C, et al., 2015, Purified IgG from patients with obstetric but not IgG from non-obstetric antiphospholipid syndrome inhibit trophoblast invasion, American Journal of Reproductive Immunology, Vol: 73, Pages: 390-401, ISSN: 1046-7408
ProblemSome patients with antiphospholipid syndrome (APS) suffer pregnancy morbidity (PM) but not vascular thrombosis (VT), whilst others suffer VT only. Therefore, we compared the effects of IgG from VT+/PM− and VT−/PM+ subjects on human first‐trimester trophoblast (HTR8) cells.Method of studyHTR‐8 cells were incubated with APS VT+/PM−, APS VT−/PM+ or healthy control (HC) IgG. We measured trophoblast invasion by cell invasion assay; mRNA expression of TLR4 and adaptor proteins; phosphorylation of p38 MAPK, NFκB and ERK; and expression of interleukin (IL)‐8 and IL‐6.ResultsVT−/PM+ IgG, but not VT+/PM− IgG significantly reduced HTR‐8 invasion. The effects on invasion were blocked by TLR‐4 inhibition. Neither VT+/PM− nor VT−/PM+ IgG altered MyD88 mRNA expression, phosphorylation of signalling molecules or cytokine expression.ConclusionsVT−/PM+ IgG exert functionally relevant effects on human trophoblast cells but VT+/PM− IgG do not.
Pericleous C, Ruiz-Limon P, Romay-Penabad Z, et al., 2015, Proof-of-concept study demonstrating the pathogenicity of affinity-purified IgG antibodies directed to domain I of beta(2)-glycoprotein I in a mouse model of anti-phospholipid antibody-induced thrombosis, Rheumatology, Vol: 54, Pages: 722-727, ISSN: 1462-0324
Objective. IgG aPL against domain I of β2-glycoprotein I (β2GPI) [anti-DI (aDI)] is associated with the pathogenesis of APS, an autoimmune disease defined by thrombosis and pregnancy morbidity. To date, however, no study has demonstrated direct pathogenicity of IgG aDI in vivo. In this proof-of-concept study, we designed a novel system to affinity purify polyclonal aDI aPL in order to assess its prothrombotic ability in a well-characterized mouse microcirculation model for APS.Methods. Two polyclonal IgG fractions were isolated from serum of a patient with APS, both with high aPL activity but differing in aDI activity (aDI-rich and aDI-poor). These IgG fractions were tested for their pathogenic ability in an in vivo mouse model of thrombosis. Male CD1 mice were injected intraperitoneally with either aDI-rich or aDI-poor IgG; as a control, IgG isolated from healthy serum was used. A pinch injury was applied to the right femoral vein and thrombus dynamics and tissue factor activity in isolated tissue were evaluated.Results. Both aDI-rich and aDI-poor IgG retained aCL and anti-β2GPI activity, while only aDI-rich IgG displayed high aDI activity, as defined by our in-house cut-offs for positivity in each assay. aDI-rich IgG induced significantly larger thrombi in vivo compared with aDI-poor IgG (P < 0.0001). Similarly, aDI-rich IgG significantly enhanced the procoagulant activity of carotid artery endothelium and peritoneal macrophages isolated from experimental animals (P < 0.01).Conclusion. These data directly demonstrate that the ability to cause thrombosis in vivo is concentrated in the aDI fraction of aPL.
Khawaja AA, Pericleous C, Thomas LW, et al., 2015, HYPOXIA INCREASES NEUTROPHIL EXTRACELLULAR TRAP FORMATION AND ADHESION TO ENDOTHELIAL CELLS, Annual Meeting of the British-Society-for-Rheumatology and British-Health-Professionals-in-Rheumatology, Publisher: OXFORD UNIV PRESS, Pages: 41-42, ISSN: 1462-0324
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- Citations: 1
Bourke L, McCormick J, Ripoll VM, et al., 2015, ANTIPHOSPHOLIPID ANTIBODIES ENHANCE CARDIOMYOCYTE APOPTOSIS IN A SIMULATED IN VITRO CARDIAC ISCHAEMIA/REPERFUSION INJURY MODEL: A PROCESS DEPENDENT ON THE PRO-APOPTOTIC KINASE P38 MAPK, Annual Meeting of the British-Society-for-Rheumatology and British-Health-Professionals-in-Rheumatology, Publisher: OXFORD UNIV PRESS, Pages: 42-43, ISSN: 1462-0324
Artim-Esen B, Pericleous C, Mackie I, et al., 2015, Anti-factor Xa antibodies in patients with antiphospholipid syndrome and their effects upon coagulation assays, Arthritis Research and Therapy, Vol: 17, ISSN: 1478-6354
IntroductionThe aim of this study was to examine the prevalence and functional effects of antibodies directed against Factor (F)Xa and other serine proteases (SP) in patients with antiphospholipid syndrome (APS).MethodsSerum from patients with APS (n = 59), systemic lupus erythematosus (SLE; n = 106), other autoimmune rheumatic disease (ARD; n = 63) and 40 healthy controls (HC) were tested for IgG activity against thrombin (Thr), FXa, FVIIa, phosphatidylserine (PS)/FXa and antithrombin (AT)-III by enzyme-linked immunosorbent assay (ELISA). Anti-FXa positive IgG were purified to measure their avidity by chaotropic ELISA and functional effects upon clotting time (FXa-ACT) and FXa enzymatic activity (± AT-III).ResultsAnti-FXa IgG were found in patients with SLE (49.1%) and APS (33.9%) (P <0.05) but not in ARD controls and HC. In contrast, anti-Thr and anti-PS/FXa IgG were identified in other ARD and anti-FVIIa IgG were low in all groups. The avidity of APS-IgG to FXa was significantly higher than SLE-IgG (P <0.05). Greatest prolongation of FXa-ACT was observed with APS-IgG and greatest inhibitory effect upon FXa enzymatic activity was found with APS-IgG followed by SLE-IgG compared to HC-IgG. ATIII inhibition of FXa was significantly reduced by APS-IgG compared with HC and SLE (P <0.05) and did not correlate with binding to AT-III.ConclusionAPS anti-FXa IgG have higher avidity to FXa and greater effects upon the enzymatic and coagulant activity of FXa compared with SLE anti-FXa IgG. Further studies of anti-FXa antibodies in APS, SLE and other non-autoimmune thrombotic disease cohorts are now required to evaluate whether targeting FXa with selective inhibitors in patients bearing anti-FXa antibodies may be an effective treatment strategy.
Cousins L, Pericleous C, Khamashta M, et al., 2015, Antibodies to domain I of beta-2-glycoprotein I and IgA antiphospholipid antibodies in patients with 'seronegative' antiphospholipid syndrome, Annals of the Rheumatic Diseases, Vol: 74, Pages: 317-319, ISSN: 0003-4967
Khawaja AA, Pericleous C, Thomas LW, et al., 2014, Hypoxia increases neutrophil extracellular trap formation and adhesion to endothelial cells, Publisher: WILEY-BLACKWELL, Pages: 118-118, ISSN: 0019-2805
Pericleous C, Rahman A, 2014, Domain I: the hidden face of antiphospholipid syndrome, LUPUS, Vol: 23, Pages: 1320-1323, ISSN: 0961-2033
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- Citations: 8
Khawaja AA, Pericleous C, Thomas LW, et al., 2014, Hypoxia Modulates Peptidyl Arginine Deiminase 4 Activity and Neutrophil Extracellular Trap Formation., Publisher: WILEY-BLACKWELL, Pages: S527-S527, ISSN: 2326-5191
Artim-Esen B, Smoktunowicz N, Ripoll VM, et al., 2014, The Cellular Effects of ANTI-Factor Xa Antibodies Isolated from Patients with Antiphospholipid Syndrome ARE Inhibited By Factorxa Inhibitors, Hydroxychloroquine and Fluvastatin., Publisher: WILEY-BLACKWELL, Pages: S1252-S1252, ISSN: 2326-5191
Pericleous C, Taylor V, Bourke L, et al., 2014, IgG Antiphospholipid Antibodies Enhance Stroke Damage: An in Vivo Ischemia/Reperfusion Study., Publisher: WILEY-BLACKWELL, Pages: S1251-S1251, ISSN: 2326-5191
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- Citations: 1
Bourke L, McCormick J, Ripoll VM, et al., 2014, PURIFIED IGG FROM PATIENTS WITH JUVENILE AND ADULT ONSET SLE ENHANCES APOPTOSIS IN NEONATAL RAT CARDIOMYOCYTES EXPOSED TO MYOCARDIAL I/R INJURY, Annual Conference of the British-Society-for-Paediatric-and-Adolescent-Rheumatology (BSPAR), Publisher: OXFORD UNIV PRESS, Pages: 16-16, ISSN: 1462-0324
Rodriguez-Garcia V, Dias SS, Nguyen H, et al., 2014, LONGER DURATION OF B CELL DEPLETION IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS IS ASSOCIATED WITH A BETTER OUTCOME, 15th Annual European Congress of Rheumatology (EULAR), Publisher: BMJ PUBLISHING GROUP, Pages: 359-359, ISSN: 0003-4967
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- Citations: 1
Bourke L, McCormick J, Ripoll VM, et al., 2014, PURIFIED IgG FROM PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS ENHANCES APOPTOSIS IN NEONATAL RAT CARDIOMYOCYTES EXPOSED TO SIMULATED MYOCARDIAL ISCHAEMIC REPERFUSION INJURY, Annual Meeting of the British-Society-for-Rheumatology and British-Health-Professionals-in-Rheumatology, Publisher: OXFORD UNIV PRESS, Pages: 182-183, ISSN: 1462-0324
Artim-Esen B, Smoktunowicz N, Pericleous C, et al., 2014, THE CELLULAR EFFECTS OF ANTI-FACTOR Xa ANTIBODIES ISOLATED FROM PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME ARE INHIBITED BY FACTOR Xa INHIBITORS, HYDROXYCHLOROQUINE AND FLUVASTATIN, Annual Meeting of the British-Society-for-Rheumatology and British-Health-Professionals-in-Rheumatology, Publisher: OXFORD UNIV PRESS, Pages: 55-56, ISSN: 1462-0324
Artim-Esen B, Pericleous C, Mackie I, et al., 2014, FACTOR-XA-REACTIVE ANTIBODIES IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND ANTIPHOSPHOLIPID SYNDROME HAVE DIFFERENTIAL EFFECTS ON COAGULATION ASSAYS, Annual Meeting of the British-Society-for-Rheumatology and British-Health-Professionals-in-Rheumatology, Publisher: OXFORD UNIV PRESS, Pages: 181-181, ISSN: 1462-0324
Croca S, Bassett P, Pericleous C, et al., 2014, Serum nitrated nucleosome levels in patients with systemic lupus erythematosus: a retrospective longitudinal cohort study, Arthritis Research and Therapy, Vol: 16, ISSN: 1478-6354
IntroductionCirculating nucleosomes released from apoptotic cells are important in the pathogenesis of systemic lupus erythematosus (SLE). Both nucleosomes and anti-nucleosome antibodies are deposited in inflamed tissues in patients with SLE. Active inflammation promotes nitration of tyrosine residues on serum proteins. Our hypothesis was that levels of nitrated nucleosomes would be elevated in patients with SLE and could be associated with disease activity. We therefore carried out a retrospective longitudinal study to investigate factors affecting levels of nitrated nucleosomes (NN) in patients with SLE.MethodsA novel serum ELISA was developed to measure serum NN and modified to measure serum nitrated albumin (NA). Levels of both NN and NA were measured in 397 samples from 49 patients with SLE followed through periods of disease flare and remission for a mean of 89 months. Anti-nucleosome antibody (anti-nuc) levels were measured in the same samples. The effects of 24 different clinical, demographic and serological variables on NN, NA and anti-nuc levels were assessed by univariable and multivariable analysis.ResultsPatients with SLE had higher mean NN than healthy controls or patients with other autoimmune rheumatic diseases (P =0.01). Serum samples from 18 out of 49 (36.7%) of SLE patients were never positive for NN. This group of 18 patients was characterized by lower anti-double stranded DNA antibodies (anti-dsDNA), disease activity and use of immunosuppressants. In the remaining 63.3%, NN levels were variable. High NN was significantly associated with anti-Sm antibodies, vasculitis, immunosuppressants, hydroxychloroquine and age at diagnosis. NN levels were raised in neuropsychiatric flares. NN levels did not completely parallel NA results, thus providing additional information over measuring nitration status alone. NN levels were not associated with anti-nuc levels.ConclusionsNN are raised in a subset of patients with SLE, particularly those who are anti-Sm p
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