Publications by authors named "Anna Radziszewska"

19 Publications

  • Page 1 of 1

Abnormal Mitochondrial Physiology in the Pathogenesis of Systemic Lupus Erythematosus.

Rheum Dis Clin North Am 2021 Aug;47(3):427-439

Department of Rheumatology, Division of Medicine, Rayne Institute, University College London, 5 University Street, London WC1E 6JF, UK; Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH, London, UK.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by abnormalities within the innate and adaptive immune systems. Activation and proliferation of a wide array of immune cells require significant up-regulation in cellular energy metabolism, with the mitochondria playing an essential role in the initiation and maintenance of this response. This article highlights how abnormal mitochondrial function may occur in SLE and focuses on how energy metabolism, oxidative stress, and impaired mitochondrial repair play a role in the pathogenesis of the disease. How this may represent an appealing novel therapeutic target for future drug therapy in SLE also is discussed.
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http://dx.doi.org/10.1016/j.rdc.2021.05.001DOI Listing
August 2021

Clear phylogeographic pattern and genetic structure of wild boar Sus scrofa population in Central and Eastern Europe.

Sci Rep 2021 May 6;11(1):9680. Epub 2021 May 6.

Department of Forensic Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland.

The wild boar Sus scrofa is one of the widely spread ungulate species in Europe, yet the origin and genetic structure of the population inhabiting Central and Eastern Europe are not well recognized. We analysed 101 newly obtained sequences of complete mtDNA genomes and 548 D-loop sequences of the species and combined them with previously published data. We identified five phylogenetic clades in Europe with clear phylogeographic pattern. Two of them occurred mainly in western and central part of the continent, while the range of the third clade covered North-Eastern, Central and South-Eastern Europe. The two other clades had rather restricted distribution. In Central Europe, we identified a contact zone of three mtDNA clades. Population genetic structure reflected clear phylogeographic pattern of wild boar in this part of Europe. The contribution of lineages originating from the southern (Dinaric-Balkan) and eastern (northern cost of the Black Sea) areas to the observed phylogeographic pattern of the species in Central and Eastern Europe was larger than those from the regions located in southern France, Iberian, and Italian Peninsulas. The present work was the first mitogenomic analysis conducted in Central and Eastern Europe to study genetic diversity and structure of wild boar population.
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http://dx.doi.org/10.1038/s41598-021-88991-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102581PMC
May 2021

A systematic review exploring the bidirectional relationship between puberty and autoimmune rheumatic diseases.

Pediatr Rheumatol Online J 2021 Mar 29;19(1):47. Epub 2021 Mar 29.

Centre for Adolescent Rheumatology Versus Arthritis, Department of Medicine, University College London, Rayne Building, London, W1CE 6JF, UK.

Background: Autoimmune rheumatic diseases (ARDs) are associated with a significant sex-bias, which becomes more evident post-puberty. This systematic review aims to elucidate the bidirectional relationship between puberty and ARD-related outcomes.

Methods: Studies published in English until October 2019 were identified using a systematic search of endocrinology and rheumatology literature. Information was extracted on study design, sample size, demographics, puberty outcome measures, disease outcome measures, and main findings. The methodological quality of the studies included was analysed using the Newcastle-Ottawa Scale (NOS).

Results: Sixteen non-randomised studies reporting on the impact of puberty on ARD outcomes (n = 7), ARD impact on puberty-related outcomes (n = 8), or both (n = 1) have been identified. The impact of puberty on ARD outcomes were investigated in patients with juvenile idiopathic arthritis (JIA)-associated uveitis (n = 1), juvenile systemic lupus erythematosus (JSLE) (n = 5) or in healthy controls who developed adult-onset SLE (n = 1) or had non-specific symptoms (n = 1). The impact of ARD on puberty outcomes was explored in JIA (n = 4) and JSLE (n = 3). Quality assessment of studies showed a small to moderate risk of bias overall (NOS 4-9/9). Due to large heterogeneity of the studies it was not possible to perform a meta-analysis. Multiple studies reported on delayed puberty in patients with JIA/JSLE, menstrual and hormonal abnormalities, and lower height and weight than controls. Earlier (pre-pubertal) onset of JSLE was correlated with more severe disease and more need for systemic treatment.

Conclusion: A bidirectional relationship exists between puberty and ARDs; however, more and better research is required to elucidate the complexity of this relationship. We propose puberty-related clinical assessments in patients with ARDs, which can improve patient outcomes and facilitate future research.
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http://dx.doi.org/10.1186/s12969-021-00528-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008606PMC
March 2021

Increased apolipoprotein-B:A1 ratio predicts cardiometabolic risk in patients with juvenile onset SLE.

EBioMedicine 2021 Mar 24;65:103243. Epub 2021 Feb 24.

Centre for Rheumatology Research, Department of Medicine, University College London, Rayne Building, London W1CE 6JF, UK. Electronic address:

Background: Cardiovascular disease is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE). Traditional factors for cardiovascular risk (CVR) prediction are less robust in younger patients. More reliable CVR biomarkers are needed for JSLE patient stratification and to identify therapeutic approaches to reduce cardiovascular morbidity and mortality in JSLE.

Methods: Serum metabolomic analysis (including >200 lipoprotein measures) was performed on a discovery (n=31, median age 19) and validation (n=31, median age 19) cohort of JSLE patients. Data was analysed using cluster, receiver operating characteristic analysis and logistic regression. RNA-sequencing assessed gene expression in matched patient samples.

Findings: Hierarchical clustering of lipoprotein measures identified and validated two unique JSLE groups. Group-1 had an atherogenic and Group-2 had an atheroprotective lipoprotien profile. Apolipoprotein(Apo)B:ApoA1 distinguished the two groups with high specificity (96.2%) and sensitivity (96.7%). JSLE patients with high ApoB:ApoA1 ratio had increased CD8+ T-cell frequencies and a CD8+ T-cell transcriptomic profile enriched in genes associated with atherogenic processes including interferon signaling. These metabolic and immune signatures overlapped statistically significantly with lipid biomarkers associated with sub-clinical atherosclerosis in adult SLE patients and with genes overexpressed in T-cells from human atherosclerotic plaque respectively. Finally, baseline ApoB:ApoA1 ratio correlated positively with SLE disease activity index (r=0.43, p=0.0009) and negatively with Lupus Low Disease Activity State (r=-0.43, p=0.0009) over 5-year follow-up.

Interpretation: Multi-omic analysis identified high ApoB:ApoA1 as a potential biomarker of increased cardiometabolic risk and worse clinical outcomes in JSLE. ApoB:ApoA1 could help identify patients that require increased disease monitoring, lipid modification or lifestyle changes.

Funding: Lupus UK, The Rosetrees Trust, British Heart Foundation, UCL & Birkbeck MRC Doctoral Training Programme and Versus Arthritis.
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http://dx.doi.org/10.1016/j.ebiom.2021.103243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992074PMC
March 2021

Specific domain V reduction of beta-2-glycoprotein I induces protein flexibility and alters pathogenic antibody binding.

Sci Rep 2021 Feb 25;11(1):4542. Epub 2021 Feb 25.

Institute of Biochemistry, University of Greifswald, Greifswald, Germany.

Beta-2-glycoprotein I (β2GPI) is a blood protein and the major antigen in the autoimmune disorder antiphospholipid syndrome (APS). β2GPI exists mainly in closed or open conformations and comprises of 11 disulfides distributed across five domains. The terminal Cys288/Cys326 disulfide bond at domain V has been associated with different cysteine redox states. The role of this disulfide bond in conformational dynamics of this protein has not been investigated so far. Here, we report on the enzymatic driven reduction by thioredoxin-1 (recycled by Tris(2-carboxyethyl)phosphine; TCEP) of β2GPI. Specific reduction was demonstrated by Western blot and mass spectrometry analyses confirming majority targeting to the fifth domain of β2GPI. Atomic force microscopy images suggested that reduced β2GPI shows a slightly higher proportion of open conformation and is more flexible compared to the untreated protein as confirmed by modelling studies. We have determined a strong increase in the binding of pathogenic APS autoantibodies to reduced β2GPI as demonstrated by ELISA. Our study is relevant for understanding the effect of β2GPI reduction on the protein structure and its implications for antibody binding in APS patients.
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http://dx.doi.org/10.1038/s41598-021-84021-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907366PMC
February 2021

Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission.

Nat Commun 2020 12 9;11(1):6317. Epub 2020 Dec 9.

Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH, London, UK.

Anecdotal evidence suggests that Coronavirus disease 2019 (COVID-19), caused by the coronavirus SARS-CoV-2, exhibits differences in morbidity and mortality between sexes. Here, we present a meta-analysis of 3,111,714 reported global cases to demonstrate that, whilst there is no difference in the proportion of males and females with confirmed COVID-19, male patients have almost three times the odds of requiring intensive treatment unit (ITU) admission (OR = 2.84; 95% CI = 2.06, 3.92) and higher odds of death (OR = 1.39; 95% CI = 1.31, 1.47) compared to females. With few exceptions, the sex bias observed in COVID-19 is a worldwide phenomenon. An appreciation of how sex is influencing COVID-19 outcomes will have important implications for clinical management and mitigation strategies for this disease.
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http://dx.doi.org/10.1038/s41467-020-19741-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726563PMC
December 2020

Preexisting and de novo humoral immunity to SARS-CoV-2 in humans.

Science 2020 12 6;370(6522):1339-1343. Epub 2020 Nov 6.

Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, Great Ormond Street Hospital (GOSH), London WC1N 3JH, UK.

Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were detectable using a flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2-uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.
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http://dx.doi.org/10.1126/science.abe1107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857411PMC
December 2020

Disease-associated and patient-specific immune cell signatures in juvenile-onset systemic lupus erythematosus: patient stratification using a machine-learning approach.

Lancet Rheumatol 2020 Aug 29;2(8):e485-e496. Epub 2020 Jul 29.

Centre for Rheumatology Research, Department of Medicine, University College London, London, UK.

Background: Juvenile-onset systemic lupus erythematosus (SLE) is a rare autoimmune rheumatic disease characterised by more severe disease manifestations, earlier damage accrual, and higher mortality than in adult-onset SLE. We aimed to use machine-learning approaches to characterise the immune cell profile of patients with juvenile-onset SLE and investigate links with the disease trajectory over time.

Methods: This study included patients who attended the University College London Hospital (London, UK) adolescent rheumatology service, had juvenile-onset SLE according to the 1997 American College of Rheumatology revised classification criteria for lupus or the 2012 Systemic Lupus International Collaborating Clinics criteria, and were diagnosed before 18 years of age. Blood donated by healthy age-matched and sex-matched volunteers who were taking part in educational events in the Centre for Adolescent Rheumatology Versus Arthritis at University College London (London, UK) was used as a control. Immunophenotyping profiles (28 immune cell subsets) of peripheral blood mononuclear cells from patients with juvenile-onset SLE and healthy controls were determined by flow cytometry. We used balanced random forest (BRF) and sparse partial least squares-discriminant analysis (sPLS-DA) to assess classification and parameter selection, and validation was by ten-fold cross-validation. We used logistic regression to test the association between immune phenotypes and k-means clustering to determine patient stratification. Retrospective longitudinal clinical data, including disease activity and medication, were related to the immunological features identified.

Findings: Between Sept 5, 2012, and March 7, 2018, peripheral blood was collected from 67 patients with juvenile-onset SLE and 39 healthy controls. The median age was 19 years (IQR 13-25) for patients with juvenile-onset SLE and 18 years (16-25) for healthy controls. The BRF model discriminated patients with juvenile-onset SLE from healthy controls with 90·9% prediction accuracy. The top-ranked immunological features from the BRF model were confirmed using sPLS-DA and logistic regression, and included total CD4, total CD8, CD8 effector memory, and CD8 naive T cells, Bm1, and unswitched memory B cells, total CD14 monocytes, and invariant natural killer T cells. Using these markers patients were clustered into four distinct groups. Notably, CD8 T-cell subsets were important in driving patient stratification, whereas B-cell markers were similarly expressed across the cohort of patients with juvenile-onset SLE. Patients with juvenile-onset SLE and elevated CD8 effector memory T-cell frequencies had more persistently active disease over time, as assessed by the SLE disease activity index 2000, and this was associated with increased treatment with mycophenolate mofetil and an increased prevalence of lupus nephritis. Finally, network analysis confirmed the strong association between immune phenotype and differential clinical features.

Interpretation: Machine-learning models can define potential disease-associated and patient-specific immune characteristics in rare disease patient populations. Immunological association studies are warranted to develop data-driven personalised medicine approaches for treatment of patients with juvenile-onset SLE.

Funding: Lupus UK, The Rosetrees Trust, Versus Arthritis, and UK National Institute for Health Research University College London Hospital Biomedical Research Centre.
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http://dx.doi.org/10.1016/S2665-9913(20)30168-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425802PMC
August 2020

Using peripheral blood immune signatures to stratify patients with adult and juvenile inflammatory myopathies.

Rheumatology (Oxford) 2020 01;59(1):194-204

Division of Medicine, University College London, London, UK.

Objective: The inflammatory idiopathic myopathies (IIM) are a group of rare autoimmune diseases defined by muscle weakness and characterized by pro-inflammatory infiltrates in muscle. Little is known about the immunological profile in peripheral blood of these patients and how this relates to IIM subtypes. This study aimed to stratify adult and juvenile-onset IIM patients according to immune cell profile.

Methods: Peripheral blood mononuclear cells from 44 patients with adult myositis (AM), 15 adolescent-onset juvenile dermatomyositis (a-JDM), and 40 age-matched healthy controls were analysed by flow cytometry to quantify 33 immune cell subsets. Adult myositis patients were grouped according to myositis subtype; DM and polymyositis; and also autoantibody specificity. Disease activity was determined by the myositis disease activity assessment tool and clinicians' decision on treatment.

Results: Unique immune signatures were identified for DM, polymyositis and a-JDM compared with healthy controls. DM patients had a T-cell signature comprising increased CD4+ and TH17 cell frequencies and increased immune cell expression of IL-6. Polymyositis patients had a B-cell signature with reduced memory B cells. A-JDM had decreased naïve B cells and increased CD4+T cells. All patient groups had decreased CD8+central memory T-cell frequencies. The distinct immune signatures were also seen when adult myositis patients were stratified according to auto-antibody expression; patients with anti-synthetase-antibodies had reduced memory B cells and patients with autoimmune rheumatic disease overlap had an elevated Th17 profile.

Conclusion: Unique immune signatures were associated with adult vs juvenile disease. The Th17 signature in DM patients supports the potential use of IL-17 inhibitors in treatment of IIMs.
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http://dx.doi.org/10.1093/rheumatology/kez252DOI Listing
January 2020

Association of Anxiety With Pain and Disability but Not With Increased Measures of Inflammation in Adolescent Patients With Juvenile Idiopathic Arthritis.

Arthritis Care Res (Hoboken) 2020 09 23;72(9):1266-1274. Epub 2020 Jul 23.

University College London, London, UK.

Objective: To explore whether anxiety and depression are associated with clinical measures of disease for adolescent patients with juvenile idiopathic arthritis (JIA) and whether anxiety and depression are associated with increased peripheral proinflammatory cytokine levels in adolescent patients with JIA and in healthy adolescent controls.

Methods: A total of 136 patients with JIA and 88 healthy controls ages 13-18 years completed questionnaires on anxiety and depressive symptoms. For patients with JIA, pain, disability, physician global assessment (using a visual analog scale [VAS]), and number of joints with active inflammation (active joint count) were recorded. In a subsample, we assessed lipopolysaccharide-stimulated interleukin 6 (IL-6) production from peripheral blood mononuclear cells, serum IL-6, cortisol, and C-reactive protein levels. Data were analyzed by linear regression analysis.

Results: Levels of anxiety and depressive symptoms in patients with JIA were not significantly different than those in healthy controls. For patients with JIA, anxiety was significantly associated with disability (β = 0.009, P = 0.002), pain (β = 0.029, P = 0.011), and physician global assessment VAS (β = 0.019, P = 0.012), but not with active joint count (β = 0.014, P = 0.120). Anxiety was not associated with any laboratory measures of inflammation for JIA patients. These relationships were also true for depressive symptoms. For healthy controls, there was a trend toward an association of anxiety (but not depressive symptoms) with stimulated IL-6 (β = 0.004, P = 0.052).

Conclusion: Adolescent patients with JIA experience equivalent levels of anxiety and depressive symptoms as healthy adolescents. For adolescent patients with JIA, anxiety and depressive symptoms are associated with pain, disability, and physician global assessment VAS, but not with inflammation.
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http://dx.doi.org/10.1002/acr.24006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496487PMC
September 2020

Sex and Pubertal Differences in the Type 1 Interferon Pathway Associate With Both X Chromosome Number and Serum Sex Hormone Concentration.

Front Immunol 2018 15;9:3167. Epub 2019 Jan 15.

Arthritis Research UK Centre for Adolescent Rheumatology at UCL, ULCH and GOSH, London, United Kingdom.

Type 1 interferons (IFN) are an antiviral cytokine family, important in juvenile onset systemic lupus erythematosus (jSLE) which is more common in females, around puberty. We report that plasmacytoid dendritic cells (pDC) from healthy females produced more type 1 IFN after toll like receptor (TLR) 7 signaling than males, even before puberty, but that puberty itself associated with increased production of type 1 IFN. A unique human model allows us to show that this was related to X chromosome number, and serum testosterone concentration, in a manner which differed depending on the number of X chromosomes present. In addition, we have showed that pDC were more activated in females overall, and immune cell gene expression was higher in females after puberty. Therefore, sex hormones and X chromosome number were associated individually and interactively with the type 1 IFN response, which contributes to our understanding of why females are more likely to develop an IFN mediated disease like jSLE after puberty.
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http://dx.doi.org/10.3389/fimmu.2018.03167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345344PMC
October 2019

CD19CD24CD38 B Cells Are Expanded in Juvenile Dermatomyositis and Exhibit a Pro-Inflammatory Phenotype After Activation Through Toll-Like Receptor 7 and Interferon-α.

Front Immunol 2018 22;9:1372. Epub 2018 Jun 22.

Centre for Adolescent Rheumatology, Arthritis Research UK, University College London Hospital and Great Ormond Street Hospital, London, United Kingdom.

Juvenile dermatomyositis (JDM) is a rare form of childhood autoimmune myositis that presents with proximal muscle weakness and skin rash. B cells are strongly implicated in the pathogenesis of the disease, but the underlying mechanisms are unknown. Therefore, the main objective of our study was to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in JDM patients. Patients were recruited through the UK JDM Cohort and Biomarker study. Peripheral blood B cell subpopulations were immunophenotyped by flow cytometry. The results identified that immature transitional B cells were significantly expanded in active JDM, actively dividing, and correlated positively with disease activity. Protein and RNAseq analysis revealed high interferon alpha (IFNα) and TLR7-pathway signatures pre-treatment. Stimulation of B cells through TLR7/8 promoted both IL-10 and IL-6 production in controls but failed to induce IL-10 in JDM patient cells. Interrogation of the CD40-CD40L pathway (known to induce B cell IL-10 and IL-6) revealed similar expression of IL-10 and IL-6 in B cells cultured with CD40L from both JDM patients and controls. In conclusion, JDM patients with active disease have a significantly expanded immature transitional B cell population which correlated with the type I IFN signature. Activation through TLR7 and IFNα may drive the expansion of immature transitional B cells in JDM and skew the cells toward a pro-inflammatory phenotype.
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http://dx.doi.org/10.3389/fimmu.2018.01372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024011PMC
June 2018

Oxidation of β2-glycoprotein I associates with IgG antibodies to domain I in patients with antiphospholipid syndrome.

PLoS One 2017 19;12(10):e0186513. Epub 2017 Oct 19.

Centre for Rheumatology Research, UCL Division of Medicine, London, United Kingdom.

Domain I (DI) of beta-2-glycoprotein I (β2GPI) contains the immunodominant epitope for pathogenic antiphospholipid antibodies (aPL). DI is exposed in the linear form of the molecule but not in the circular form that comprises 90% of serum β2GPI. The majority of circulating β2GPI is biochemically reduced with two free thiols in Domain V. However, increased levels of oxidised β2GPI are found in patients with antiphospholipid syndrome (APS). It is not known whether oxidation of β2GPI favours the linear form of the molecule and thus promotes development of anti-DI antibodies. We investigated whether the proportion of oxidised β2GPI associates with the presence of anti-DI in APS patients. Serum samples from 44 APS patients were screened for IgG, IgM and IgA anti-DI, anti-β2GPI, anti-cardiolipin (anti-CL) and biochemically reduced β2GPI. A negative correlation was found between the proportion of β2GPI in the biochemically reduced form and IgG anti-DI levels (r = -0.54, p = 0.0002), but not with IgM or IgA anti-DI. Moreover, the proportion of β2GPI in the reduced form was lower in IgG anti-DI positive than anti-DI negative APS patients (p = 0.02). The relative amount of reduced β2GPI was no different between patients who were positive or negative for IgG, IgM and IgA anti-β2GPI or anti-CL. This study demonstrates that oxidised β2GPI lacking free cysteine-thiol groups most closely associates with IgG anti-DI positivity compared to IgG anti-CL and anti-β2GPI. Future studies are required to ascertain the directionality of this association to define causation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186513PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648189PMC
November 2017

Antibodies to Cyclic Citrullinated Peptides in Patients With Juvenile Idiopathic Arthritis and Patients With Rheumatoid Arthritis: Shared Expression of the Inherently Autoreactive 9G4 Idiotype.

Arthritis Rheumatol 2017 07 5;69(7):1387-1395. Epub 2017 Jun 5.

Arthritis Research UK Centre for Adolescent Rheumatology, University College London, London, UK.

Objective: Antibodies to cyclic citrullinated peptides (anti-CCP) in rheumatoid arthritis (RA) can express the inherently autoreactive gene V 4-34, detected using the rat monoclonal antibody 9G4. Patients with the polyarticular subtype of juvenile idiopathic arthritis (JIA) share some but not all of the features of adult patients with RA. This study was undertaken to compare serologic findings for rheumatoid factor (RF), anti-CCP, and 9G4-expressing anti-CCP in a large JIA cohort with a cohort of adult RA patients.

Methods: Serum from 88 patients with polyarticular JIA, 29 patients with enthesitis-related arthritis, 38 patients with extended oligoarthritis, 31 adolescent controls, 35 patients with RA, and 30 adult controls were tested for RF, for IgG, IgA, and IgM anti-CCP, and for 9G4-expressing anti-CCP by enzyme-linked immunosorbent assay. Total serum 9G4-positive IgM was also measured.

Results: Of 65 patients with RF-negative polyarticular JIA, 4 (6.2%) were IgG anti-CCP positive. Sera from 20 of 23 patients with RF-positive polyarticular JIA (87.0%), 24 of 35 patients with RA (68.6%), and 1 patient with extended oligoarthritis contained IgG anti-CCP. IgA and IgM anti-CCP levels were lower in the adolescent group (P < 0.01). Levels of 9G4-expressing anti-CCP were higher in patients with RF-positive polyarticular JIA than in those with RF-negative polyarticular JIA (P < 0.0001). Median levels of 9G4-expressing anti-CCP in patients with RF-positive polyarticular JIA and those with RA did not differ. Expression of 9G4 on serum total IgM was greater in patients with RF-positive polyarticular JIA than other adolescent groups (P < 0.01), but similar to adult RF-positive RA.

Conclusion: In healthy individuals, 9G4-positive B cells comprise 5-10% of the peripheral blood pool but serum immunoglobulins utilizing V 4-34 are disproportionately low. The idiotope recognized by 9G4 was detected on anti-CCP antibodies in >80% of patients with RF-positive polyarticular JIA. V 4-34 usage by anti-CCP in both JIA and RA patients suggest elicitation of these autoantibodies through shared pathogenic B cell selection processes.
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http://dx.doi.org/10.1002/art.40117DOI Listing
July 2017

MicroRNA 497 modulates interleukin 1 signalling via the MAPK/ERK pathway.

FEBS Lett 2012 Nov 22;586(23):4165-72. Epub 2012 Oct 22.

Division of Infection and Immunity, University College London, 5 University Street, London WC1E 6JF, UK.

The MAPK/ERK signalling pathway has been described to mediate IL-1 induction of target genes and is known to be regulated by microRNAs (miRNA). We describe a novel miRNA regulating the expression of the MEK1 gene and how it impacts IL-1 induced IL-6 transcription. miR-497 was predicted to target MEK1 3'UTR using bioinformatic tools. Transfection of miR-497 into HeLa cells inhibited MEK1 protein expression by 50%. In transient transfection experiments, the luciferase activity of a MEK1 3'UTR luciferase reporter construct was reduced in the presence of miR-497, and mutation of the predicted miR-497 binding site restored activity. miR-497 also decreased protein levels of RAF1 and ERK1 but not ERK2. Addition of miR-497 was further shown to inhibit IL-1 induced IL-6 gene transcription.
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http://dx.doi.org/10.1016/j.febslet.2012.10.014DOI Listing
November 2012

Deletion of Fas in the pancreatic beta-cells leads to enhanced insulin secretion.

Am J Physiol Endocrinol Metab 2009 Dec 15;297(6):E1304-12. Epub 2009 Sep 15.

Institute of Medical Science, Ontario Cancer Institute, Ontario, Canada.

Fas/Fas ligand belongs to the tumor necrosis factor superfamily of receptors/ligands and is best known for its role in apoptosis. However, recent evidence supports its role in other cellular responses, including proliferation and survival. Although Fas has been implicated as an essential mediator of beta-cell death in the pathogenesis of type 1 diabetes, the essential role of Fas specifically in pancreatic beta-cells has been found to be controversial. Moreover, the role of Fas on beta-cell homeostasis and function is not clear. The objective of this study is to determine the role of Fas specifically in beta-cells under both physiological and diabetes models. Mice with Fas deletion specifically in the beta-cells were generated using the Cre-loxP system. Cre-mediated Fas deletion was under the control of the rat insulin promoter. Absence of Fas in beta-cells leads to complete protection against FasL-induced cell death. However, Fas is not essential in determining beta-cell mass or susceptibility to streptozotocin- or HFD-induced diabetes. Importantly, Fas deletion in beta-cells leads to increased p65 expression, enhanced glucose tolerance, and glucose-stimulated insulin secretion, with increased exocytosis as manifested by increased changes in membrane capacitance and increased expression of Syntaxin1A, VAMP2, and munc18a. Together, our study shows that Fas in the beta-cells indeed plays an essential role in the canonical death receptor-mediated apoptosis but is not essential in regulating beta-cell mass or diabetes development. However, beta-cell Fas is critical in the regulation of glucose homeostasis through regulation of the exocytosis machinery.
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http://dx.doi.org/10.1152/ajpendo.00217.2009DOI Listing
December 2009

Absence of caspase-3 protects pancreatic {beta}-cells from c-Myc-induced apoptosis without leading to tumor formation.

J Biol Chem 2009 Apr 12;284(16):10947-56. Epub 2009 Feb 12.

Department of Medical Biophysics and Institute of Medical Science, Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2M9, Canada.

c-Myc is a powerful trigger of beta-cell apoptosis, proliferation, and dedifferentiation in rodent islets in vivo. In a transgenic mouse model, c-Myc induction causes rapid beta-cell apoptosis and overt diabetes. When suppression of apoptosis is achieved by overexpression of Bcl-x(L) in an inducible model of c-Myc activation, a full spectrum of tumor development, including distant metastasis, occurs. Caspase-3 is a key pro-apoptotic protein involved in the execution phase of multiple apoptotic pathways. To test whether caspase-3 is an essential mediator of apoptosis in this model of tumorigenesis, we generated caspase-3 knock-out mice containing the inducible c-myc transgene (c-Myc(+)Casp3(-/-)). In contrast to Bcl-x(L)-overexpressing c-Myc(+) mice, c-Myc(+)Casp3(-/-) mice remained euglycemic for up to 30 days of c-Myc activation, and there was no evidence of tumor formation. Interestingly, caspase-3 deletion also led to the suppression of proliferation, perhaps through regulation of the cell cycle inhibitory protein p27, suggesting a possible mechanism for maintaining a balance between suppression of apoptosis and excessive proliferation in the context of c-Myc activation. Additionally, c-Myc-activated Casp3(-/-) mice were protected from streptozotocin-induced diabetes. Our studies demonstrate that caspase-3 deletion confers protection from c-Myc-induced apoptosis and diabetes development without unwanted tumorigenic effects. These results may lead to further elucidation of the mechanisms of c-Myc biology relevant to beta-cells, which may result in novel therapeutic strategies for diabetes.
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http://dx.doi.org/10.1074/jbc.M806960200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667780PMC
April 2009

PTEN deletion and concomitant c-Myc activation do not lead to tumor formation in pancreatic beta cells.

J Biol Chem 2009 Jan 4;284(5):2917-2922. Epub 2008 Dec 4.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario M5G 2M9, Canada; Department of Medicine and Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada. Electronic address:

Phosphatase and tensin homologue (PTEN) deleted on chromosome 10 is a dual-specific phosphatase and a potent antagonist of the phosphoinositide 3-kinase signaling pathway. Although first discovered as a tumor suppressor, emerging evidence supports PTEN as a potential therapeutic target for diabetes. PTEN deletion in beta cells leads to increased beta cell mass and protection from streptozotocin-induced diabetes. Importantly, PTEN deletion does not lead to tumor formation in beta cells. To further assess the potential tumorigenic role of PTEN, we tested the biological role of PTEN in the context of activation of the proto-oncogene c-Myc. We generated and characterized beta cell-specific PTEN knock-out mice expressing an inducible c-Myc transgene in beta cells. Surprisingly, we found that PTEN loss did not confer protection from the overwhelming apoptosis and diabetes development seen with c-Myc activation. Importantly, despite the combined effect of the loss of a tumor suppressor and activation of an oncogene in beta cells, there was no evidence of tumor development with sustained c-Myc activation.
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http://dx.doi.org/10.1074/jbc.M805183200DOI Listing
January 2009

Distinct in vivo roles of caspase-8 in beta-cells in physiological and diabetes models.

Diabetes 2007 Sep 11;56(9):2302-11. Epub 2007 Jun 11.

Department of Medical Biophysics, Ontario Cancer Institute, and the University of Toronto, Toronto, Ontario, Canada.

Inadequate pancreatic beta-cell mass resulting from excessive beta-cell apoptosis is a key defect in type 1 and type 2 diabetes. Caspases are the major molecules involved in apoptosis; however, in vivo roles of specific caspases in diabetes are unclear. The purpose of this study is to examine the role of Caspase (Casp)8 in beta-cells in vivo. Using the Cre-loxP system, mice lacking Casp8 in beta-cells (RIPcre(+)Casp8(fl/fl) mice) were generated to address the role of Casp8 in beta-cells in physiological and diabetes models. We show that islets isolated from RIPcre(+)Casp8(fl/fl) mice were protected from Fas ligand (FasL)-and ceramide-induced cell death. Furthermore, RIPcre(+)Casp8(fl/fl) mice were protected from in vivo models of type 1 and type 2 diabetes. In addition to being the central mediator of apoptosis in diabetes models, we show that Casp8 is critical for maintenance of beta-cell mass under physiological conditions. With aging, RIPcre(+)Casp8(fl/fl) mice gradually develop hyperglycemia and a concomitant decline in beta-cell mass. Their islets display decreased expression of molecules involved in insulin/IGF-I signaling and show decreased pancreatic duodenal homeobox-1 and cAMP response element binding protein expression. At the level of individual islets, we observed increased insulin secretory capacity associated with increased expression of exocytotic proteins. Our results show distinct context-specific roles of Casp8 in physiological and disease states; Casp8 is essential for beta-cell apoptosis in type 1 and type 2 diabetes models and in regulating beta-cell mass and insulin secretion under physiological conditions.
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http://dx.doi.org/10.2337/db06-1771DOI Listing
September 2007
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