Complement Factor I in Health and Disease. Nilsson, Sara
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Clinical Study High Complement Factor I Activity in the Plasma of Children with Autism Spectrum Disorders
Hindawi Publishing Corporation Autism Research and Treatment Volume 2012, Article ID 868576, 6 pages doi:10.1155/2012/868576 Clinical Study High Complement Factor I Activity in the Plasma of Children with Autism Spectrum Disorders Naghi Momeni,1 Lars Brudin,2 Fatemeh Behnia,3 Berit Nordstrom,¨ 4 Ali Yosefi-Oudarji,5 Bengt Sivberg,4 Mohammad T. Joghataei,5 and Bengt L. Persson1 1 School of Natural Sciences, Linnaeus University, 39182 Kalmar, Sweden 2 Department of Clinical Physiology, Kalmar County Hospital, 39185 Kalmar, Sweden 3 Department of Occupational Therapy, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran 4 Department of Health Sciences, Autism Research, Faculty of Medicine, Lund University, Box 157, 22100 Lund, Sweden 5 Cellular and Molecular Research Centre, Tehran University of Medical Sciences (TUMS), Tehran, Iran Correspondence should be addressed to Bengt Sivberg, [email protected] Received 17 June 2011; Revised 22 August 2011; Accepted 22 August 2011 Academic Editor: Judy Van de Water Copyright © 2012 Naghi Momeni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Autism spectrum disorders (ASDs) are neurodevelopmental and behavioural syndromes affecting social orientation, behaviour, and communication that can be classified as developmental disorders. ASD is also associated with immune system abnormality. Im- mune system abnormalities may be caused partly by complement system factor I deficiency. Complement factor I is a serine pro- tease present in human plasma that is involved in the degradation of complement protein C3b, which is a major opsonin of the complement system. -
Advances in Hematology
ADVANCES IN HEMATOLOGY Current Developments in the Management of Hematologic Disorders Hematology Section Editor: Craig M. Kessler, MD Atypical Hemolytic Uremic Syndrome: The Role of Complement Pathway Gene Mutation Analysis Ilene C. Weitz, MD Associate Professor of Clinical Medicine Jane Anne Nohl Division of Hematology Keck School of Medicine of USC Los Angeles, California H&O What causes atypical hemolytic uremic H&O Which mutations in complement alternative syndrome (aHUS)? pathway genes are linked to aHUS? IW We think that most people with aHUS have problems IW Multiple genetic mutations have been linked to with regulation of complement. As a result of excess com- aHUS, especially those involved in the complement plement, endothelial and organ damage occur. We know alternative pathway. These include mutations in comple- that mutations in the genes of complement regulatory pro- ment factor H, complement factor I, membrane cofactor teins are associated with aHUS. In addition, factors other protein, complement factor B, and C3 nephritic factor. than underlying mutations may play a role in increasing Mutations may cause the protein to be normal but low in activation and the expression of the clinical syndrome. quantity, or normal in quantity but abnormal in function; the degree of the abnormality may depend on whether the H&O How is the complement system activated patient is heterozygous or homozygous. and regulated? In addition, other factors such as thrombomodulin have been described that work through other enzymes. IW The complement system is a part of the innate Thrombomodulin is involved in complement regulation immune system that is necessary for fighting infections by activating thrombin activatable fibrinolytic inhibitor and aberrant immunologic stimuli. -
Properdin Factor D: Effects on Thrombin-Induced Platelet Aggregation
Properdin factor D: effects on thrombin-induced platelet aggregation. A E Davis 3rd, D M Kenney J Clin Invest. 1979;64(3):721-728. https://doi.org/10.1172/JCI109515. Research Article Factor D, when preincubated with platelet suspensions, at concentrations as low as 1.2 micrograms/ml, inhibited thrombin-induced platelet aggregation. No inhibition of collagen or arachidonic acid-induced platelet aggregation was found. Inhibition occurred, but to a lesser extent, when thrombin and factor D were added to platelets at the same time. No inhibition occurred when factor D was added after thrombin. Thrombin was able to overcome inhibition by factor D by increasing its concentration. Diisopropyl-phosphorofluoridate-inactivated factor D also inhibited thrombin-induced platelet aggregation so that enzymatic activity of factor D was not required for inhibition. Factor D absorbed with hirudin coupled to Sepharose 6B showed no decrease in inhibitory capacity. 125I-Factor D bound to platelets in a manner suggesting an equilibrium reaction similar to thrombin. At low factor D input, binding was linear, whereas at higher input, binding began to approach saturation. Binding of 125I-labeled thrombin to platelets was inhibited by factor D. Analysis of these data show that factor D does not alter the total number of thrombin molecules which bind to the platelet surface at saturation. However, the dissociation constant for thrombin is altered from 2.78 to 6.90 nM in the presence of factor D (20 micrograms/ml). Factor D is thus a competitive inhibitor of thrombin binding, although the affinity of factor D for the platelet thrombin receptor is much less […] Find the latest version: https://jci.me/109515/pdf Properdin Factor D EFFECTS ON THROMBIN-INDUCED PLATELET AGGREGATION ALVIN E. -
367.Full.Pdf
Human Complement Factor I Does Not Require Cofactors for Cleavage of Synthetic Substrates This information is current as Stefanos A. Tsiftsoglou and Robert B. Sim of October 2, 2021. J Immunol 2004; 173:367-375; ; doi: 10.4049/jimmunol.173.1.367 http://www.jimmunol.org/content/173/1/367 Downloaded from References This article cites 41 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/173/1/367.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human Complement Factor I Does Not Require Cofactors for Cleavage of Synthetic Substrates1 Stefanos A. Tsiftsoglou2 and Robert B. Sim Complement factor I (fI) plays a major role in the regulation of the complement system. It circulates in an active form and has very restricted specificity, cleaving only C3b or C4b in the presence of a cofactor such as factor H (fH), complement receptor type 1, membrane cofactor protein, or C4-binding protein. -
Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease
Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................ -
Complement Activation in Factor D-Deficient Mice
Complement activation in factor D-deficient mice Yuanyuan Xu*†, Minghe Ma‡, Gregory C. Ippolito*, Harry W. Schroeder, Jr.*, Michael C. Carroll‡, and John E. Volanakis*§ *Department of Medicine, University of Alabama, Birmingham, AL 35294; ‡Department of Pathology, Harvard Medical School, Boston, MA 02138; and §Biomedical Sciences Research Center ‘‘A. Fleming,’’ Vari 166 72, Greece Edited by Douglas T. Fearon, University of Cambridge, Cambridge, United Kingdom, and approved October 18, 2001 (received for review August 15, 2001) To assess the contribution of the alternative pathway in comple- mice. The results indicate that factor D is indispensable for ment activation and host defense and its possible role in the complement activation through the AP and that it plays a regulation of systemic energy balance in vivo, factor D-deficient significant role in opsonization of bacteria by ‘‘natural’’ IgM mice were generated by gene targeting. The mutant mice have no antibody. It is also shown that factor D does not play a major role apparent abnormality in development and their body weights are in fat metabolism. Interestingly, the data revealed a unique mode similar to those of factor D-sufficient littermates. Complement of factor B activation, which provides valuable insights into the activation could not be initiated in the serum of deficient mice by mechanism of AP activation. the alternative pathway activators rabbit erythrocytes and zymo- san. Surprisingly, injection of cobra venom factor (CVF) caused a Materials and Methods profound and reproducible reduction in serum C3 levels, whereas, Generation of Factor D-Deficient Mice. A gene targeting vector, as expected, there was no C3 reduction in factor B-deficient mice Adn͞TK, was constructed (9) on the backbone of pBluescript treated similarly. -
Innate Immunity: the Inside Story on Complement Activation
RESEARCH HIGHLIGHTS Nature Reviews Immunology | AOP, published online 31 December 2013; doi:10.1038/nri3603 INNATE IMMUNITY The inside story on complement activation The evolutionarily ancient comple- inconsistent with de novo protein — the production of interferon-γ ment system might have started life production, so the authors looked (IFNγ) and interleukin-17 was sig- as an intracellular activation pathway for a potential role of endogenous nificantly decreased but could be par- rather than as a liver-derived serum proteases. They showed that rest- tially rescued by the addition of C3a. effector cascade. Other recent studies ing human T cells express mRNA Cytokine production was not affected have suggested the importance of encoding cathepsin L (CTSL), and in serum-free medium or in the T cell-derived local complement acti- that CTSL cleaves C3 into biologi- presence of a C3 convertase inhibitor, vation in the autocrine stimulation of cally active C3a and C3b fragments which shows that the CTSL-mediated T helper 1 (T 1) cell responses, but in vitro. C3 and CTSL were found to C3 activation pathway is sufficient H intracellular Claudia Kemper, John Atkinson and be colocalized in resting T cells in for autocrine C3aR-induced T cell colleagues are the first to show that C3a the endoplasmic reticulum (ER) and effector function in humans. the C3 activation products C3a and generation ER-derived secretory vesicles. The in vivo relevance of this C3b can be generated intracellularly … is both Intracellular C3a was detected in pathway was shown in synovial fluid in human CD4+ T cells. resting T cells, and the increase in CD4+ T cells from patients with juve- Activation of mouse T cells is upregulated intracellular C3a levels observed after nile idiopathic arthritis. -
Structural and Functional Analysis of Complement Factor H: a Crucial Protein in Several Disorders
UNIVERSITÀ DEGLI STUDI DI MILANO SCUOLA DI DOTTORATO IN MEDICINA MOLECOLARE CICLO XXVII Anno Accademico 2013/2014 TESI DI DOTTORATO DI RICERCA settore scientifico disciplinare: BIO13 STRUCTURAL AND FUNCTIONAL ANALYSIS OF COMPLEMENT FACTOR H: A CRUCIAL PROTEIN IN SEVERAL DISORDERS Dottorando : Silvia BERRA Matricola N° R09657 TUTORE: Prof. Alberto CLIVIO COORDINATORE DEL DOTTORATO: Prof. Mario CLERICI Sommario Il Fattore H del complemento (FH) è un importante regolatore della via alternativa del complemento: protegge infatti le cellule dell’ospite dall’attacco del sistema del complemento e carenze di FH sia qualitative e quantitative dovute a mutazioni nel gene CFH sono spesso associate ad una serie di malattie umane, come la glomerulonefrite membranoproliferativa (MPGN), la sindrome emolitico-uremica atipica (aHUS) e la degenerazione maculare della retina legata all’età (AMD). Mentre esiste una caratterizzazione genetica per tutte queste malattie, i dati funzionali a livello di proteine sono spesso carenti. Inoltre, il FH gioca un ruolo significativo nelle malattie infettive: molti agenti patogeni sono infatti in grado di reclutare il FH sulla loro superficie sfruttandolo per proteggersi dagli attacchi del complemento. Mentre per alcuni agenti patogeni l'interazione con il FH è stata ben descritta, per gli altri gli "interattori" diretti sono ancora sconosciuti. Tuttavia, lo studio del FH è complicato dalla presenza di proteine FH-related (FHRs) che posseggono un elevato grado di somiglianza con il FH e ne rendono quindi difficile la purificazione e la analisi diretta. Il primo obiettivo di questo progetto è stato lo sviluppo di saggi quantitativi e funzionali FH-specifici, utilizzando un anticorpo monoclonale (Mab 5H5) prodotto nel nostro laboratorio, che si è dimostrato essere specifico per FH. -
A Family with Complement Factor D Deficiency
A family with complement factor D deficiency Douwe H. Biesma,1 André J. Hannema,2 Heleen van Velzen-Blad,3 Leontine Mulder,3 Rob van Zwieten,2 Irma Kluijt,4 and Dirk Roos2,5 1Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands 2Central Laboratory of the Netherlands Blood Transfusion Service, Amsterdam, The Netherlands 3Department of Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein, The Netherlands 4Department of Clinical Genetics, and 5Laboratory for Experimental and Clinical Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Address correspondence to: Douwe H. Biesma, Department of Internal Medicine, St. Antonius Hospital, PO Box 2500, 3430 EM Nieuwegein, The Netherlands. Phone: 31-30-6099111; Fax: 31-30-6056357; E-mail: [email protected]. Received for publication December 15, 2000, and accepted in revised form June 11, 2001. A complement factor D deficiency was found in a young woman who had experienced a serious Neis- seria meningitidis infection, in a deceased family member with a history of meningitis, and in three rel- atives without a history of serious infections. The patient and these three relatives showed a normal activity of the classical complement pathway, but a very low activity of the alternative complement pathway and a very low capacity to opsonize Escherichia coli and N. meningitidis (isolated from the patient) for phagocytosis by normal human neutrophils. The alternative pathway-dependent hemolytic activity and the opsonizing capacity of these sera were restored by addition of purified fac- tor D. The family had a high degree of consanguinity, and several other family members exhibited decreased levels of factor D. -
Targeting of Mannan-Binding Lectin-Associated Serine Protease-2 Confers Protection from Myocardial and Gastrointestinal Ischemia/Reperfusion Injury
Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury Wilhelm J. Schwaeblea,1, Nicholas J. Lyncha, James E. Clarkb, Michael Marberb, Nilesh J. Samanic, Youssif Mohammed Alia,d, Thomas Dudlere, Brian Parente, Karl Lhottaf, Russell Wallisa, Conrad A. Farrarg, Steven Sacksg, Haekyung Leeh, Ming Zhangh, Daisuke Iwakii, Minoru Takahashii, Teizo Fujitai, Clark E. Tedforde, and Cordula M. Stovera Departments of aInfection, Immunity, and Inflammation and cCardiovascular Sciences, University of Leicester, Leicester LE1 9HN, United Kingdom; bBritish Heart Foundation Centre and gMedical Research Council Centre for Transplantation and National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust, King’s College London, London SE1 9RT, United Kingdom; dFaculty of Pharmacy, Department of Microbiology, University of Mansoura, Mansoura 35516, Egypt; eOmeros Corporation, Seattle, WA 98101; fLandeskrankenhaus Feldkirch, 6807 Feldkirch, Austria; hDepartment of Anesthesiology, State University of New York-Downstate Medical Center, New York, NY 11203; and iDepartment of Immunology, Fukushima Medical University, Fukushima 960-1295, Japan Edited* by Douglas T. Fearon, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, and approved March 16, 2011 (received for review February 1, 2011) Complement research experienced a renaissance with the discovery aberrant glycosylation -
Factor D Catalog Number
Name: Factor D Catalog Number: A136 Sizes Available: 25 µg/vial Concentration: 0.1 mg/mL (see Certificate of Analysis for actual concentration) Form: Frozen liquid Activity: >95% versus normal human serum standard Purity: >95% by SDS-PAGE Buffer: 10 mM sodium phosphate, 145 mM NaCl, pH 7.3 Extinction Coeff.: A280 nm = 1.1 at 1.0 mg/mL Molecular weight: 24,000 Da (single chain) Preservative: None, 0.22 µm filtered Storage: -70oC or below. Avoid freeze/thaw. Source: Normal human serum (shown by certified tests to be negative for HBsAg and for antibodies to HCV, HIV-1 and HIV-II). Precautions: Use normal precautions for handling human blood products. Origin: Manufactured in the USA. General Description Factor D is a glycosylated protein composed of a single 24,000 Da polypeptide chain. It is an essential component of the alternative pathway of complement activation. Its only known function is to cleave and activate factor B when factor B is bound to C3b or a C3b-like protein such as C3(H2O) or CVF. Factor D is a serine protease that circulates as a mature protease, but it exhibits a highly restricted specificity and it appears to be substrate activated. Factor D cleaves factor B bound to C3b between Arg233 and Lys234 causing the release of the Ba fragment (33,000 Da) and leaving the 60,000 Bb fragment bound to C3b. The C3b,Bb complex is called a C3 or C5 convertase because it converts these proteins to their active forms by cleaving off the small peptides C3a and C5a, respectively (Law, S.K.A. -
Complement in Tumourigenesis and the Response to Cancer Therapy
cancers Review Complement in Tumourigenesis and the Response to Cancer Therapy Rebecca M. O’Brien 1,2, Aoife Cannon 1, John V. Reynolds 1, Joanne Lysaght 1,2 and Niamh Lynam-Lennon 1,* 1 Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; [email protected] (R.M.O.); [email protected] (A.C.); [email protected] (J.V.R.); [email protected] (J.L.) 2 Cancer Immunology and Immunotherapy Group, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland * Correspondence: [email protected] Simple Summary: Increasing evidence supports a role for complement in the development of cancer and the response to cancer treatments. Dysregulated complement expression within the tumour microenvironment has been linked to the suppression of anti-tumour immunity and poor clinical outcomes. Complement signals have been demonstrated to alter the immune milieu, promote proliferation and facilitate metastasis. Targeting complement signalling in combination with current treatments may have the potential to achieve improved control of tumour growth. Abstract: In recent years, our knowledge of the complement system beyond innate immunity has progressed significantly. A modern understanding is that the complement system has a multifaceted role in malignancy, impacting carcinogenesis, the acquisition of a metastatic phenotype and response to therapies. The ability of local immune cells to produce and respond to complement components has provided valuable insights into their regulation, and the subsequent remodeling of the tumour Citation: O’Brien, R.M.; Cannon, A.; Reynolds, J.V.; Lysaght, J.; microenvironment.