Are Complement Deficiencies Really Rare?
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The Pathophysiology of Paroxysmal Nocturnal Haemoglobinuria.Pdf
The Pathophysiology of Paroxysmal Nocturnal Haemoglobinuria Richard John Kelly Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Medicine January 2014 1 Jointly-Authored Publications The candidate confirms that the work submitted is his own, except where work which has formed part of jointly authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated below. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others. The work in Chapter 3 of the thesis has appeared in publication as follows: Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011;117:6786-6792. I was responsible for designing the study, collecting and analysing the data and writing the paper. Dena Cohen and Walter Gregory performed the statistical analysis. All the other authors reviewed the paper. The work in Chapter 4 of the thesis has appeared in publication as follows: Kelly R, Arnold L, Richards S, Hill A, Bomken C, Hanley J, Loughney A, Beauchamp J, Khursigara G, Rother RP, Chalmers E, Fyfe A, Fitzsimons E, Nakamura R, Gaya A, Risitano AM, Schubert J, Norfolk D, Simpson N, Hillmen P. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J Haematol 2010;149:446-450. I was responsible for designing the study, collecting and analysing the data and writing the paper. -
Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia
BASIC RESEARCH www.jasn.org Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia Yoshiyasu Ueda,1 Takashi Miwa,1 Damodar Gullipalli,1 Sayaka Sato,1 Daisuke Ito,1 Hangsoo Kim,1 Matthew Palmer,2 and Wen-Chao Song1 Departments of 1Systems Pharmacology and Translational Therapeutics and 2Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania ABSTRACT Background Properdin (P) is a positive regulator of the alternative pathway of complement activation. Although P inhibition is expected and has been shown to ameliorate the alternative pathway of comple- ment-mediated tissue injury in several disease models, it unexpectedly exacerbated renal injury in a murine model of C3 glomerulopathy. The role of P in atypical hemolytic uremic syndrome (aHUS) is uncertain. Methods We blocked P function by genetic deletion or mAb-mediated inhibition in mice carrying a factor H (FH) point mutation, W1206R (FHR/R), that causes aHUS and systemic thrombophilia with high mortality. Results Pdeficiency completely rescued FHR/R mice from premature death and prevented thrombocyto- penia, hemolytic anemia, and renal disease. It also eliminated macrovessel thrombi that were prevalent in FHR/R mice. All mice that received a function-blocking anti-P mAb for 8 weeks survived the experimental period and appeared grossly healthy. Platelet counts and hemoglobin levels were significantly improved in FHR/R mice after 4 weeks of anti-P mAb treatment. One half of the FHR/R mice treated with an isotype control mAb but none of the anti-P mAb-treated mice developed stroke-related neurologic disease. Anti-P mAb-treated FHR/R mice showed largely normal renal histology, and residual liver thrombi were detected in only three of 15 treated mice. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
The Case for Lupus Nephritis
Journal of Clinical Medicine Review Expanding the Role of Complement Therapies: The Case for Lupus Nephritis Nicholas L. Li * , Daniel J. Birmingham and Brad H. Rovin Department of Internal Medicine, Division of Nephrology, The Ohio State University, Columbus, OH 43210, USA; [email protected] (D.J.B.); [email protected] (B.H.R.) * Correspondence: [email protected]; Tel.: +1-614-293-4997; Fax: +1-614-293-3073 Abstract: The complement system is an innate immune surveillance network that provides defense against microorganisms and clearance of immune complexes and cellular debris and bridges innate and adaptive immunity. In the context of autoimmune disease, activation and dysregulation of complement can lead to uncontrolled inflammation and organ damage, especially to the kidney. Systemic lupus erythematosus (SLE) is characterized by loss of tolerance, autoantibody production, and immune complex deposition in tissues including the kidney, with inflammatory consequences. Effective clearance of immune complexes and cellular waste by early complement components protects against the development of lupus nephritis, while uncontrolled activation of complement, especially the alternative pathway, promotes kidney damage in SLE. Therefore, complement plays a dual role in the pathogenesis of lupus nephritis. Improved understanding of the contribution of the various complement pathways to the development of kidney disease in SLE has created an opportunity to target the complement system with novel therapies to improve outcomes in lupus nephritis. In this review, we explore the interactions between complement and the kidney in SLE and their implications for the treatment of lupus nephritis. Keywords: lupus nephritis; complement; systemic lupus erythematosus; glomerulonephritis Citation: Li, N.L.; Birmingham, D.J.; Rovin, B.H. -
Comprehensive Genetic Testing for Primary Immunodeficiency
Woon and Ameratunga Allergy Asthma Clin Immunol (2016) 12:65 Allergy, Asthma & Clinical Immunology DOI 10.1186/s13223-016-0169-2 RESEARCH Open Access Comprehensive genetic testing for primary immunodeficiency disorders in a tertiary hospital: 10‑year experience in Auckland, New Zealand See‑Tarn Woon and Rohan Ameratunga* Abstract Background and purpose: New Zealand is a developed geographically isolated country in the South Pacific with a population of 4.4 million. Genetic diagnosis is the standard of care for most patients with primary immunodeficiency disorders (PIDs). Methods: Since 2005, we have offered a comprehensive genetic testing service for PIDs and other immune-related disorders with a published sequence. Here we present results for this program, over the first decade, between 2005 and 2014. Results: We undertook testing in 228 index cases and 32 carriers during this time. The three most common test requests were for X-linked lymphoproliferative (XLP), tumour necrosis factor receptor associated periodic syndrome (TRAPS) and haemophagocytic lymphohistiocytosis (HLH). Of the 32 suspected XLP cases, positive diagnoses were established in only 2 patients. In contrast, genetic defects in 8 of 11 patients with suspected X-linked agammaglobu‑ linemia (XLA) were confirmed. Most XLA patients were initially identified from absence of B cells. Overall, positive diagnoses were made in about 23% of all tests requested. The diagnostic rate was lowest for several conditions with locus heterogeneity. Conclusions: Thorough clinical characterisation of patients can assist in prioritising which genes should be tested. The clinician-driven customised comprehensive genetic service has worked effectively for New Zealand. Next genera‑ tion sequencing will play an increasing role in disorders with locus heterogeneity. -
Widely Used Commercial Elisa Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin As a Potential Second Member of the Zonulin Family
ORIGINAL RESEARCH published: 05 February 2018 doi: 10.3389/fendo.2018.00022 Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family Lucas Scheffler1, Alyce Crane1, Henrike Heyne1, Anke Tönjes2, Dorit Schleinitz1, Christian H. Ihling3, Michael Stumvoll2, Rachel Freire4, Maria Fiorentino4, Alessio Fasano4, Peter Kovacs1* and John T. Heiker5* 1 Leipzig University Medical Center, IFB Adiposity Diseases, Leipzig, Germany, 2 Divisions of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany, 3 Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle, Germany, 4 Mucosal Immunology And Biology Research Center, Massachusetts General Hospital––Harvard Medical School, Boston, MA, United States, 5 Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, University of Leipzig, Leipzig, Germany Background: There is increasing evidence for the role of impaired intestinal permeability Edited by: in obesity and associated metabolic diseases. Zonulin is an established serum marker for Dr Saumen Kumar Maitra, Visva-Bharati University, India intestinal permeability and identical to pre-haptoglobin2. Here, we aimed to investigate Reviewed by: the relationship between circulating zonulin and metabolic traits related to obesity. Yicong Li, Johns Hopkins Medicine, Methods: Serum zonulin was measured by using a widely used commercial ELISA kit in United States 376 subjects from the metabolically well-characterized cohort of Sorbs from Germany. In Asamanja Chattoraj, addition, haptoglobin genotype was determined in DNA samples from all study subjects. Institute of Bio-Resources and Sustainable Development, India Results: As zonulin concentrations did not correlate to the haptoglobin genotypes, *Correspondence: we investigated the specificity of the zonulin ELISA assay using antibody capture John T. -
Hereditary Angioedema: a Broad Review for Clinicians
REVIEW ARTICLE Hereditary Angioedema A Broad Review for Clinicians Ugochukwu C. Nzeako, MD, MPH; Evangelo Frigas, MD; William J. Tremaine, MD ereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10000 to 1 in 150000 persons; HAE has been reported in all races, and no sex predomi- nance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known trig- Hgers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named “type 3” HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal sys- tems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corti- costeroids, antihistamines, and epinephrine can be useful adjuncts but typically are not effica- cious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. -
O) 2 Platelets Mediated by Properdin and C3(H Complement Activation on Stimulated Identification of a Novel Mode Of
Identification of a Novel Mode of Complement Activation on Stimulated Platelets Mediated by Properdin and C3(H2 O) This information is current as of October 1, 2021. Gurpanna Saggu, Claudio Cortes, Heather N. Emch, Galia Ramirez, Randall G. Worth and Viviana P. Ferreira J Immunol 2013; 190:6457-6467; Prepublished online 15 May 2013; doi: 10.4049/jimmunol.1300610 Downloaded from http://www.jimmunol.org/content/190/12/6457 Supplementary http://www.jimmunol.org/content/suppl/2013/05/17/jimmunol.130061 Material 0.DC1 http://www.jimmunol.org/ References This article cites 72 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/190/12/6457.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Identification of a Novel Mode of Complement Activation on Stimulated Platelets Mediated by Properdin and C3(H2O) Gurpanna Saggu,*,1 Claudio Cortes,*,†,1 Heather N. -
Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency
Practice parameter Practice parameter for the diagnosis and management of primary immunodeficiency Francisco A. Bonilla, MD, PhD, David A. Khan, MD, Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD, David I. Bernstein, MD, Joann Blessing-Moore, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Chief Editor: Francisco A. Bonilla, MD, PhD Co-Editor: David A. Khan, MD Members of the Joint Task Force on Practice Parameters: David I. Bernstein, MD, Joann Blessing-Moore, MD, David Khan, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Primary Immunodeficiency Workgroup: Chairman: Francisco A. Bonilla, MD, PhD Members: Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD GlaxoSmithKline, Merck, and Aerocrine; has received payment for lectures from Genentech/ These parameters were developed by the Joint Task Force on Practice Parameters, representing Novartis, GlaxoSmithKline, and Merck; and has received research support from Genentech/ the American Academy of Allergy, Asthma & Immunology; the American College of Novartis and Merck. -
NIH Public Access Author Manuscript J Allergy Clin Immunol
NIH Public Access Author Manuscript J Allergy Clin Immunol. Author manuscript; available in PMC 2008 December 12. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: J Allergy Clin Immunol. 2007 October ; 120(4): 776±794. doi:10.1016/j.jaci.2007.08.053. The International Union of Immunological Societies (IUIS) Primary Immunodeficiency Diseases (PID) Classification Committee Raif. S. Geha, M.D., Luigi. D. Notarangelo, M.D. [Co-chairs], Jean-Laurent Casanova, M.D., Helen Chapel, M.D., Mary Ellen Conley, M.D., Alain Fischer, M.D., Lennart Hammarström, M.D., Shigeaki Nonoyama, M.D., Hans D. Ochs, M.D., Jennifer Puck, M.D., Chaim Roifman, M.D., Reinhard Seger, M.D., and Josiah Wedgwood, M.D. Abstract Primary immune deficiency diseases (PID) comprise a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, NK cells, as well as T and B lymphocytes. The study of these diseases has provided essential insights into the functioning of the immune system. Over 120 distinct genes have been identified, whose abnormalities account for more than 150 different forms of PID. The complexity of the genetic, immunological, and clinical features of PID has prompted the need for their classification, with the ultimate goal of facilitating diagnosis and treatment. To serve this goal, an international Committee of experts has met every two years since 1970. In its last meeting in Jackson Hole, Wyoming, United States, following three days of intense scientific presentations and discussions, the Committee has updated the classification of PID as reported in this article. -
Package Insert Has Been Approved by the U.S
HIGHLIGHTS OF PRESCRIBING INFORMATION **Doses up to 1,000 U every 3 to 4 days may be considered based on These highlights do not include all the information needed to use individual patient response. ® CINRYZE safely and effectively. See full prescribing information for ---------------------- DOSAGE FORMS AND STRENGTHS -------------------- CINRYZE. Approximately 500 Units (lyophilized) in an 8 mL vial. (3) CINRYZE (C1 Esterase Inhibitor [Human]) ---------------------------- CONTRAINDICATIONS ------------------------------- For Intravenous Use, Freeze-Dried Powder for Reconstitution Patients who have manifested life-threatening immediate hypersensitivity Initial U.S. Approval: 2008. reactions, including anaphylaxis, to the product (4). --------------------------- RECENT MAJOR CHANGES -------------------------- ----------------------------- WARNINGS/PRECAUTIONS ------------------------ • Indications and Usage (1) 06/2018 • Hypersensitivity reactions may occur. Have epinephrine immediately • Dosage and Administration (2.1) 06/2018 available for treatment of acute severe hypersensitivity reaction (5.1) • --------------------------- INDICATIONS AND USAGE --------------------------- Serious arterial and venous thromboembolic (TE) events have been CINRYZE is a C1 esterase inhibitor indicated for routine prophylaxis against reported at the recommended dose of C1 Esterase Inhibitor (Human) angioedema attacks in adults, adolescents and pediatric patients (6 years of products, including CINRYZE, following administration in patients with age and older) -
Uva-DARE (Digital Academic Repository)
UvA-DARE (Digital Academic Repository) Flow cytometric immunophenotyping in the diagnosis and follow-up of immunodeficient children de Vries, E.; Noordzij, J.G.; Kuijpers, T.W.; van Dongen, J.J.M. DOI 10.1007/s004310100797 Publication date 2001 Published in European Journal of Pediatrics Link to publication Citation for published version (APA): de Vries, E., Noordzij, J. G., Kuijpers, T. W., & van Dongen, J. J. M. (2001). Flow cytometric immunophenotyping in the diagnosis and follow-up of immunodeficient children. European Journal of Pediatrics, 160(10), 583-591. https://doi.org/10.1007/s004310100797 General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:25 Sep 2021 Eur J Pediatr -2001) 160: 583±591 DOI 10.1007/s004310100797 REVIEW Esther de Vries á Jeroen G.