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      Diseases of complement dysregulation—an overview

      1 , 2 , , 1 , 2

      Seminars in Immunopathology

      Springer Berlin Heidelberg

      Complement, C3G, aHUS, PNH

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          Abstract

          Atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and paroxysmal nocturnal hemoglobinuria (PNH) are prototypical disorders of complement dysregulation. Although complement overactivation is common to all, cell surface alternative pathway dysregulation (aHUS), fluid phase alternative pathway dysregulation (C3G), or terminal pathway dysregulation (PNH) predominates resulting in the very different phenotypes seen in these diseases. The mechanism underlying the dysregulation also varies with predominant acquired autoimmune (C3G), somatic mutations (PNH), or inherited germline mutations (aHUS) predisposing to disease. Eculizumab has revolutionized the treatment of PNH and aHUS although has been less successful in C3G. With the next generation of complement therapeutic in late stage development, these archetypal complement diseases will provide the initial targets.

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          Most cited references 146

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          The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease.

          The efficient sequestration of hemoglobin by the red blood cell membrane and the presence of multiple hemoglobin clearance mechanisms suggest a critical need to prevent the buildup of this molecule in the plasma. A growing list of clinical manifestations attributed to hemoglobin release in a variety of acquired and iatrogenic hemolytic disorders suggests that hemolysis and hemoglobinemia should be considered as a novel mechanism of human disease. Pertinent scientific literature databases and references were searched through October 2004 using terms that encompassed various aspects of hemolysis, hemoglobin preparations, clinical symptoms associated with plasma hemoglobin, nitric oxide in hemolysis, anemia, pulmonary hypertension, paroxysmal nocturnal hemoglobinuria, and sickle-cell disease. Hemoglobin is released into the plasma from the erythrocyte during intravascular hemolysis in hereditary, acquired, and iatrogenic hemolytic conditions. When the capacity of protective hemoglobin-scavenging mechanisms has been saturated, levels of cell-free hemoglobin increase in the plasma, resulting in the consumption of nitric oxide and clinical sequelae. Nitric oxide plays a major role in vascular homeostasis and has been shown to be a critical regulator of basal and stress-mediated smooth muscle relaxation and vasomotor tone, endothelial adhesion molecule expression, and platelet activation and aggregation. Thus, clinical consequences of excessive cell-free plasma hemoglobin levels during intravascular hemolysis or the administration of hemoglobin preparations include dystonias involving the gastrointestinal, cardiovascular, pulmonary, and urogenital systems, as well as clotting disorders. Many of the clinical sequelae of intravascular hemolysis in a prototypic hemolytic disease, paroxysmal nocturnal hemoglobinuria, are readily explained by hemoglobin-mediated nitric oxide scavenging. A growing body of evidence supports the existence of a novel mechanism of human disease, namely, hemolysis-associated smooth muscle dystonia, vasculopathy, and endothelial dysfunction.
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            Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.

            Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy with manifestations of hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies have shown that mutations in complement regulatory proteins predispose to non-Shiga toxin-associated HUS (non-Stx-HUS). We undertook genetic analysis on membrane cofactor protein (MCP), complement factor H (CFH), and factor I (IF) in 156 patients with non-Stx-HUS. Fourteen, 11, and 5 new mutational events were found in MCP, CFH, and IF, respectively. Mutation frequencies were 12.8%, 30.1%, and 4.5% for MCP, CFH, and IF, respectively. MCP mutations resulted in either reduced protein expression or impaired C3b binding capability. MCP-mutated patients had a better prognosis than CFH-mutated and nonmutated patients. In MCP-mutated patients, plasma treatment did not impact the outcome significantly: remission was achieved in around 90% of both plasma-treated and plasma-untreated acute episodes. Kidney transplantation outcome was favorable in patients with MCP mutations, whereas the outcome was poor in patients with CFH and IF mutations due to disease recurrence. This study documents that the presentation, the response to therapy, and the outcome of the disease are influenced by the genotype. Hopefully this will translate into improved management and therapy of patients and will provide the way to design tailored treatments.
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              C3 glomerulopathy: consensus report

              C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.
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                Author and article information

                Contributors
                +44 (0) 191 282 5094 , david.kavanagh@ncl.ac.uk
                Journal
                Semin Immunopathol
                Semin Immunopathol
                Seminars in Immunopathology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1863-2297
                1863-2300
                11 January 2018
                11 January 2018
                2018
                : 40
                : 1
                : 49-64
                Affiliations
                [1 ]The National Renal Complement Therapeutics Centre, aHUS Service, Building 26, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP UK
                [2 ]ISNI 0000 0001 0462 7212, GRID grid.1006.7, Institute of Cellular Medicine, , Newcastle University, ; Newcastle upon Tyne, UK
                Author notes

                This article is a contribution to the special issue on Complement in Health and Disease: Novel Aspects and Insights - Guest Editors: Paul Morgan and David Kavanagh

                Article
                663
                10.1007/s00281-017-0663-8
                5794843
                29327071
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: Newcastle University
                Categories
                Review
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                Pathology

                complement, pnh, c3g, ahus

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