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      Complement System Part II: Role in Immunity

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          Abstract

          The complement system has been considered for a long time as a simple lytic cascade, aimed to kill bacteria infecting the host organism. Nowadays, this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing opsonization and a direct killing by C5b–9 membrane attack complex and by triggering inflammatory responses with the anaphylatoxins C3a and C5a. Opsonization plays also a major role in the mounting of an adaptive immune response, involving antigen presenting cells, T-, and B-lymphocytes. Nevertheless, it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Inadequate complement activation becomes a disease cause, as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus. Age-related macular degeneration and cancer will be described as examples showing that complement contributes to a large variety of conditions, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target.

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          Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009.

          Different types of cell death are often defined by morphological criteria, without a clear reference to precise biochemical mechanisms. The Nomenclature Committee on Cell Death (NCCD) proposes unified criteria for the definition of cell death and of its different morphologies, while formulating several caveats against the misuse of words and concepts that slow down progress in the area of cell death research. Authors, reviewers and editors of scientific periodicals are invited to abandon expressions like 'percentage apoptosis' and to replace them with more accurate descriptions of the biochemical and cellular parameters that are actually measured. Moreover, at the present stage, it should be accepted that caspase-independent mechanisms can cooperate with (or substitute for) caspases in the execution of lethal signaling pathways and that 'autophagic cell death' is a type of cell death occurring together with (but not necessarily by) autophagic vacuolization. This study details the 2009 recommendations of the NCCD on the use of cell death-related terminology including 'entosis', 'mitotic catastrophe', 'necrosis', 'necroptosis' and 'pyroptosis'.
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            Complement: a key system for immune surveillance and homeostasis.

            Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.
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              Complement System Part I – Molecular Mechanisms of Activation and Regulation

              Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here, we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex. We will also discuss the importance of structure–function relationships using the example of atypical hemolytic uremic syndrome. Lastly, we will discuss the development and benefits of therapies using complement inhibitors.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/211378
                URI : http://frontiersin.org/people/u/210906
                URI : http://frontiersin.org/people/u/238813
                URI : http://frontiersin.org/people/u/203575
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                26 May 2015
                2015
                : 6
                : 257
                Affiliations
                [1] 1UMRS 1138, Centre de Recherche des Cordeliers, INSERM , Paris, France
                [2] 2UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Paris Cité, Université Paris Descartes , Paris, France
                [3] 3UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, UPMC Université Paris 06 , Paris, France
                [4] 4Ecole Pratique des Hautes Études (EPHE) , Paris, France
                [5] 5Service d’Immunologie Biologique, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou , Paris, France
                Author notes

                Edited by: Cordula M. Stover, University of Leicester, UK

                Reviewed by: Robert Braidwood Sim, University of Leicester, UK; Kenneth Reid, University of Oxford, UK

                *Correspondence: Lubka T. Roumenina, Centre de Recherche des Cordeliers, 15 rue de l’Ecole de Médecine, Paris, France, lubka.roumenina@ 123456crc.jussieu.fr

                Specialty section: This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2015.00257
                4443744
                26074922
                9612ed72-607e-4c17-9d7d-e66ae0142cc3
                Copyright © 2015 Merle, Noe, Halbwachs-Mecarelli, Fremeaux-Bacchi and Roumenina.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 February 2015
                : 09 May 2015
                Page count
                Figures: 12, Tables: 0, Equations: 0, References: 282, Pages: 26, Words: 21023
                Funding
                Funded by: SIRIC-CARPEM
                Award ID: ARC no. PJA 20141201954
                Funded by: ANR Genopath 2009–2012
                Award ID: 09geno03101I
                Funded by: APHP-PHRC
                Award ID: AOM08198
                Funded by: EU FP7
                Award ID: 2012-305608
                Categories
                Immunology
                Review

                Immunology
                complement system,adaptive immunity,crosstalk tlr-complement,pathogen strategies for immune evasion,complement in cancer,complement and innate immunity,complement-related diseases,anaphylatoxins

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