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      How apoptotic cells aid in the removal of their own cold dead bodies

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          Abstract

          Apoptotic cell clearance facilitates the removal of aged, damaged, infected or dangerous cells although minimizing perturbation of surrounding tissues, and is a vital process in the development and homeostasis of multicellular organisms. Importantly, failure to correctly execute programmed cell death and subsequent corpse clearance is broadly associated with chronic inflammatory and/or autoimmune diseases such as systemic lupus erythematosus. Apoptotic cells develop dramatic morphological changes including contraction, membrane blebbing and apoptotic body formation, which were among the first and most readily identifiable features of cellular suicide. However, understanding the purpose of apoptotic cell morphological changes has proven to be elusive, and recent studies have made somewhat surprising, and occasionally opposing, conclusions about the contribution of blebbing to phagocytic clearance and prevention of inflammatory/autoimmune disease. We review the evidence indicating how apoptotic blebs actively promote corpse recognition, uptake, and generation of auto-reactive antibodies.

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          Most cited references53

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          Sex differences in autoimmune disease.

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            Autoimmunity and the clearance of dead cells.

            To maintain organismal homeostasis, phagocytes engulf dead cells, which are recognized as dead by virtue of a characteristic "eat me" signal exposed on their surface. The dead cells are then transferred to lysosomes, where their cellular components are degraded for reuse. Inefficient engulfment of dead cells activates the immune system, causing disease such as systemic lupus erythematosus, and if the DNA of the dead cells is not properly degraded, the innate immune response becomes activated, leading to severe anemia and chronic arthritis. Here, we discuss how the endogenous components of dead cells activate the immune system through both extracellular and intracellular pathways. (c) 2010 Elsevier Inc. All rights reserved.
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              Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.

              The complement system plays a paradoxical role in the development and expression of autoimmunity in humans. The activation of complement in systemic lupus erythematosus (SLE) contributes to tissue injury. In contrast, inherited deficiency of classical pathway components, particularly C1q (ref. 1), is powerfully associated with the development of SLE. This leads to the hypothesis that a physiological action of the early part of the classical pathway protects against the development of SLE (ref. 2) and implies that C1q may play a key role in this respect. C1q-deficient (C1qa-/-) mice were generated by gene targeting and monitored for eight months. C1qa-/- mice had increased mortality and higher titres of autoantibodies, compared with strain-matched controls. Of the C1qa-/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies. Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls. The phenotype associated with C1q deficiency was modified by background genes. These findings are compatible with the hypothesis that C1q deficiency causes autoimmunity by impairment of the clearance of apoptotic cells.
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                Author and article information

                Journal
                Cell Death Differ
                Cell Death Differ
                Cell Death and Differentiation
                Nature Publishing Group
                1350-9047
                1476-5403
                May 2012
                16 March 2012
                1 May 2012
                : 19
                : 5
                : 735-742
                Affiliations
                [1 ]simpleBeatson Institute for Cancer Research , Glasgow G61 1BD, UK
                Author notes
                [* ]simpleBeatson Institute for Cancer Research , Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. Tel: +44 (0)141 330 3654; Fax: +44 (0)141 330 6521; E-mail: m.olson@ 123456beatson.gla.ac.uk
                Article
                cdd201225
                10.1038/cdd.2012.25
                3321633
                22421963
                e489a50b-76f4-47f9-a639-f5b808bbb755
                Copyright © 2012 Macmillan Publishers Limited

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 23 November 2011
                : 08 February 2012
                : 13 February 2012
                Categories
                Review

                Cell biology
                apoptosis,cytoskeleton,actin,efferocytosis
                Cell biology
                apoptosis, cytoskeleton, actin, efferocytosis

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