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The role of defective clearance of apoptotic cells in systemic autoimmunity

Abstract

The inefficient clearance of dying cells can result in the accumulation of apoptotic cell remnants. This occurrence is considered an intrinsic defect that can cause the permanent presence of cellular debris responsible for the initiation of systemic autoimmunity in diseases such as systemic lupus erythematosus (SLE). If postapoptotic debris accumulates in germinal centers, activates complement and functions as a survival signal for B cells that have become autoreactive by somatic hypermutation, autoimmunity could arise (etiology). The accumulation of postapoptotic remnants and fragments derived from secondary necrotic cells in the presence of autoantibodies against apoptotic cells or adaptor molecules obliges their pathological elimination and maintains autoinflammation. The autoimmunity that occurs in patients with SLE involves complex antigens that contain nucleic acids, which can function as virus mimetics. Complexes of autoantibodies, proteins and nucleic acids are likely to be mistaken by the immune system for opsonized viruses, resulting in the production of type I interferons, a hallmark of SLE (pathogenesis). The pathogenicity of autoantibodies is thought to strongly increase if autoantigens are accessible for immune-complex formation. The immune complex could be considered a binary pyrogen formed from less proinflammatory components. The accessibility of cognate autoantigens, in turn, is likely to be related to impaired or delayed clearance of apoptotic cells.

Key Points

  • The clearance of apoptotic cells does not usually induce inflammation, and might even be anti-inflammatory

  • Patients with systemic lupus erythematosus (SLE) often display a deficiency in clearing apoptotic cells

  • In germinal centers, apoptotic remnants serve as survival signals for B cells that have accidentally acquired autoreactivity during somatic hypermutation

  • Genetic or acquired deficiencies in molecules that function during the opsonization of apoptotic cells promote autoimmunity (etiology)

  • Antibodies that recognize and bind to cell debris associated with secondary necrosis precipitate inflammation (pathogenesis)

  • Clearance deficiency is involved in the etiology of autoimmunity in SLE and in the pathogenesis of inflammatory tissue damage in SLE

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Figure 1: Clearance of apoptotic cells by professional phagocytes.
Figure 2: Danger signals from primary and secondary necrotic cells induce an alert immune system.
Figure 3: Shifting clearance from tolerance to autoimmunity by autoantibodies recognizing opsonins.
Figure 4: Etiology and pathogenesis of SLE.
Figure 5: Autoantibodies and nucleic-acid-containing autoantigens are binary pyrogens.

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Acknowledgements

This work was supported by the grant ELAN M3-09.03.18.1 to L. E. Muñoz, by the Deutsche Forschungsgemeinschaft (DFG) projects Lo437/5-3 to M. Schiller, SFB685/A2 to K. Lauber, and SFB643/B5 to M. Herrmann, by the K. und R. Wucherpfennigstiftung to M. Herrmann, and by Ministero della Salute and Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) to A. A. Manfredi.

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Muñoz, L., Lauber, K., Schiller, M. et al. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol 6, 280–289 (2010). https://doi.org/10.1038/nrrheum.2010.46

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