Defects in the disposal of dying cells lead to autoimmunity

Gaipl, Udo S.; Franz, Sandra; Voll, Reinhard; Sheriff, Ahmed; Kalden, Joachim R.; Herrmann, Martin

doi:10.1007/s11926-004-0016-1

Cited by 31 publications

(25 citation statements)

References 85 publications

(92 reference statements)

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“…Only when clearance mechanisms are defective or overwhelmed by excessive apoptosis do apoptotic cells accumulate, which is thought to underlie autoimmune diseases such as systemic lupus erythematosus (SLE) 3 (6). Apoptotic cells express several ligands that enhance phagocytosis such as phosphatidylserine and calreticulin, and they down-regulate molecules that may work as "do not eat me" signals (7).…”

mentioning

confidence: 99%

C4b-binding Protein and Factor H Compensate for the Loss of Membrane-bound Complement Inhibitors to Protect Apoptotic Cells against Excessive Complement Attack

Trouw

Bengtsson

Gelderman

et al. 2007

Journal of Biological Chemistry

126

125

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Apoptotic cells have been reported to down-regulate membrane-bound complement regulatory proteins (m-C-Reg) and to activate complement. Nonetheless, most apoptotic cells do not undergo complement-mediated lysis. Therefore, we hypothesized that fluid phase complement inhibitors would bind to apoptotic cells and compensate functionally for the loss of m-C-Reg. We observed that m-C-Reg are down-regulated rapidly upon apoptosis but that complement activation follows only after a gap of several hours. Coinciding with, but independent from, complement activation, fluid phase complement inhibitors C4b-binding protein (C4BP) and factor H (fH) bind to the cells. C4BP and fH do not entirely prevent complement activation but strongly limit C3 and C9 deposition. Late apoptotic cells, present in blood of healthy controls and systemic lupus erythematosus patients, are also positive for C4BP and fH. Upon culture, the percentage of late apoptotic cells increases, paralleled by increased C4BP binding. C4BP binds to dead cells mainly via phosphatidylserine, whereas fH binds via multiple interactions with CRP playing no major role for binding of C4BP or fH. In conclusion, during late apoptosis, cells acquire fluid phase complement inhibitors that compensate for the downregulation of m-C-Reg and protect against excessive complement activation and lysis.Cell death via apoptosis is an essential process for development, maintenance of tissue integrity, and resolution of inflammation (1). Several active processes ensure that the cell dies in a way that results in fast removal, to prevent release of its potential pro-inflammatory content as is the case in primary or secondary necrosis (2-4).Although billions of cells die via apoptosis every day, only a few apoptotic cells are present at any given point in time under healthy conditions (5) as the result of a very efficient clearance process. Only when clearance mechanisms are defective or overwhelmed by excessive apoptosis do apoptotic cells accumulate, which is thought to underlie autoimmune diseases such as systemic lupus erythematosus (SLE) 3 (6). Apoptotic cells express several ligands that enhance phagocytosis such as phosphatidylserine and calreticulin, and they down-regulate molecules that may work as "do not eat me" signals (7). In addition, apoptotic cells have been reported to bind complement-initiating molecules such as mannose-binding lectin and C1q that enhance uptake by phagocytes (8 -10). Some discrepancies exist in reports of the stage of cell death necessary for binding of such recognition molecules, which can partly be explained by differences in semantics, experimental design, and readout (9,(11)(12)(13)(14).The complement system is an integral part of the innate immune defense and is also involved in the instruction of adaptive immunity and clearance of waste such as dead cells and immune complexes (15,16). This potent enzyme cascade system has both membrane-bound and fluid phase inhibitors that protect host surfaces and prevent systemic depletion of complement activi...

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mentioning

confidence: 99%

C4b-binding Protein and Factor H Compensate for the Loss of Membrane-bound Complement Inhibitors to Protect Apoptotic Cells against Excessive Complement Attack

Trouw

Bengtsson

Gelderman

et al. 2007

Journal of Biological Chemistry

126

125

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“…Certainly, the lysoPC/G2A receptor system apparently plays a predominant role in the clearance of apoptotic cells. It is now widely accepted that defects in the removal of apoptotic cells can lead to autoimmunity (2). Interestingly, G2A knock-out mice develop an autoimmune syndrome (29) similar to mice with a deficiency in certain eat-me signals, such as MFG-E8 or C1q (30,31).…”

Section: Figure 6 Expression Of G2a Reconstitutes Migration To Acs Amentioning

confidence: 99%

“…Secreted find-me and eat-me signals exposed by the dying cell, together with bridging proteins and phagocyte receptors, comprise the central elements for removal of apoptotic cells and prevention of secondary necrosis (1). Growing evidence suggests that the defective clearance of apoptotic cells favors the onset of autoimmune diseases (2).…”

mentioning

confidence: 99%

Migration to Apoptotic “Find-me” Signals Is Mediated via the Phagocyte Receptor G2A

Peter

Waibel

Radu

et al. 2008

Journal of Biological Chemistry

215

180

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Phagocytosis of apoptotic cells is fundamentally important throughout life, because non-cleared cells become secondarily necrotic and release intracellular contents, thus instigating inflammatory and autoimmune responses. Secreted "find-me" and exposed "eat-me" signals displayed by the dying cell in concert with the phagocyte receptors comprise the phagocytic synapse of apoptotic cell clearance. In this scenario, lysophospholipids (lysoPLs) are assumed to act as find-me signals for the attraction of phagocytes. However, both the identity of the lysoPLs released from apoptotic cells and the nature of the phagocyte receptor are largely unknown. By a detailed analysis of the structural requirements we show here that lysophosphatidylcholine (lysoPC), but none of the lysoPC metabolites or other lysoPLs, represents the essential apoptotic attraction signal able to trigger a phagocyte chemotactic response. Furthermore, using RNA interference and expression studies, we demonstrate that the G-protein-coupled receptor G2A, unlike its relative GPR4, is involved in the chemotaxis of monocytic cells. Thus, our study identifies lysoPC and G2A as the crucial receptor/ligand system for the attraction of phagocytes to apoptotic cells and the prevention of autoimmunity.

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“…While not wholly causal for systemic lupus erythematosus, failure to effectively clear apoptotic cells contributes to the severity of disease. 64 We have recently undertaken studies to describe the signaling mechanisms responsible for apoptotic cell-induced dendritic cell tolerance. Initial results suggest that apoptotic cells block proinflammatory stimuli through inhibition of the NF-κB pathway.…”

Section: Immunoregulation Of Dendritic Cells By Il-10mentioning

confidence: 99%

Immunoregulation of Dendritic Cells

Wallet¹,

Sen²,

Tisch

2005

Clinical Medicine & Research

122

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The paradigm of tolerogenic/immature versus inflammatory/mature dendritic cells has dominated the recent literature regarding the role of these antigen-presenting cells in mediating immune homeostasis or self-tolerance and response to pathogens, respectively. This issue is further complicated by the identification of distinct subtypes of dendritic cells that exhibit different antigen-presenting cell effector functions. The discovery of pathogen-associated molecular patterns and toll-like receptors provides the mechanistic basis for dendritic cell recognition of specific pathogens and induction of appropriate innate and adaptive immune responses. Only recently has insight been gained into how dendritic cells contribute to establishing and/or maintaining immunological tolerance to self. Soluble and cellular mediators have been reported to effectively regulate the function of dendritic cells by inducing several outcomes ranging from non-inflammatory dendritic cells that lack the ability to induce T lymphocyte activation to dendritic cells that actively suppress T lymphocyte responses. A thorough discussion of these stimuli and their outcomes is essential to understanding the potential for modulating dendritic cell function in the treatment of inflammatory disease conditions.

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Defects in the disposal of dying cells lead to autoimmunity

Cited by 31 publications

References 85 publications

C4b-binding Protein and Factor H Compensate for the Loss of Membrane-bound Complement Inhibitors to Protect Apoptotic Cells against Excessive Complement Attack

C4b-binding Protein and Factor H Compensate for the Loss of Membrane-bound Complement Inhibitors to Protect Apoptotic Cells against Excessive Complement Attack

Migration to Apoptotic “Find-me” Signals Is Mediated via the Phagocyte Receptor G2A

Immunoregulation of Dendritic Cells

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