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Walport, Mark J.

doi:10.1186/ar586

Cited by 252 publications

(80 citation statements)

References 168 publications

(147 reference statements)

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“…However, this does not mean that a proper interaction of complement with dead cells is not relevant. Although C1q binding to apoptotic cells is a relatively late event, C1q deficiency leads to SLE in 90% of the cases, which according to the waste disposal theory is because of defective clearance of late apoptotic cells (51). This indicates that there are moments when apoptotic cells are not cleared before the stage when complement comes into play.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Homozygous hereditary deficiency of each of the initial proteins in the classical pathway has been associated with an increased risk of SLE, and the risk varies depending on the protein affected (C1q>C4>C2) [38]. SLE affects > 75% of individuals with C1q deficiency (71 reported cases of C1q deficiency reported thus far) [39].…”

Section: Rare Variants In Systemic Lupus Erythematosusmentioning

confidence: 99%

Rare variants, autoimmune disease, and arthritis

Chung

Shum²

2016

Current Opinion in Rheumatology

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Purpose of review We review select studies of newly discovered rare variants in autoimmune diseases with a focus on newly described monogenic disorders, rheumatoid arthritis, and systemic lupus erythematosus. Recent findings Two new monogenic syndromes of inflammatory arthritis were discovered using whole exome sequencing: the COPA syndrome due to rare mutations in COPA and Haploinsufficiency of A20 (HA20) resulting from rare mutations in TNFAIP3. Targeted exon sequencing identified rare variants in IL2RA and IL2RB associated with rheumatoid arthritis. Rare variants in TREX1 and other genes associated with monogenic interferonopathies are also associated with systemic lupus erythematosus. Summary Rare genetic variants contribute to the heritability of autoimmunity and provide key insight into both novel and previously implicated immunological pathways that are disrupted in autoimmune diseases.

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“…Accordingly, because SLE is associated with deficient clearance of AC material6–8 and ICs,9 clearance of MPs is likely to be impaired in SLE. Clearance of ACs is normally a non-inflammatory process; ACs are rapidly phagocytised following recognition via receptors for opsonins, phosphatidylserine or β2-glycoprotein I, exposed on the cell membrane 7…”

Section: Introductionmentioning

confidence: 99%

Surface complement C3 fragments and cellular binding of microparticles in patients with SLE

2017

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ObjectivesTo examine microparticles (MPs) from patients with SLE and healthy controls (HCs) by determining the cellular origin of the MPs, quantifying attached fragments of complement component 3 (C3) and assessing the ability of MPs to bind to circulating phagocytes and erythrocytes. These features may be relevant for clearance of MPs in SLE pathogenesis.MethodsAttached C3 fragments (C3b, iC3b, C3d), membrane integrity and cell surface markers of MPs from 18 patients with SLE and 11 HCs were measured by adding specific antibodies, 7-aminoactinomycin D (7AAD) and annexin V. MPs from all subjects were labelled with carboxyfluorescein diacetate succinimidyl ester and allowed to bind to autologous phagocytes and erythrocytes in the presence of autologous serum, and the binding to individual cell populations was assessed by flow cytometry.ResultsThe proportion of MPs bearing C3 fragments was higher in patients with SLE than in HCs (p=0.026), but the amount of opsonising C3b/iC3b molecules was lower (p=0.004). The C3b/iC3b level correlated with the concentration of circulating C3 (rs=0.53, p=0.036). Phagocytes and erythrocytes from patients and HCs bound autologous MPs, and granulocytes from patients bound 13% more MPs than those from HCs (p=0.043). The presence of erythrocytes inhibited the MP binding to granulocytes by approximately 50%.ConclusionsOur demonstration of altered composition of C3 fragments on MPs from patients with SLE, including decreased numbers of opsonising C3 fragments, and competitive binding of MPs to circulating phagocytes and erythrocytes corroborates the hypothesis of defective clearance of apoptotic material in SLE, and indicates that differences in both MP opsonisation and binding of MPs to cells are important in the pathogenesis of SLE.

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Untitled

Cited by 252 publications

References 168 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

Rare variants, autoimmune disease, and arthritis

Surface complement C3 fragments and cellular binding of microparticles in patients with SLE

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