Apoptotic cell clearance in systemic lupus erythematosus: I. Opsonization by antiphospholipid antibodies

Manfredi, Angelo A.; Rovere, Patrizia; Galati, Giacomo; Heltai, Silvia; Bozzolo, Enrica; Soldini, Laura; Davoust, Jean; Balestrieri, G.; Tincani, Anǵela; Sabbadini, Maria Grazia

doi:10.1002/1529-0131(199802)41:2<205::aid-art4>3.3.co;2-s

Cited by 65 publications

(79 citation statements)

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“…This systemic exposure could enable the binding of phospholipid-binding proteins such as ␤ 2 -glycoprotein I (␤ 2 GPI) to apoptotic cell membranes (37) and may also trigger the production of aPL antibodies (38,39). Phospholipid-␤ 2 GPI complexes on the surface of membrane blebs are recognized by aPL antibodies (37,38,40,41), which leads to opsonization of apoptotic cells that are then phagocytosed by FcR-positive macrophages (40,41). Considering that aPL (10,11), especially those with reactivity to ␤ 2 GPI (42,43), show IgG2-dominant distribution, such antibodies would be predicted to be poor opsonins in RR homozygous subjects.…”

Section: Discussionmentioning

confidence: 99%

Role of the Fcγ receptor IIA polymorphism in the antiphospholipid syndrome: An international meta‐analysis

Karassa¹,

Bijl²,

Davies³

et al. 2003

Arthritis & Rheumatism

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Objective. To assess the impact of the Fc␥RIIA-R/ H131 polymorphism on the risk for antiphospholipid syndrome (APS), both primary and secondary to systemic lupus erythematosus (SLE).Methods. This international meta-analysis combined data from 9 research teams. Fc␥RIIA-R/H131 genotypes were determined in 481 APS cases (206 with primary APS), 1,420 SLE controls, and 1,655 diseasefree controls. Data were combined using fixed-effects and random-effects models.Results. Compared with disease-free controls, the RR genotype was enriched in the entire group of APS cases (odds ratio [OR] 1.65, 95% confidence interval [95% CI] 1.28-2.14); this was driven mostly by patients with secondary APS (OR 1.95, 95% CI 1.45-2.63). The excess of RR homozygotes but not heterozygotes among APS patients suggested a recessive mode of inheritance, rather than the additive model seen for SLE susceptibility, where RR conferred greatest risk, and RH intermediate risk, for SLE. This probably reflected the additional influence of another opposing genetic effect of HH homozygosity on APS predisposition (OR 0.72 for RH versus HH, 95% CI 0.55-0.96). Among SLE patients, those with APS were more frequently HH homozygotes than heterozygotes (OR 0.56 for RH versus HH, 95% CI 0.39-0.81). HH homozygosity also tended to predominate in primary APS compared with secondary APS (OR 0.50 for RR versus HH, 95% CI 0.25-0.99 by fixed-effects model). There was no significant betweenstudy heterogeneity for any of these effects.Conclusion. The Fc␥RIIA-R/H131 polymorphism is an important determinant of predisposition to APS, with different influences on SLE and APS susceptibility per se.

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Section: Discussionmentioning

confidence: 99%

Role of the Fcγ receptor IIA polymorphism in the antiphospholipid syndrome: An international meta‐analysis

Karassa¹,

Bijl²,

Davies³

et al. 2003

Arthritis & Rheumatism

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“…34 In contrast to these inhibitory effects on uptake, polyclonal anti-phospholipid antibodies increased the uptake of apoptotic cells. 16 'Natural' IgM has also been shown to have an enhanced ability to bind to apoptotic cells, and to promote phagocytosis. 12 These observations differed from ours (as well as those of others 33,34 ); normal human IgM was included as a control in all our experiments, but was never found to bind to an extent equivalent to RN86.…”

Section: Reactivity Of the Immunizing Antibody (Rn86) Is Shown For Rementioning

confidence: 99%

“…21 Apoptotic cells induce immunosuppressive cytokine responses even in the presence of a proinflammatory signal such as LPS. 35 However, the presence of human polyclonal anti-phospholipid antibodies during phagocytosis can enhance the secretion of TNF-a by macrophages 16 and the binding of polyclonal human anti-Ro and anti-La antibodies to apoptotic fetal cardiocytes results in enhanced TNF-a secretion by cocultured macrophages. 36 When PR5 was employed as the opsonizing antibody, TNF-a secretion was significantly increased, even though no difference was observed in the number of phagocytosed cells over the control.…”

Section: Reactivity Of the Immunizing Antibody (Rn86) Is Shown For Rementioning

confidence: 99%

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Anti-idiotype-mediated epitope spreading and diminished phagocytosis by a human monoclonal antibody recognizing late-stage apoptotic cells

et al. 2006

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Apoptotic cells are considered an important auto-antigenic source in diseases such as systemic lupus erythematosus (SLE). A human monoclonal antibody demonstrating exquisite specificity towards late-stage apoptotic cells was generated from an SLE patient. Polyreactive recognition of ribonucleoproteins Ro52 and Ro60 was observed. The antibody significantly diminished the phagocytosis of apoptotic cells and a concomitant decrease in transforming growth factor-b (TGF-b) secretion was observed. Light and heavy chain sequencing revealed the antibody to be in essentially germline configuration. Elicited anti-idiotypic antibodies bound distinct self-antigens and showed augmented reactivity towards apoptotic cells as well. Thus, near-germline encoded antibodies recognizing antigens externalized during the process of apoptosis can mediate a variety of potentially pathogenic effects; decreases in the phagocytic uptake of dying cells would constitute a disease-perpetuating event and stimulation of the idiotypic network could lead to intermolecular epitope spreading, increasing the range of molecular targets.

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“…2 and 3). Among these are collectin receptors, calreticulin/CD91, Fc␥ receptors, c-Mer, the ␤ 2 -glycoprotein I receptor, integrins such as ␣v␤3, lectins, CD14, ABC transporters, scavenger receptors including thrombospondin (TSP) receptor CD36, and a putative, not-yet-identified phosphatidylserine (PS) receptor, which appears to be recognized and blocked by the monoclonal antibody (mAb) 217G8E9 (4)(5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages

Böttcher

Gaipl

Fürnrohr³

et al. 2006

Arthritis & Rheumatism

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Objective. Uningested dead cells may be an important source of autoantigens and may trigger autoimmune diseases such as systemic lupus erythematosus (SLE). Multiple receptors involved in the clearance of apoptotic cells have been described; however, little is known about the receptors and ligands involved in uptake of necrotic cells that release autoantigens as well.Methods. The uptake of autologous necrotic peripheral blood lymphocytes into human monocyte-derived macrophages was qualitatively and quantitatively monitored by confocal microscopy and 2-color flow cytometry, respectively. Blocking experiments were performed to examine the receptors and molecules involved in the phagocytosis of necrotic cells. Cytokine secretion by lipopolysaccharide-activated monocytes and macrophages was determined by enzyme-linked immunosorbent assay.

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Apoptotic cell clearance in systemic lupus erythematosus: I. Opsonization by antiphospholipid antibodies

Cited by 65 publications

References 0 publications

Role of the Fcγ receptor IIA polymorphism in the antiphospholipid syndrome: An international meta‐analysis

Role of the Fcγ receptor IIA polymorphism in the antiphospholipid syndrome: An international meta‐analysis

Anti-idiotype-mediated epitope spreading and diminished phagocytosis by a human monoclonal antibody recognizing late-stage apoptotic cells

Involvement of phosphatidylserine, αvβ3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages

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