F(ab)′2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins

Bašta, Milan; Goor, Fredric Van; Luccioli, Stefano; Billings, Eric M.; Vortmeyer, Alexander O.; Baranyi, Lajos; Szebeni, János; Alving, Carl R.; Carroll, Michael; Berkower, Ira; Stojilković, Stanko S.; Metcalfe, Dean D.

doi:10.1038/nm836

Cited by 217 publications

(137 citation statements)

References 34 publications

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“…47 Potentially, susceptible MG patients would be screened for the polymorphism and as soon as treatment-resistant ophthalmoparesis ensues, appropriate additional anticomplement therapy may be initiated. Intravenous immunoglobulin also reduces complement factors C3a and C5a, 48 and, although expensive, would be a reasonable intervention to attempt early on in susceptible individuals in an effort to reduce the significant morbidity associated with ophthalmoplegic complications.…”

Section: Discussionmentioning

confidence: 99%

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

et al. 2009

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Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198C4G SNP (odds ratio ¼ 8.6; P ¼ 0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5 0 -flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198C4G SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression.

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Section: Discussionmentioning

confidence: 99%

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

et al. 2009

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“…Previous work suggests different mechanisms in the therapeutic action of i.v. Ig (IVIG) in animal models of immune thrombocytopenic purpura and asthma (42,43). In the immune thrombocytopenic purpura study, it is reported that administration of IVIG protects against disease in a Fc␥RIIB-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Macrophages Induce the Inflammatory Response in the Pulmonary Arthus Reaction through Gαi2 Activation That Controls C5aR and Fc Receptor Cooperation

Skokowa¹,

Ali²,

Felda

et al. 2005

The Journal of Immunology

111

116

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Complement and FcγR effector pathways are central triggers of immune inflammation; however, the exact mechanisms for their cooperation with effector cells and their nature remain elusive. In this study we show that in the lung Arthus reaction, the initial contact between immune complexes and alveolar macrophages (AM) results in plasma complement-independent C5a production that causes decreased levels of inhibitory FcγRIIB, increased levels of activating FcγRIII, and highly induced FcγR-mediated TNF-α and CXCR2 ligand production. Blockade of C5aR completely reversed such changes. Strikingly, studies of pertussis toxin inhibition show the essential role of Gi-type G protein signaling in C5aR-mediated control of the regulatory FcγR system in vitro, and analysis of the various C5aR-, FcγR-, and Gi-deficient mice verifies the importance of Gαi2-associated C5aR and the FcγRIII-FcγRIIB receptor pair in lung inflammation in vivo. Moreover, adoptive transfer experiments of C5aR- and FcγRIII-positive cells into C5aR- and FcγRIII-deficient mice establish AM as responsible effector cells. AM lacking either C5aR or FcγRIII do not possess any such inducibility of immune complex disease, whereas reconstitution with FcγRIIB-negative AM results in an enhanced pathology. These data suggest that AM function as a cellular link of C5a production and C5aR activation that uses a Gαi2-dependent signal for modulating the two opposing FcγR, FcγRIIB and FcγRIII, in the initiation of the inflammatory cascade in the lung Arthus reaction.

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“…However, a study involving 23 sensitized patients demonstrated that the predominant mechanism of IVIG is inhibition of complement activation but not anti-idiotypic activity (11). IVIG has been reported to bind C3b and C4b, to decrease their deposition on the cell membrane, and to neutralize C3a and C5a, thereby preventing the generation of the C5b-C9 membrane-attack complex (12). IVIG-derived Ig aggregates, monomers, and dimers compete for activating Fc␥Rs, thereby blocking immune activation and enhancing the clearance of anti-HLA antibodies.…”

Section: Intravenous Igmentioning

confidence: 99%

Desensitization Protocols and Their Outcome

Marfo

Ling

et al. 2011

Clinical Journal of the American Society of Nephrology

233

184

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SummaryIn the last decade, transplantation across previously incompatible barriers has increasingly become popular because of organ donor shortage, availability of better methods of detecting and characterizing anti-HLA antibodies, ease of diagnosis, better understanding of antibody-mediated rejection, and the availability of effective regimens. This review summarizes all manuscripts published since the first publication in 2000 on desensitized patients and discusses clinical outcomes including acute and chronic antibody-mediated rejection rate, the new agents available, kidney paired exchange programs, and the future directions in sensitized patients. There were 21 studies published between 2000 and 2010, involving 725 patients with donor-specific anti-HLA antibodies (DSAs) who underwent kidney transplantation with different desensitization protocols. All studies were single center and retrospective. The patient and graft survival were 95% and 86%, respectively, at a 2-year median follow-up. Despite acceptable short-term patient and graft survivals, acute rejection rate was 36% and acute antibody-mediated rejection rate was 28%, which is significantly higher than in nonsensitized patients. Recent studies with longer follow-up of those patients raised concerns about long-term success of desensitization protocols. The studies utilizing protocol biopsies in desensitized patients also reported higher subclinical and chronic antibody-mediated rejection. An association between the strength of DSAs determined by median fluorescence intensity values of Luminex single-antigen beads and risk of rejection was observed. Two new agents, bortezomib, a proteasome inhibitor, and eculizumab, an anti-complement C5 antibody, were recently introduced to desensitization protocols. An alternative intervention is kidney paired exchange, which should be considered first for sensitized patients.

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F(ab)′2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins

Cited by 217 publications

References 34 publications

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

Macrophages Induce the Inflammatory Response in the Pulmonary Arthus Reaction through Gαi2 Activation That Controls C5aR and Fc Receptor Cooperation

Desensitization Protocols and Their Outcome

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