IgG subclasses of anti‐FVIII antibodies during immune tolerance induction in patients with hemophilia A

Helden, P. M. W. Van; Berg, H. M. Van Den; Gouw, Samantha C.; Kaijen, Paul; Zuurveld, Marleen; Mauser‐Bunschoten, E. P.; Aalberse, Rob C.; Vidarsson, Gestur; Voorberg, Jan

doi:10.1111/j.1365-2141.2008.07232.x

Cited by 84 publications

(93 citation statements)

References 29 publications

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“…The results are shown in Table 1 for 25 subjects from CHU Sainte-Justine (subjects 1-25) and Table 2 for 7 subjects [26][27][28][29][30][31][32]. fVIII antigen concentration and activity were determined as previously reported.…”

Section: Results Fviii Antigen Concentration and Activity In Hemophilmentioning

confidence: 99%

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Quantitation of anti–factor VIII antibodies in human plasma

Krudysz-Amblo

Parhami-Seren

Butenas

et al. 2009

Blood

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The presence of antibodies (Abs) in hemophilia A patients can potentially influence the therapeutic qualities of factor VIII (fVIII) administration. Much work has been focused on the presence of inhibitory antibodies, whereas the quantitation of noninhibitory anti-fVIII antibodies has been largely undetermined. Our objective was to develop a sensitive and specific fluorescencebased immunoassay (FLI) for the quantitation of anti-fVIIIAbs in human plasma. Affinity-purified human anti-fVIIIAb, isolated from a hemophilia A subject, was used as a calibrator with a detectability limit of 40 (؎1.5) pM. The calibrator and the human plasma anti-fVIIIAb were captured on recombinant fVIII (rfVIII)-coupled microspheres and probed with mouse anti-human Ig-R-phycoerythrin. Plasma samples from 150 healthy donors and 39 inhibitor-negative hemophilia A subjects were compared with 4 inhibitor-positive hemophilia A plasma samples with inhibitor titers of 1 BU/mL (94.6 ؎ 0.8 nM), 11 BU/mL (214.3 ؎ 7.1 nM), 106 BU/mL (2209.4 ؎ 84.9 nM), 140 BU/mL (2417.7 ؎ 3.8 nM) as measured by the Nijmegen method. We also describe the validation of a mouse anti-human fVIIIAb as a surrogate calibrator. Four healthy individuals (3%) showed detectable antifVIIIAb in the range of 0.6 to 6.2 nM, whereas 13 (33%) of the 39 inhibitor-free hemophilia A subjects were positive for anti-fVIIIAb in the range of 0.5 to 20 nM. The method may be useful for therapeutic management of hemophilia A patients.

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Section: Results Fviii Antigen Concentration and Activity In Hemophilmentioning

confidence: 99%

“…Immunoassays have been used to detect anti-fVIII antibodies, but report only the presence of antibody relative to controls or quantitation based on recombinant constructs as calibrators. [27][28][29][30][31][32][33][34] An assay for the detection of such antibodies with a suitable calibrator for absolute quantitation has been unavailable.…”

Section: Introductionmentioning

confidence: 99%

Quantitation of anti–factor VIII antibodies in human plasma

Krudysz-Amblo

Parhami-Seren

Butenas

et al. 2009

Blood

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“…IgG 1 and IgG 4 also predominated in patients with inhibitors in acquired and in congenital hemophilia A [15], in blistering skin diseases [16], and in other autoimmune diseases [17]. Interestingly, and inexplicably, absolute levels of IgG 1 and IgG 4 were always inversely correlated.…”

Section: Discussionmentioning

confidence: 99%

IgG subclass distribution of anti‐ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura

Ferrari

Mudde²,

Rieger

et al. 2009

Journal of Thrombosis and Haemostasis

168

154

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Summary. Background: ADAMTS13‐neutralizing IgG autoantibodies are the major cause of acquired thrombotic thrombocytopenic purpura (TTP). Objective: To analyze the IgG subclass distribution of anti‐ADAMTS13 antibodies and a potential relationship between subclass distribution and disease prognosis. Methodology: An enzyme‐linked immunosorbent assay‐based method was used to quantify the relative amounts of IgG subclasses of anti‐ADAMTS13 antibodies in acquired TTP plasma. Results: IgG4 (52/58, 90%) was the most prevalent IgG subclass in patients with acquired TTP, followed by IgG1 (52%), IgG2 (50%), and IgG3 (33%). IgG4 was found either alone (17/52) or with other IgG subclasses (35/52). IgG4 was not detected in 10% of the patients. There was an inverse correlation between the frequency and abundance of IgG4 and IgG1 antibodies (P < 0.01). Patients with high IgG4 levels and undetectable IgG1 are more prone to relapse than patients with low IgG4 levels and detectable IgG1. Conclusions: All IgG subclasses of anti‐ADAMTS13 antibodies were detected in patients with acquired TTP, with IgG4, followed by IgG1, antibodies dominating the anti‐ADAMTS13 immune response. Levels of IgG4 could be useful for the identification of patients at risk of disease recurrence.

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“…Monoclonal antibodies against different FVIII domains CLB-CAg12, CLB-CAg117 and CLB-EL14 have been described previously. [16][17][18][19] Monoclonal antibody CLB-RAg20 against VWF has been described previously.…”

Section: Methodsmentioning

confidence: 99%

von Willebrand factor binds to the surface of dendritic cells and modulates peptide presentation of factor VIII

et al. 2015

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It has been proposed that von Willebrand factor might affect factor VIII immunogenicity by reducing factor VIII uptake by antigen presenting cells. Here we investigate the interaction of recombinant von Willebrand factor with immature monocyte-derived dendritic cells using flow cytometry and confocal microscopy. Surprisingly, von Willebrand factor was not internalized by immature dendritic cells, but remained bound to the cell surface. As von Willebrand factor reduces the uptake of factor VIII, we investigated the repertoire of factor VIII presented peptides when in complex with von Willebrand factor. Interestingly, factor VIII-derived peptides were still abundantly presented on major histocompatibility complex class II molecules, even though a reduction of factor VIII uptake by immature dendritic cells was observed. Inspection of peptide profiles from 5 different donors showed that different core factor VIII peptide sequences were presented upon incubation with factor VIII/von Willebrand factor complex when compared to factor VIII alone. No von Willebrand factor peptides were detected when immature dendritic cells were pulsed with different concentrations of von Willebrand factor, confirming lack of von Willebrand factor endocytosis. Several von Willebrand factor derived peptides were recovered when cells were pulsed with von Willebrand factor/factor VIII complex, suggesting that factor VIII promotes endocytosis of small amounts of von Willebrand factor by immature dendritic cells. Taken together, our results establish that von Willebrand factor is poorly internalized by immature dendritic cells. We also show that von Willebrand factor modulates the internalization and presentation of factor VIII-derived peptides on major histocompatibility complex class II.

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IgG subclasses of anti‐FVIII antibodies during immune tolerance induction in patients with hemophilia A

Cited by 84 publications

References 29 publications

Quantitation of anti–factor VIII antibodies in human plasma

Quantitation of anti–factor VIII antibodies in human plasma

IgG subclass distribution of anti‐ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura

von Willebrand factor binds to the surface of dendritic cells and modulates peptide presentation of factor VIII

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