Human antibodies with specificity for the C2 domain of factor VIII are derived from VH1 germline genes

Brink, Edward N. van den; Turenhout, Ellen A.M.; Davies, Julian; Bovenschen, Niels; Fijnvandraat, Karin; Ouwehand, Willem H.; Peters, Marjolein; Voorberg, Jan

doi:10.1182/blood.v95.2.558

Cited by 51 publications

(41 citation statements)

References 28 publications

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“…This study conducted a longitudinal analysis of the subclass distribution of anti-FVIII antibodies in a cohort of severe haemophilia A patients during ITI. The previously described FVIII-specific single chain variable fragment (scFv) EL-14 was converted into full length human IgG of different subclass (Van den Brink et al, 2000). FVIII-specific human monoclonal EL-14 IgG1, IgG2, IgG3 and IgG4 were subsequently used as an internal standard to determine the relative contribution of the different IgG subclasses to the total amount of anti-FVIII IgG in patient samples.…”

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confidence: 99%

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

et al. 2008

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SummaryThe eradication of inhibitory antibodies in patients with haemophilia A can be accomplished by frequent administration of high or intermediate doses of factor VIII (FVIII), so-called immune tolerance induction (ITI). This study monitored the distribution of IgG subclasses of anti-FVIII antibodies during ITI. FVIII-specific antibodies of subclass IgG1 were detected in all inhibitor patients tested, anti-FVIII IgG4 in 16, IgG2 in 10 and IgG3 in one of 20 patients analysed. Levels of anti-FVIII IgG1 and IgG4 correlated well with inhibitor titres as measured by Bethesda assay. In low-titre inhibitor patients, anti-FVIII antibodies consisted primarily of subclass IgG1 whereas, anti-FVIII antibodies of subclass IgG4 were more prominent in patients with high titre inhibitors who needed prolonged treatment or who failed ITI. Longitudinal analysis of 14 patients undergoing ITI revealed that the relative contribution of IgG subclasses was constant for most of the patients analysed. In two patients, the relative contribution of IgG4 increased during ITI. Overall, our findings document the distribution and dynamics of anti-FVIII IgG subclasses during ITI. Future studies will need to address whether monitoring the relative contribution of anti-FVIII subclasses IgG1 and IgG4 may be useful for the identification of patients who are at risk of failing ITI.

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

et al. 2008

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“…In approximately 25% of patients with severe hemophilia A, inhibitory antibodies against FVIII develop that prohibit treatment with FVIII [2]. These so-called FVIII inhibitors are primarily composed of IgG1 and IgG4 isotypes and have undergone affinity maturation through somatic hypermutation [3][4][5][6]. Both somatic hypermutation and class switching are processes that are dependent on CD4 + T cells.…”

Section: Introductionmentioning

confidence: 99%

Enhanced uptake of blood coagulation factor VIII containing immune complexes by antigen presenting cells

Hartholt

Wroblewska

Herczenik

et al. 2017

Journal of Thrombosis and Haemostasis

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Background A major complication in the treatment of hemophilia A is the development of inhibitory antibodies targeting coagulation factor VIII (FVIII). Eradication of these inhibitors can be established by immune tolerance induction (ITI), which consists of daily administration of high dosages of FVIII. FVIII immune complexes (FVIII-IC) could be formed following FVIII infusion in patients with pre-existing anti-FVIII antibodies. Objectives Here we studied endocytosis of FVIII-IC by bone marrow-derived dendritic cells (BMDCs). Methods BMDCs were pulsed with FVIII/FVIII-IC and uptake was assessed by flow cytometry and confocal imaging. Results BMDCs were able to efficiently internalize FVIII-IC in a dose-dependent manner, 3-4-fold more efficiently when compared with equimolar concentrations of non-complexed FVIII. Uptake of FVIII-IC, but not FVIII alone, could be inhibited with anti-Fcγ receptor (FcγR) antibody 2.4G2, indicating functional involvement of FcγR. No internalization of FVIII-IC was observed in BMDCs lacking FcγRI, FcγRIIb, FcγRIII and FcγRIV. Genetic ablation of FcγRIIb, FcγRIII or FcγRIV individually did not affect the ability of anti-FVIII IgG to promote the uptake of FVIII. BMDCs lacking FcγRI showed lower FVIII-IC uptake levels when compared with other single FcγR null BMDCs. Expression of the inhibitory FcγRIIb alone was sufficient to internalize FVIII-IC more efficiently than FVIII. Conclusions FcγR are critical in the internalization of FVIII-IC by BMDCs and multiple FcγR can contribute independently to this process. Our findings provide a basis for future studies to address whether the outcome of ITI is dependent on the interplay between FVIII-IC and inhibitory and activating FcγR.

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“…FVIII inhibitor development appears to depend on antigen-specific T-cell help. Evidence for this includes somatic hypermutations in the genes coding for the variable part of anti-FVIII antibodies [19], a large proportion of anti-FVIII antibodies belonging to the IgG 1 and IgG 4 subclasses, indicating isotype switching [20], and the presence of FVIII-specific memory B cells [21]. Direct evidence of the involvement of helper T cells in FVIII inhibitor responses came from a study of severe haemophilia A inhibitor subjects infected with human immunodeficiency virus type 1.…”

Section: Introductionmentioning

confidence: 99%

HLA‐DR‐restricted T‐cell responses to factor VIII epitopes in a mild haemophilia A family with missense substitution A2201P

Ettinger

James²,

Kwok

et al. 2010

Haemophilia

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Summary. An HLA-DRA-DRB1*0101-restricted Tcell epitope in the factor VIII (FVIII) C2 domain occurred in a mild haemophilia A patient with missense substitution FVIII-A2201P. His T cells responded to synthetic peptides FVIII 2186 -2205 and FVIII 2194 -2213 (J Thromb Haemost 2007; 5: 2399). T cells from family members with genotype FVIII-A2201P were analysed to determine if FVIII-specific T cells occur in individuals with a haemophilic mutation but no clinically significant inhibitor response. Fluorescent MHC class II tetramers corresponding to subjectsÕ HLA-DRB1 types were loaded with 20-mer peptides and utilized to label antigen-specific CD4+ T cells. T-cell responses to peptides spanning the FVIII-C2 sequence were evaluated. T cells recognizing specific peptides were cloned, and antigen specificity was verified by proliferation assays. Plasma and/or purified IgG samples were tested for FVIII inhibitory activity. CD4+ T cells and T-cell clones from two brothers who shared the DRB1*0101 allele responded to FVIII [2194][2195][2196][2197][2198][2199][2200][2201][2202][2203][2204][2205][2206][2207][2208][2209][2210][2211][2212][2213] . A haemophilic cousinÕs HLA-DRA-DRB1*1104-restricted response to FVIII [2202][2203][2204][2205][2206][2207][2208][2209][2210][2211][2212][2213][2214][2215][2216][2217][2218][2219][2220][2221] was detected only when CD4+CD25+ cells were depleted. A great uncle and two obligate carriers had no detectable FVIII-C2-specific T cells. Concentrated IgG from the brother without a clinical inhibitor response showed a low-titre FVIII inhibitor. FVIII-specific T cells and inhibitory IgG were found in a previously infused, haemophilic subject who had a sub-clinical FVIII inhibitor. CD4+CD25+ depleted T cells from a non-infused haemophilic cousin recognized an overlapping FVIII epitope, indicating a latent HLA-DRA-DRB1*1104-restricted T-cell response to FVIII. Specific T-cell responses to FVIII can occur without clinically significant inhibitors.

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Human antibodies with specificity for the C2 domain of factor VIII are derived from VH1 germline genes

Cited by 51 publications

References 28 publications

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

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

Enhanced uptake of blood coagulation factor VIII containing immune complexes by antigen presenting cells

HLA‐DR‐restricted T‐cell responses to factor VIII epitopes in a mild haemophilia A family with missense substitution A2201P

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