Identification of a F.VIII epitope recognized by a human hemophilic inhibitor

Lubahn, BC; Ware, Jerry; Stafford, DW; Reisner, H

doi:10.1182/blood.v73.2.497.497

Cited by 34 publications

(14 citation statements)

References 17 publications

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“…There was no data to differentiate the exact fraction of their findings that recognized a3 from those that recognized A3-C1. Human antibodies directed to the a1 region are rare, occurring only at an incidence of 1´8±7% (Fulcher et al, 1987;Lubahn et al, 1989;Scandella et al, 1989;Prescott et al, 1997). We found 14´3% (4 out of 28) for a1, which is the highest number reported; however, explanations for this high incidence are not clear.…”

Section: Discussionmentioning

confidence: 59%

“…Immunological screening using a phage library for mapping human anti-FVIII antibodies has been demonstrated in only a few instances (Lubahn et al, 1989;Kuwabara et al, 1999). The previously identified a1 epitope (Lubahn et al, 1989) and the C domain epitope (Kuwabara et al, 1999) were deduced from the smallest region shared by all the positive clones. Our results of phage library screening with TWN-112 would have confined the epitope to Q334-V357 if the same concept from the above two laboratories had been used.…”

Section: Discussionmentioning

confidence: 99%

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Epitope mapping of factor VIII inhibitor antibodies of Chinese origin

et al. 2001

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Summary. Epitopes recognized by factor VIII (FVIII) inhibitors of Chinese origin were analysed by immunoblotting with full-length recombinant FVIII (rFVIII), thrombinactivated FVIII (FVIIIa) and 16 FVIII fusion proteins synthesized by bacteria. Twenty-eight patients, 12 with haemophilia A and 16 with autoimmune diseases, were recruited. Antibodies from 22 patients showed reactivity with rFVIII, 20 with FVIIIa, and one reacted only with FVIII fusion proteins. Of these 22 cases, most were reactive with A2-a2 and A3-C1-C2 of FVIII(a). Of the nine cases that depicted binding to the fusion proteins, three were reactive with the A domains, three with only the B domain, and the other three with both the A and B (or C) domains. An epitope for a neutralizing antibody of a haemophilia A patient, designated TWN-112, was localized to residues 323±390, specified by FVIII fusion proteins. The same epitope also appeared on an FVIII-expression phage library screening. Immunoabsorption of antibodies from with the epitope reduced the neutralizing activity of the inhibitor by 33%. The incidence of a1 of FVIII is higher, and that of a3 is lower, than previously reported. Two novel epitopes, reported for the first time in this paper, were localized on the 8B2 (amino acid residues 1022±1204) and 8A2(V) (residues 673±740) fusion proteins. These two epitopes were able to reduce inhibitory antibody activity by 24% and 25% respectively. Changes of FVIII fragment specificity were also observed in one of six patients for whom multiple samples, collected at different times, were available. Our initial finding showed that the FVIII inhibitors in these Chinese patients shared epitopes with those of patients from very different genetic backgrounds, suggesting a common mechanism for the development of FVIII inhibitors.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Epitope mapping of factor VIII inhibitor antibodies of Chinese origin

et al. 2001

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“…Thus, factor VIII inhibitors that bind to the heavy chain of factor VIII prevent the cleavage of factor VIII by thrombin and its subsequent activation. [38][39][40][41] Light chain-specific inhibitors prevent the interaction of factor VIII with activated IX 42 or phospholipids, or von Willebrand factor (vWF), or a combination of these. [43][44][45][46] Factor VIII inhibitors may also bind to epitopes formed by the association of factor VIII and vWF, thus reducing the dissociation rate of factor VIII from vWF.…”

Section: Mechanisms Of Action Of Factor VIII Inhibitorsmentioning

confidence: 99%

Natural Antibodies to Factor VIII

Lacroix‐Desmazes

Moreau²,

Pashov³

et al. 2000

Semin Thromb Hemost

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Anti-factor VIII antibodies represent a unique model to study the relationship between natural autoreactivity (natural antibodies to factor VIII of healthy individuals), disease-associated autoimmunity ("spontaneous" factor VIII inhibitors of patients with anti-factor VIII autoimmune disease) and antigen-driven immune responses (immune inhibitors in multitransfused patients with hemophilia A) to a single human protein antigen. Although natural and disease-associated anti-factor VIII antibodies are not readily distinguished based on the comparison of their isotypic distribution and epitope mapping, available studies of cross-reacting idiotypes suggest that factor VIII inhibitors in patient's plasma encompass two populations of anti-factor VIII antibodies. Some antibodies result from the clonal expansion of B lymphocytes that exist before treatment with factor VIII and secrete anti-factor VIII antibodies with properties similar to those of natural anti-factor VIII antibodies present in healthy individuals; other inhibitors are produced by B cell clones that have undergone affinity maturation and hypermutation of the V regions of the antibodies they produce. The implications for the treatment of patients with anti-factor VIII inhibitors are discussed.

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“…These antibodies are detected by functional assays (Bethesda and Oxford assays) that measure their ability to bind epitopes involved in coagulant activity (Kasper et al, 1975). In fact, the fine specificity of antibodies has been clustered on discrete regions of the 44 kD, 55 kD and 72 kD thrombin fragments (Scandella et al, 1988(Scandella et al, , 1989Lubahan et al, 1989;Foster et al, 1990;Ware et al, 1992).…”

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confidence: 99%

High incidence of anti‐FVIII antibodies against non‐coagulant epitopes in haemophilia A patients: a possible role for the half‐life of transfused FVIII

Dazzi¹,

Tison²,

Vianello³

et al. 1996

Br J Haematol

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The occurrence of antibodies (Abs) capable of inhibiting factor VIII (FVIII) coagulant activity is a severe complication in haemophilia A, leading to the inhibition of transfused FVIII activity. It is not known whether, or to what extent, post-transfusion antibodies may also arise against non-coagulant epitopes. Therefore we set up a system capable, in theory, to detect all the FVIII-induced antibodies by use of an enzyme-linked immunoassorbent assay (ELISA) based on coating human recombinant FVIII onto polystyrene microtitre plates. Serum samples from 23 patients affected by haemophilia A of different gravity (22 referred to our Centre and one to the Bari Centre) were analysed. Although only one patient was positive at Bethesda assay, the presence of antibodies in ELISA was detected in 39% of patients in variable degrees; transfusion with FVIII was found to induce a raise in antibody titre, arguing in favour of the specificity of the phenomenon. The clinical relevance of these non-inhibitory antibodies was evaluated in three patients; although half-life did not show any change in the patients without or with low amount of antibodies, FVIII clearance was found enhanced in the patient displaying high titre antibodies. We propose detection of anti-FVIII antibodies by ELISA when routinely assessing haemophilia A patients.

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Identification of a F.VIII epitope recognized by a human hemophilic inhibitor

Cited by 34 publications

References 17 publications

Epitope mapping of factor VIII inhibitor antibodies of Chinese origin

Epitope mapping of factor VIII inhibitor antibodies of Chinese origin

Natural Antibodies to Factor VIII

High incidence of anti‐FVIII antibodies against non‐coagulant epitopes in haemophilia A patients: a possible role for the half‐life of transfused FVIII

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