CD4+ T-cell clones specific for wild-type factor VIII: a molecular mechanism responsible for a higher incidence of inhibitor formation in mild/moderate hemophilia A

Jacquemin, Marc; Vantomme, Valérie; Buhot, Cécile; Lavend’homme, Renaud; Burny, Wivine; Demotte, Nathalie; Chaux, Pascal; Peerlinck, Kathelijne; Vermylen, Jos; Maillère, Bernard; Bruggen, Pierre van der; Saint-Remy, Jean-Marie

doi:10.1182/blood-2002-05-1369

Cited by 106 publications

(127 citation statements)

References 40 publications

(36 reference statements)

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…Our hypothesis of inhibitor formation through alloimmunisation implies a switch from an initially alloreactive immune response towards a response that is both alloreactive and autoreactive. Current notion of inhibitor formation in CRM-positive haemophilia A is that allogeneic FVIII-derived peptides presented on MHC class II trigger a specific, alloreactive CD4 T cell response [13]. Subsequently, armed CD4 T helper cells can stimulate reactive B cells to produce alloreactive antibodies.…”

Section: Discussionmentioning

confidence: 99%

Acquired haemophilia caused by non-haemophilic factor VIII gene variants

Tiede¹,

Eisert²,

Czwalinna³

et al. 2010

Ann Hematol

View full text Add to dashboard Cite

The aetiology of anti-factor VIII (FVIII) autoantibody formation in acquired haemophilia remains unknown. We hypothesised that encounter of antigenically different, allogeneic FVIII may challenge inhibitor formation after presentation on MHC class II. Eighteen consecutive cases with acquired haemophilia were enrolled (9 females, 9 males). A control group comprised 50 male and 50 female healthy blood donors. The coding region of the FVIII gene and the HLA-DRB1 genotype were studied. The presentation of foreign FVIII variants on the patient's MHC class II alleles was predicted using SYFPEITHI algorithm. A rare FVIII variant (E2004K) was found in 1 patient with acquired haemophilia after massive transfusion; the 2004K allele was predicted to be presented on the patient's HLA-DRB1*0101. Moreover, distribution of a polymorphism (D1241E) was significantly skewed comparing patients and controls. 3 of 3 patients with transfusion-associated disease carried 1241D in homozygous or hemizygous form and were predicted to present 1241E (foreign), but not 1241D (self), on their HLA-DRB1*0301. Therefore, encounter of 1241E may result in the presentation of a new T cell epitope in these patients. The same conditions were not found in any patient with acquired haemophilia of other causes. The expected frequency in the general Caucasoid population undergoing transfusion is 3 to 4 %. In conclusion, encounter of variant allogeneic FVIII presented on a suitable MHC background could be a risk factor for inhibitor formation.Response to Reviewers: Dear Professor Eichinger, Thank you for considering our manuscript for publication in Annals of Hematology. We would also like to thank the reviewer for valuable comments. We have addressed the comments as follows: *Only 3 cases of transfusion-associated acquired hemophilia: Indeed, acquired hemophilia associated with transfusion has rarely been reported. In our series, 3 cases among 18 consecutive patients are even more than expected from the literature. Our study suggest that immune recognition of certain FVIII variants could play a role in the pathogenesis, but formal proof would require much higher numbers of transfusion-associated cases that, in all probability, will never be collected. *Transfusion in the other cases: No, transfusion was not documented in any other case of our series. Medical histories were taken by the authors or other well-trained physicians of the department.We are sure that an association with transfusion would not have been missed in these patients. We have acknowledged this fact in the Methods section (p. 4, first para). *Frequency of 1241E in blood donations: Based on the known allelic distribution of the 1241E allele and the known sex distribution of blood donors, we determined the frequency of 1241E in singledonor blood products as 21 % (p. 4, last para). *Transfused units and interval between transfusion and acquired hemophilia: all transfusionassociated cases received multiple transfusions. Time between first transfusion and acquired hemophilia ranged...

show abstract

Section: Discussionmentioning

confidence: 99%

Acquired haemophilia caused by non-haemophilic factor VIII gene variants

Tiede¹,

Eisert²,

Czwalinna³

et al. 2010

Ann Hematol

View full text Add to dashboard Cite

show abstract

“…[6][7][8]40,41 The relative incidence of inhibitors in mild HA patients varies with mutation, with several recurrent mutations such as R593C and R2150H having a stronger association with inhibitor development. 6,[42][43][44][45] The present study did not identify T-cell epitopes corresponding to the most common F8 polymorphisms in the African American population, D1241E and M2238V, whereas control experiments carried out using aliquots of the same blood samples routinely produced distinct tetramer-positive populations from which tetanus-specific T-cell clones and polyclonal lines could be expanded.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5] Several studies have demonstrated that mild HA inhibitor subjects showed HLA-restricted T-cell responses to epitopes that included the wild-type FVIII sequence at the hemophilic missense site. [6][7][8] Thus, even slight sequence variations in therapeutic FVIII could contribute to inhibitor risk.…”

Section: Introductionmentioning

confidence: 99%

Factor VIII gene variants and inhibitor risk in African American hemophilia A patients

Gunasekera

Ettinger

Fletcher

et al. 2015

Blood

View full text Add to dashboard Cite

• Immune responses to FVIII sequence variants encoded by ns-SNPs do not contribute appreciably to inhibitor development in African Americans.• African American HA subjects with an intron-22 inversion had a 2-to 3-times-higher inhibitor incidence than whites with the same mutation.African American hemophilia A (HA) patients experience a higher incidence of neutralizing anti-factor VIII (FVIII) antibodies ("inhibitors") vis-à-vis white patients. Nonsynonymous single-nucleotide polymorphisms (ns-SNPs) in the F8 gene encoding FVIII-H484, FVIII-E1241, and FVIII-V2238 are more prevalent in African Americans. This study tested the hypothesis that immune responses to these sites provoke inhibitors. Blood samples were obtained from 174 African American and 198 white HA subjects and their F8 gene sequences determined. Major histocompatibility complex class II binding and T-cell recognition of polymorphic sequences were evaluated using quantitative binding assays and HLA-DRB1 tetramers. Peptides corresponding to 4 common ns-SNPs showed limited binding to 11 HLA-DRB1 proteins. CD4 T cells from 22 subjects treated with FVIII products having sequences at residues FVIII-484, 1241, and 2238 differing from those of putative proteins encoded by their F8 genes did not show high-avidity tetramer binding, whereas positive-control staining of tetanus-specific CD4 T cells was routinely successful. African Americans with an intron-22 inversion mutation showed a 2-3 times-higher inhibitor incidence than whites with the same mutation (odds ratio 5 2.3 [1.1-5.0, P 5 .04]), but this did not correlate with any of the ns-SNPs. We conclude that immune responses to "sequence-mismatched" FVIII products are unlikely to contribute appreciably to the inhibitor incidence in African Americans. (Blood. 2015;126(7):895-904)

show abstract

“…Les lymphocytes T CD4 exercent un rôle majeur dans l'apparition des anticorps, car ils fournissent l'aide nécessaire au développe-ment des lymphocytes B en plasmocytes sécréteurs d'anticorps (fonction helper) (Figure 1). Les réponses immunes contre les protéines thérapeutiques sont dépendantes des lymphocytes T CD4 comme l'attestent des observations faites principalement chez les patients hémophiles : les anticorps inhibiteurs sont des IgG et contiennent des mutations somatiques (reflétant la génération d'IgG de haute affinité), deux caractéris-tiques qui dépendent des lymphocytes T CD4 [10]. Chez des patients hémophiles avec un taux établi d'anticorps anti-facteur VIII (FVIII), l'infection par le VIH (virus de l'immunodéficience humaine), par la diminution du nombre heureusement limité de patients [6,34].…”

unclassified

“…taux de lymphocytes T CD4 qu'elle entraîne, peut provoquer la disparition des anticorps spécifiques [11]. Des lymphocytes T CD4 spéci-fiques du FVIII ont été identifiés chez certains de ces patients porteurs d'anticorps inhibiteurs [10]. Chez l'animal, l'absence d'activation des lymphocytes T CD4 est suffisante pour empêcher le déclenchement d'une réponse immunitaire, par exemple contre l'interféron bêta [12].…”

unclassified