Risk factors initiating tolerance breakdown towards coagulation factor VIII during immune tolerance induction therapy
Risk factors initiating tolerance breakdown towards coagulation factor VIII during immune tolerance induction therapy
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01.07.2028Art der Hochschulschrift
DissertationPrüfungsdatum
03.06.2026Datum der Veröffentlichung
18.06.2026Erstgutachter
Kurts, ChristianZweitgutachter
McVey, JohnMetadaten
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Inhalt
Hemophilia A (HA) is a hereditary bleeding disorder caused by a deficiency in coagulation factor VIII (FVIII). Despite FVIII replacement therapy, a significant proportion of patients develop neutralizing FVIII-specific antibodies (inhibitors), rendering the treatment ineffective. To address this, a high-dose regimen known as immune tolerance induction (ITI) has been developed, aiming to re-establish peripheral FVIII tolerance and eradicate these inhibitors. In a recent study, our group identified FVIII-specific regulatory T cells (Tregs) as key players in ITI success. Here, we investigate how immunological challenges, specifically Staphylococcus aureus (USA300 LAC) infection, can impact the stability of peripherally induced tolerance.
Using in vivo and in vitro models, we demonstrate that Staphylococcus aureus infection disrupts ITI by reactivating FVIII-specific B cells through direct stimulation of TLR2 and subsequent activation of the mTOR/STAT3 pathways, which are downregulated in tolerized B cells when compared to prophylactically activated cells. Infection induced a spike in FVIII-specific inhibitor production by directly stimulating B cells and by promoting the differentiation of Tregs and naïve T cells into follicular helper T cells, thereby enhancing the humoral response. Although FVIII-specific Tregs expand in vivo during infection, they acquire pro-inflammatory features, including increased proliferation and expression of transcription factors such as T-bet. Functional suppression assays in vitro reveal that these bacteria-exposed Tregs are dysfunctional, exhibiting reduced suppressive capacity and phenotypic instability driven by TLR2 signaling.
Importantly, PD-1 stimulation mitigates infection-induced B cell activation by inhibiting the mTOR pathway and the STAT3 pathway, possibly through PTEN activation, identifying PD-1 signaling as an attractive candidate for therapy to prevent S. aureus-mediated tolerance modulation. This may apply to other bacterial infections potently activating the mTOR/STAT3 pathway.
Collectively, the data elucidates mechanisms by which bacterial infections destabilize immune tolerance and identify candidate biomarkers and therapeutic targets to predict and prevent ITI failure.
Using in vivo and in vitro models, we demonstrate that Staphylococcus aureus infection disrupts ITI by reactivating FVIII-specific B cells through direct stimulation of TLR2 and subsequent activation of the mTOR/STAT3 pathways, which are downregulated in tolerized B cells when compared to prophylactically activated cells. Infection induced a spike in FVIII-specific inhibitor production by directly stimulating B cells and by promoting the differentiation of Tregs and naïve T cells into follicular helper T cells, thereby enhancing the humoral response. Although FVIII-specific Tregs expand in vivo during infection, they acquire pro-inflammatory features, including increased proliferation and expression of transcription factors such as T-bet. Functional suppression assays in vitro reveal that these bacteria-exposed Tregs are dysfunctional, exhibiting reduced suppressive capacity and phenotypic instability driven by TLR2 signaling.
Importantly, PD-1 stimulation mitigates infection-induced B cell activation by inhibiting the mTOR pathway and the STAT3 pathway, possibly through PTEN activation, identifying PD-1 signaling as an attractive candidate for therapy to prevent S. aureus-mediated tolerance modulation. This may apply to other bacterial infections potently activating the mTOR/STAT3 pathway.
Collectively, the data elucidates mechanisms by which bacterial infections destabilize immune tolerance and identify candidate biomarkers and therapeutic targets to predict and prevent ITI failure.
Schlagwörter
Immunology, Hemophilia A, Tolerance, B cells, Tregs, Infection, Humoral immunity, Cell Signalling, Metabolism
Klassifikation (DDC)
570 Biowissenschaften, BiologieAbdelmageed, Amina: Risk factors initiating tolerance breakdown towards coagulation factor VIII during immune tolerance induction therapy. - Bonn, 2026. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-90664
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-90664
@phdthesis{handle:20.500.11811/14217,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-90664,
doi: https://doi.org/10.48565/bonndoc-888,
author = {{Amina Abdelmageed}},
title = {Risk factors initiating tolerance breakdown towards coagulation factor VIII during immune tolerance induction therapy},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2026,
month = jun,
note = {Hemophilia A (HA) is a hereditary bleeding disorder caused by a deficiency in coagulation factor VIII (FVIII). Despite FVIII replacement therapy, a significant proportion of patients develop neutralizing FVIII-specific antibodies (inhibitors), rendering the treatment ineffective. To address this, a high-dose regimen known as immune tolerance induction (ITI) has been developed, aiming to re-establish peripheral FVIII tolerance and eradicate these inhibitors. In a recent study, our group identified FVIII-specific regulatory T cells (Tregs) as key players in ITI success. Here, we investigate how immunological challenges, specifically Staphylococcus aureus (USA300 LAC) infection, can impact the stability of peripherally induced tolerance.
Using in vivo and in vitro models, we demonstrate that Staphylococcus aureus infection disrupts ITI by reactivating FVIII-specific B cells through direct stimulation of TLR2 and subsequent activation of the mTOR/STAT3 pathways, which are downregulated in tolerized B cells when compared to prophylactically activated cells. Infection induced a spike in FVIII-specific inhibitor production by directly stimulating B cells and by promoting the differentiation of Tregs and naïve T cells into follicular helper T cells, thereby enhancing the humoral response. Although FVIII-specific Tregs expand in vivo during infection, they acquire pro-inflammatory features, including increased proliferation and expression of transcription factors such as T-bet. Functional suppression assays in vitro reveal that these bacteria-exposed Tregs are dysfunctional, exhibiting reduced suppressive capacity and phenotypic instability driven by TLR2 signaling.
Importantly, PD-1 stimulation mitigates infection-induced B cell activation by inhibiting the mTOR pathway and the STAT3 pathway, possibly through PTEN activation, identifying PD-1 signaling as an attractive candidate for therapy to prevent S. aureus-mediated tolerance modulation. This may apply to other bacterial infections potently activating the mTOR/STAT3 pathway.
Collectively, the data elucidates mechanisms by which bacterial infections destabilize immune tolerance and identify candidate biomarkers and therapeutic targets to predict and prevent ITI failure.},
url = {https://hdl.handle.net/20.500.11811/14217}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-90664,
doi: https://doi.org/10.48565/bonndoc-888,
author = {{Amina Abdelmageed}},
title = {Risk factors initiating tolerance breakdown towards coagulation factor VIII during immune tolerance induction therapy},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2026,
month = jun,
note = {Hemophilia A (HA) is a hereditary bleeding disorder caused by a deficiency in coagulation factor VIII (FVIII). Despite FVIII replacement therapy, a significant proportion of patients develop neutralizing FVIII-specific antibodies (inhibitors), rendering the treatment ineffective. To address this, a high-dose regimen known as immune tolerance induction (ITI) has been developed, aiming to re-establish peripheral FVIII tolerance and eradicate these inhibitors. In a recent study, our group identified FVIII-specific regulatory T cells (Tregs) as key players in ITI success. Here, we investigate how immunological challenges, specifically Staphylococcus aureus (USA300 LAC) infection, can impact the stability of peripherally induced tolerance.
Using in vivo and in vitro models, we demonstrate that Staphylococcus aureus infection disrupts ITI by reactivating FVIII-specific B cells through direct stimulation of TLR2 and subsequent activation of the mTOR/STAT3 pathways, which are downregulated in tolerized B cells when compared to prophylactically activated cells. Infection induced a spike in FVIII-specific inhibitor production by directly stimulating B cells and by promoting the differentiation of Tregs and naïve T cells into follicular helper T cells, thereby enhancing the humoral response. Although FVIII-specific Tregs expand in vivo during infection, they acquire pro-inflammatory features, including increased proliferation and expression of transcription factors such as T-bet. Functional suppression assays in vitro reveal that these bacteria-exposed Tregs are dysfunctional, exhibiting reduced suppressive capacity and phenotypic instability driven by TLR2 signaling.
Importantly, PD-1 stimulation mitigates infection-induced B cell activation by inhibiting the mTOR pathway and the STAT3 pathway, possibly through PTEN activation, identifying PD-1 signaling as an attractive candidate for therapy to prevent S. aureus-mediated tolerance modulation. This may apply to other bacterial infections potently activating the mTOR/STAT3 pathway.
Collectively, the data elucidates mechanisms by which bacterial infections destabilize immune tolerance and identify candidate biomarkers and therapeutic targets to predict and prevent ITI failure.},
url = {https://hdl.handle.net/20.500.11811/14217}
}
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