Hemophilia A Inhibitor Subjects Show Unique PBMC Gene Expression Profiles That Include Up-Regulated Innate Immune Modulators

@article{Karim2020HemophiliaAI,
  title={Hemophilia A Inhibitor Subjects Show Unique PBMC Gene Expression Profiles That Include Up-Regulated Innate Immune Modulators},
  author={Ahmad Faisal Karim and Anthony R. Soltis and Gauthaman Sukumar and Christoph K{\"o}nigs and Nadia P. Ewing and Clifton L. Dalgard and Matthew D. Wilkerson and Kathleen P. Pratt},
  journal={Frontiers in Immunology},
  year={2020},
  volume={11}
}
Formation of pathological anti-FVIII antibodies, or “inhibitors,” is the most serious complication of therapeutic FVIII infusions, affecting up to 1/3 of severe Hemophilia A (HA) patients. Inhibitor formation is a classical T-cell dependent adaptive immune response. As such, it requires help from the innate immune system. However, the roles of innate immune cells and mechanisms of inhibitor development vs. immune tolerance, achieved with or without Immune Tolerance Induction (ITI) therapy, are… Expand
1 Citations
The Possible Non-Mutational Causes of FVIII Deficiency: Non-Coding RNAs and Acquired Hemophilia A
TLDR
Acquired HA is increasingly reported and as more cases are identified, the description of the disease might become challenging, as cases without FVIII autoantibodies might be identified. Expand

References

SHOWING 1-10 OF 72 REFERENCES
CD4+ T cell response to factor VIII in hemophilia A, acquired hemophilia, and healthy subjects.
TLDR
Detailed characterization and comparison of the CD4+ repertoire in healthy subjects with that of hemophilia patients with and without inhibitors will help clarify which mechanism explains the absence of productive inhibitor synthesis in certain individuals. Expand
Review of immune tolerance induction in hemophilia A.
TLDR
Hemophilia A will be used as an example to discuss current concepts of tolerance induction as they are applied in patient care and extrapolate tolerance findings in hemophilia B to related pathways known to affect auto-immune disorders or allergy. Expand
T‐cell responses over time in a mild hemophilia A inhibitor subject: epitope identification and transient immunogenicity of the corresponding self‐peptide
TLDR
An HLA‐DRA‐DRB1*0101 restricted T‐cell epitope containing the wild‐type A2201 sequence was identified, suggesting the possible involvement of CD4+CD25+ regulatory T cells in modulating immune responses. Expand
Tolerating Factor VIII: Recent Progress
TLDR
Recent exciting studies that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development are described, highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority. Expand
Modulation of factor VIII‐specific memory B cells
TLDR
Modulators that either amplify or inhibit the re‐stimulation of FVIII‐specific murine memory B cells are defined that are investigating whether the same modulators operate in patients with haemophilia A and FV III inhibitors. Expand
Recognition of coagulation factor VIII by CD4+ T cells of healthy humans
TLDR
A CD4+ T cell response to FVIII, which first involves Th1 cells, is common among subjects with a normal procoagulant function, and anti‐FVIII antibodies may occur also in healthy subjects. Expand
Immune tolerance induction: What have we learned over time?
TLDR
Clinicians believe that available clinical guidelines and consensus recommendations for ITI therapy are not always in complete agreement, but collectively the guidelines provide a reasonable level of guidance for administering ITI Therapy under different clinical scenarios. Expand
Mechanism of the immune response to human factor VIII in murine hemophilia A.
TLDR
Hemophilic mice develop an immune response to hfVIII administered intravenously similar to that of hemophilia A patients; their anti-hfV III antibodies can be inhibitors and belong to IgG subclasses homologous to those of inhibitors in hemophilic patients, and both Th1 and Th2 cytokines, and especially IL-10, may drive the antibody synthesis. Expand
Recombinant factor VIII Fc fusion protein drives regulatory macrophage polarization.
TLDR
It is shown that rFVIIIFc, but not rFVIII, uniquely skews macrophages toward an alternatively activated regulatory phenotype and initiates signaling events that result in morphological changes, as well as a specific gene expression and metabolic profile that is characteristic of the regulatory type Mox/M2-like macrophage. Expand
Induction of activated T follicular helper cells is critical for anti-FVIII inhibitor development in hemophilia A mice.
TLDR
It is demonstrated that the induction of activated TFH cells in FVIIInull mice is critical for FVIII inhibitor development, suggesting that inhibition of FV III-specific TFH-cell activation may be a promising strategy for preventing anti-FVIII inhibitors formation in patients with hemophilia A. Expand
...
1
2
3
4
5
...