Polymorphisms in the cytotoxic T lymphocyte-associated protein-4 immune regulatory gene and their impact on inhibitor development in patients with hemophilia A

Abdulqader, Aveen M. Raouf; Mohammed, Ali Ibrahim; Rachid, Shwan

doi:10.1177/0300060519860329

Cited by 8 publications

(4 citation statements)

References 39 publications

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“…We found that CTLA4-expression was inversely related to the presence of inhibitors and positively correlated with the induction of tolerance, underscoring earlier research in which polymorphisms in the CTLA4 gene were associated with the risk of inhibitor development. 54 – 57 Moreover, a hemophilic mouse model also showed a beneficial role of CTLA4 in ITI. 58 In this study, injection of CTLA4-immunoglobulin (CTLA4-Ig) prevented the primary (inhibitor) antibody response to FVIII.…”

Section: Discussionmentioning

confidence: 99%

Role of Regulatory Cells in Immune Tolerance Induction in Hemophilia A

et al. 2021

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The main complication of hemophilia A treatment is the development of neutralizing antibodies (inhibitors) against factor VIII (FVIII). Immune tolerance induction (ITI) is the prescribed treatment for inhibitor eradication, although its working mechanism remains unresolved. To clarify this mechanism, we compared blood samples of hemophilia A patients with and without inhibitors for presence of immunoregulatory cells and markers, including regulatory B-cells (Bregs), regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs), and expression of regulatory markers on T-cells (programmed cell death protein 1 [PD1], inducable T-cell costimulator, cytotoxic T-lymphocyte-associated protein 4 [CTLA4]), by use of flow cytometry. By cross-sectional analysis inhibitor patients (N = 20) were compared with inhibitor-negative (N = 28) and ex-inhibitor (N = 17) patients. In another longitudinal study, changes in immunoregulatory parameters were evaluated during ITI (N = 12) and compared with inhibitor-negative hemophilia A patients (N = 36). The frequency of Bregs, but not of Tregs nor MDSCs, was significantly reduced in inhibitor patients (3.2%) compared with inhibitor-negative (5.9%) and ex-inhibitor patients (8.9%; P < 0.01). CTLA4 expression on T-cells was also reduced (mean fluorescence intensity 133 in inhibitor versus 537 in inhibitor-negative patients; P < 0.01). Fittingly, in patients followed during ITI, inhibitor eradication associated with increased Bregs, increased Tregs, and increased expression of CTLA4 and PD1 on CD4+ T-cells. In conclusion, inhibitor patients express significantly lower frequency of Bregs and Tregs marker expression, which are restored by successful ITI. Our findings suggest that an existing anti-FVIII immune response is associated with deficits in peripheral tolerance mechanisms and that Bregs and changes in immunoregulatory properties of CD4+ T-cells likely contribute to ITI in hemophilia A patients with inhibitors.

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Section: Discussionmentioning

confidence: 99%

Role of Regulatory Cells in Immune Tolerance Induction in Hemophilia A

et al. 2021

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“…The CTLA-4 rs5742909 polymorphism ( C > T ) is in the promoter region of exon 1 of the CTLA-4 gene, affecting the ATG transcription initiation codon [ 54 ]. This SNP could alter the transcription factor binding site [ 22 , 55 , 56 , 57 ]. In addition, the CTLA-4 rs5742909-T allele has been linked to increased RNAm expression and higher levels of the CTLA-4 protein [ 53 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of Single-Nucleotide Polymorphisms of CTLA-4, CD80 and CD86 on the Effectiveness of Abatacept in Patients with Rheumatoid Arthritis

Pete

Montoro

Ramírez

et al. 2020

JPM

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Abatacept (ABA) is used as a first-line treatment in patients diagnosed with moderate and severe rheumatoid arthritis (RA). The interindividual response to ABA therapy is very variable in these patients. The objective of our study was therefore to investigate the role of polymorphisms of the CTLA-4, CD80 and CD86 genes, as well as that of clinical factors of the disease, in the response to ABA in patients with RA. A retrospective cohort study was carried out in 109 patients receiving treatment with ABA and diagnosed with RA. The genetic variables were analyzed using real-time PCR with TaqMan® probes. The patients were classified according to the European League Against Rheumatism (EULAR) criteria at 6 and 12 months from start of treatment. The independent variables associated with higher EULAR response were lower duration of previous biologic disease-modifying anti-rheumatic drugs and lower baseline values of the disease activity score 28 after 6 months of ABA treatment; and lower baseline patient’s visual analogue scale (PVAS) after 12 months. In addition, a significant association was found between duration of ABA treatment, non-administration of concomitant glucocorticoids and lower baseline values of the number of inflamed joints and erythrocyte sedimentation rate clinical variables, with remission of the disease after 6 months’ treatment with ABA. Finally, remission of the disease after 12 months’ treatment with ABA was associated with earlier age at start of ABA therapy and lower number of previous biologic therapies (BTs). The CTLA-4rs5742909-T allele and the CTLA-4rs231775-G allele were found to be associated with satisfactory EULAR response and low disease activity (LDA) after 12 months’ treatment with ABA (CTLA-4rs5742909 T vs. CC; OR = 5.88; CI95% = 1.48–23.29 and OR = 4.75; CI95% = 1.35–17.94, respectively, and CTLA-4rs231775 G vs. AA, OR = 3.48; CI95% = 1.20–10.09 and OR = 4.68; CI95% = 1.49–17.94, respectively). In conclusion, patients with RA treated with ABA showed better EULAR response and LDA rate when they had the CTLA-4 rs5742909-T or CTLA-4 rs231775-G polymorphisms; furthermore, this remission rate increased in patients that began ABA treatment earlier, those with a lower number of previous BTs and those with a lower PVAS value.

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“…In autoimmune diseases, polymorphisms in the immune response genes were reported to be related to the formation of antibody. In addition, SNPs in the regulatory regions of cytokine genes are crucial components in the pathogenesis of various diseases, including HA [21,22]. Individual immune response traits might in uence a patient's reaction to exogenous factor VIII.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in FCGR2A (131H/R) and FCGR2B (232I/T) are associated with the development of inhibitors in Chinese hemophilia A patients

Qi¹,

Chen²,

Zeng³

et al. 2020

Preprint

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Background: Present study was to explore the association between gene polymorphisms in Fc gamma receptor IIa (FCGR2A) and Iib (FCGR2B) and factor VIII (FVIII) inhibitor development in patients with hemophili A (HA) in a Chinese Han population.Methods: FCGR2A (131H/R) and FCGR2B (232I/T) polymorphsims were genotyped using PCR and direct sequencing method in 108 HA patients, including 23 cases with inhibitors and 85 without inhibitors. Chi-square (c2) test was applied to compare the genotype and allele frequencies between two groups. Odds ratio (OR) and 95% confidence interval (95%CI) were calculated to indicate the relative susceptibility of HA.Results: FCGR2A 131RH genotype frequency had a significantly increased trend in inhibitor group compared with the non-inhibitor group, suggesting a momentous role of 131H/R polymorphism for inhibitor development in HA patients. Individuals carrying 131RH genotype showed higher risk to be attacked by the inhibitor development in HA patients (OR=4.929; 95%CI=1.029-23.605). However, there were no significant differences of FCGR2B (232I/T) polymorphism genotype and allele frequencies between inhibitor and non-inhibitor groups.Conclusion: FCGR2A (131H/R) was in relation to the susceptibility of FVIII inhibitors development in HA patients.

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Polymorphisms in the cytotoxic T lymphocyte-associated protein-4 immune regulatory gene and their impact on inhibitor development in patients with hemophilia A

Cited by 8 publications

References 39 publications

Role of Regulatory Cells in Immune Tolerance Induction in Hemophilia A

Role of Regulatory Cells in Immune Tolerance Induction in Hemophilia A

Impact of Single-Nucleotide Polymorphisms of CTLA-4, CD80 and CD86 on the Effectiveness of Abatacept in Patients with Rheumatoid Arthritis

Polymorphisms in FCGR2A (131H/R) and FCGR2B (232I/T) are associated with the development of inhibitors in Chinese hemophilia A patients

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