Importance of immune response genes in hemophilia A

Abstract

Hemophilia A is a disease caused by a deficiency of coagulation factor VIII resulting from genetic inheritance linked to chromosome X. One treatment option is the administration of plasma or recombinant FVIII. However, some patients develop inhibitors or antibodies against this factor. Inhibitors are alloantibodies that bind to the epitope of factor VIII causing it to be recognized by the immune system as a foreign peptide. This is the most serious complication in hemophilia patients in respect to replacement therapy. Some studies have suggested that genetic factors influence the development of factor VIII inhibitors such as ethnicity, family history, mutations in the factor VIII gene and in genes of the immune system. The aim of this study was to conduct a literature review to assess the influence of genetic factors of immune response genes, especially genes of the major histocompatibility complex and cytokines, which may be related to the development of factor VIII inhibitors in hemophilia A patients. Understanding these risk factors will help to determine future differential treatment in the control and prevention of the development of inhibitors.

B cell–activating factor modulates the factor VIII immune response in hemophilia A

“…Our pediatric HA patient data indicate that BAFF levels correlate most strongly with the FVIII inhibitor and the neutralizing IgG4 titers but also with anti-FVIII IgG1 whereas other T-helper cytokines tested here did not. Prior studies have shown correlation of polymorphisms in regulatory elements of certain cytokines with inhibitors but few have assessed cytokine levels; the results from either method are inconsistent between populations of distinct geographic origins (78)(79)(80)(81)(82). As genetic polymorphisms that predispose patients to elevated BAFF levels have been characterized in people of Sardinian and continental Italian descent compared to northern Europeans (46), we measured BAFF levels from an Italian adult HA cohort.…”

New associations: INFG and TGFB1 genes and the inhibitor development in severe haemophilia A

“…Recently, we reported that the variants HLA*C16 and HLA‐DRB1*14 are associated with the risk of inhibitors . Polymorphisms in cytokine genes have contributed to determinate the inhibitor risks in HA patients, mainly IL10 and TNF gene polymorphisms . Thus, the objective of this study was to investigate a possible association of polymorphisms in regulatory regions of cytokine genes and the risk of inhibitor development of FVIII in patients with severe haemophilia A.…”

Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene

“…In addition to bleeding phenotype, we demonstrated that injection of FVIII into F8 TKO animals showed no significant difference in the amount of anti‐FVIII IgG antibodies compared with E16‐B6/S129 mice. However, it is known that strain background affects immunogenicity of FVIII in mouse models , just as differences in immune regulatory genes are known to affect the immune response to FVIII in humans .…”