Factor VIII-specific B cell responses in haemophilia A patients with inhibitors

Abstract

Development of inhibitory antibodies to factor VIII (FVIII) provides a major complication of replacement therapy in patients with haemophilia A. The risk of inhibitor formation is influenced by the underlying FVIII gene defect. Moreover, genetic determinants in the promoter region of IL-10 and TNFalpha have been linked to an increased risk of inhibitor development. Recent cohort-studies have provided evidence that the risk of inhibitor formation is linked to intensity of treatment. Eradication of FVIII inhibitors can be achieved by frequent infusion of high dosages of FVIII, so-called immune tolerance induction (ITI). Until now, the mechanisms involved in downmodulation of the immune response to FVIII during ITI have not been unraveled. Studies performed in an animal model for haemophilia A have suggested that elimination of FVIII-specific memory B cells by high dosages of FVIII contributes to the decline in FVIII inhibitor levels during ITI. Limited knowledge is available with respect to the development and persistence of FVIII-specific memory B cells in patients with haemophilia A. Two recent studies suggest that the frequency of peripheral FVIII-specific memory B cells in haemophilia A patients with inhibitors range from <0.01 to 0.40% of that of total IgG(+) B cells. No or very low frequencies of FVIII-specific memory B cells are observed in haemophilia A patients without inhibitors and in patients treated successfully by ITI. Possible implications of these findings are discussed in the context of currently available information on the role of antigen-specific memory B cells and long-living antibody producing plasma cells in humoral immunity.