Role of B Cells in Breaking and Maintaining Tolerance to Clotting Factor VIII in Congenital and Acquired Hemophilia A

Abstract

Immune responses directed against clotting factor FVIII (FVIII) seriously complicate treatments for patients with hemophilia A. This response can manifest in congenital hemophilia A patients who generate inhibitor antibodies that bind and inactivate -transplanted‖ replacement FVIII, as well as in acquired hemophiliacs, whose immune systems have lost tolerance to self-FVIII. Regardless of the mechanism by which production of anti-FVIII inhibitor antibody is triggered, the maintenance of this deleterious response in both congenital and acquired hemophiliacs likely relies upon FVIII specific memory B cells. In this review, the similarities and differences in the kinetics, specificities, and subclasses of antibodies produced in response to allo-and auto-FVIII is outlined. A brief description of the immune cell interactions that contribute to maintenance of antibody response, focusing on development of memory B cells and/or long lived plasma cells is also presented. As current treatments for inhibitor antibodies are not successful in all patients, a better understanding of the functions and persistence of memory B cells specific for FVIII is required. Herein, both clinical and experimental data regarding the effects of immune tolerance induction on memory B cell subpopulations is discussed. Finally, the outcomes of B cell-specific depletion via rituximab in hemophilia and other autoimmune diseases are discussed to highlight insights into the subpopulations of memory B cells that contribute to the development and maintenance of successful tolerance to FVIII.

Regulatory B Cells Are Functionally Impaired in Patients Having Hemophilia A With Inhibitors

“…Several clinical and experimental studies have shown that B cells are key in maintaining and breaking tolerance to FVIII. 13 In fact, the production of neutralizing Abs relies on the development FVIII specific memory B cells or long-lived plasma cells, on one hand, while generation of several distinct regulatory cells may prevent inhibitor formation on the other hand, as evidenced in animal models using anti-CD3 monoclonal antibody therapy. 14 In this study, we explored whether these newly identified Breg cells might play a role, with other cells, in the development of neutralizing Abs in patients with hemophilia A. Interestingly, our findings showed that levels of circulating Breg cells were significantly reduced in hemophilia A patients with inhibitors compared to patients without inhibitors or healthy controls.…”