Together, these data suggest that MZ B-cell depletion likely prevents an initial antibody response following FVIII exposure, but our data do not rule out a role of MZ B cells in immunological tolerance

Together, these data suggest that MZ B-cell depletion likely prevents an initial antibody response following FVIII exposure, but our data do not rule out a role of MZ B cells in immunological tolerance. Open in a separate window Figure 4. Rechallenge with FVIII after MZ B-cell repopulation results in primary immune response. demonstrating that MZ B-cell depletion did not result in FVIII tolerance. Although recipient exposure to the ABT-239 viral-like adjuvant polyinosinic:polycytidylic acid enhanced anti-FVIII antibody formation, MZ B-cell depletion Rabbit polyclonal to ACMSD continued to display similar effectiveness in preventing inhibitor ABT-239 formation following FVIII infusion in this inflammatory setting. These data strongly suggest that MZ B cells play a critical role in initiating FVIII inhibitor formation and suggest a potential strategy to prevent anti-FVIII alloantibody formation in patients with hemophilia A. Visual Abstract Open in a separate window Introduction Hemophilia A is an X-linked bleeding disorder characterized by a deficiency or absence of the blood coagulation protein, factor VIII (FVIII). Patients with hemophilia A depend on FVIII replacement by IV ABT-239 infusion for acute bleeding episodes or prevention of bleeding.1 The most significant complication of factor replacement therapy is the development of neutralizing immunoglobulin G (IgG) alloantibodies to FVIII.2-5 These alloantibodies, known as inhibitors, block the activity of FVIII, decreasing or even ABT-239 eliminating the effectiveness of factor replacement.2,6 As a result, FVIII inhibitors, which occur in 20% to 40% of patients with severe hemophilia A and 5% of patients with mild/moderate hemophilia A, render FVIII infusions ineffective. This, in turn, makes bleeding difficult to control and prevent, resulting in increased morbidity and mortality, increased cost of care, and decreased quality of life.7,8 The principal strategy currently available for inhibitor eradication is immune tolerance induction, which entails frequent and prolonged exposure to the FVIII protein in an effort to induce peripheral tolerance. Although successful in 60% to 70% of cases, this treatment continues to suffer from the significant time and considerable expense required for implementation,8-10 making strategies to avoid inhibitor formation altogether paramount to effective patient care. However, despite the significant clinical implications of inhibitor development, there are currently no prophylactic agents available for inhibitor prevention. Previous studies suggest that a combination of genetic and environmental factors likely influence inhibitor development.11,12 However, the immune mechanisms underlying inhibitor formation are incompletely understood. CD4 T cells, in particular T follicular helper cells, work in concert with follicular B cells to drive germinal center reactions within B-cell follicles, which in turn generates B cells that produce high-affinity antibodies and B-cell memory.13,14 As a result, several studies have defined key aspects of the T- and B-cell response to FVIII, including dominant CD4 T-cell and B-cell FVIII epitopes.15-19 However, before a germinal center reaction can occur, antigenic substrate must be available. Recent studies suggest that ABT-239 the transport of antigen to the B-cell follicle is itself a highly regulated process that allows the immune system to discriminate antigenic material from self.20-23 In particular, within the blood compartment, cells within the marginal sinus of the spleen, which resides at the interface of the red and white pulp, appear to be uniquely poised to survey blood for this very purpose.24,25 Although a variety of cells facilitate this process, marginal zone (MZ) B cells represent an innate-like B-cell population and are the only cells in the MZ known to possess antigen-specific receptors by virtue of the unique recombination events that generate their B-cell receptors.20-23 As a result, although a variety of cells may engage FVIII within the MZ, MZ B cells may possess the unique capacity to specifically recognize and then respond to FVIII. MZ B cells not only possess the ability to immediately generate antibody in response to antigenic challenge and then traffic that antigen to the B-cell follicle,21,26,27.