Background: Development of antibodies against infused Factor VIII (FVIII) or "inhibitors" represents a major challenge following FVIII replacement therapy in patients with hemophilia A (HA). Recent studies have shown that certain cellular compartments of the immune system contribute to the production of such antibodies. Herein, we determined the frequency of class-switched ­CD19+IgD−CD27+ on-class-switched ­CD19+IgD+CD27+ memory B cell subsets and ­CD19 + CD27hiCD38hi plasmablasts in patients with severe HA and their association with the development of inhibitors in these patients. Methods: This cross-sectional case–control study enrolled 32 patients with severe HA, including 8 with and 24 without inhibitors, and 24 healthy individuals. The frequencies of the memory B cell subsets and plasmablasts were determined using flow cytometry. Results: The frequency of ­­CD19+IgD+CD27+ non-class-switched memory B cells was significantly lower in patients with HA (including both patients with and without inhibitors) than in healthy controls. The percentages of both ­CD19+IgD−CD27+ class-switched and ­­CD19+IgD+CD27+ non-class-switched memory B cells did not differ significantly between patients with and without inhibitors. HA patients with inhibitors had significantly higher proportions of ­CD19+CD27hiCD38hi plasmablasts than the control group as well as the inhibitor (-) ones. No significant correlation was observed between the inhibitor levels with the percentages of memory B cell subsets and plasmablasts. Conclusion This study is the first to demonstrate a dysregulated proportion of ­CD19+IgD+CD27+ non-class-switched memory B cells and ­CD19+CD27hiCD38hi plasmablasts in patients with severe HA. Therefore, strategies targeting memory B-cell/plasmablast differentiation may have promising outcomes in the management of inhibitor formation in patients with severe HA.

Background: Development of antibodies against infused Factor VIII (FVIII) or "inhibitors" represents a major challenge following FVIII replacement therapy in patients with hemophilia A (HA). Recent studies have shown that certain cellular compartments of the immune system contribute to the production of such antibodies. Herein, we determined the frequency of class-switched ­CD19+IgD−CD27+ on-class-switched ­CD19+IgD+CD27+ memory B cell subsets and ­CD19 + CD27hiCD38hi plasmablasts in patients with severe HA and their association with the development of inhibitors in these patients. Methods: This cross-sectional case–control study enrolled 32 patients with severe HA, including 8 with and 24 without inhibitors, and 24 healthy individuals. The frequencies of the memory B cell subsets and plasmablasts were determined using flow cytometry. Results: The frequency of ­­CD19+IgD+CD27+ non-class-switched memory B cells was significantly lower in patients with HA (including both patients with and without inhibitors) than in healthy controls. The percentages of both ­CD19+IgD−CD27+ class-switched and ­­CD19+IgD+CD27+ non-class-switched memory B cells did not differ significantly between patients with and without inhibitors. HA patients with inhibitors had significantly higher proportions of ­CD19+CD27hiCD38hi plasmablasts than the control group as well as the inhibitor (-) ones. No significant correlation was observed between the inhibitor levels with the percentages of memory B cell subsets and plasmablasts. Conclusion This study is the first to demonstrate a dysregulated proportion of ­CD19+IgD+CD27+ non-class-switched memory B cells and ­CD19+CD27hiCD38hi plasmablasts in patients with severe HA. Therefore, strategies targeting memory B-cell/plasmablast differentiation may have promising outcomes in the management of inhibitor formation in patients with severe HA.

Background: Development of antibodies against infused Factor VIII (FVIII) or "inhibitors" represents a major challenge following FVIII replacement therapy in patients with hemophilia A (HA). Recent studies have shown that certain cellular compartments of the immune system contribute to the production of such antibodies. Herein, we determined the frequency of class-switched ­CD19+IgD−CD27+ on-class-switched ­CD19+IgD+CD27+ memory B cell subsets and ­CD19 + CD27hiCD38hi plasmablasts in patients with severe HA and their association with the development of inhibitors in these patients. Methods: This cross-sectional case–control study enrolled 32 patients with severe HA, including 8 with and 24 without inhibitors, and 24 healthy individuals. The frequencies of the memory B cell subsets and plasmablasts were determined using flow cytometry. Results: The frequency of ­­CD19+IgD+CD27+ non-class-switched memory B cells was significantly lower in patients with HA (including both patients with and without inhibitors) than in healthy controls. The percentages of both ­CD19+IgD−CD27+ class-switched and ­­CD19+IgD+CD27+ non-class-switched memory B cells did not differ significantly between patients with and without inhibitors. HA patients with inhibitors had significantly higher proportions of ­CD19+CD27hiCD38hi plasmablasts than the control group as well as the inhibitor (-) ones. No significant correlation was observed between the inhibitor levels with the percentages of memory B cell subsets and plasmablasts. Conclusion This study is the first to demonstrate a dysregulated proportion of ­CD19+IgD+CD27+ non-class-switched memory B cells and ­CD19+CD27hiCD38hi plasmablasts in patients with severe HA. Therefore, strategies targeting memory B-cell/plasmablast differentiation may have promising outcomes in the management of inhibitor formation in patients with severe HA.