Severe haemophilia A patients have reduced numbers of peripheral memory B cells

Irigoyen, M. B.; Felippo, Marta; Primiani, L.; Candela, M.; Bianco, R.; Bracco, M; Galassi, N.

doi:10.1111/j.1365-2516.2011.02642.x

Cited by 4 publications

(6 citation statements)

References 25 publications

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“…Limited data are available regarding the role of memory B cell subsets in the development of inhibitors in patients with HA [ 17 ], and no information is currently available regarding the proportion of plasmablasts in these patients.…”

Section: Introductionmentioning

confidence: 99%

Abnormal frequency of the memory B cell subsets and plasmablasts in patients with congenital severe hemophilia A: correlation with “Inhibitor” formation

Zekavat,

Movahednezhad,

Shahsavani

et al. 2024

Blood Res.

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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+/non-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.

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Section: Introductionmentioning

confidence: 99%

Abnormal frequency of the memory B cell subsets and plasmablasts in patients with congenital severe hemophilia A: correlation with “Inhibitor” formation

Zekavat,

Movahednezhad,

Shahsavani

et al. 2024

Blood Res.

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“…However, to date, all potentially important immunological mechanisms of tolerance have been studied in animals (Matsui et al , ; Su et al , , ; Waters & Lillicrap, ; Gaitonde et al , ; Kallas et al , ; Reipert et al , ; Sule et al , ); advances in mouse, dog and non‐human primate models have recently been reviewed and/or reported (Reipert et al , ; van Helden et al , ; Qadura et al , ). Several such observations have been or are being corroborated through the in vitro study of haemophilic inhibitor plasma (Waters & Lillicrap, ; Ettinger et al , ; Reipert et al , ; van Helden et al , ; Gilles, ; Sakurai et al , ; Pautard et al , ; Irigoyen et al , ). In fact, there have been few in vivo corroborative studies.…”

Section: Haemophilia A: Immune Tolerance For Fviii Inhibitorsmentioning

confidence: 87%

“…Considerable progress in our understanding of the immunology of FVIII antibody development and eradication may eventually enable a safe and more uniformly successful approach to treatment (Waters & Lillicrap, ). The mechanisms of central and peripheral tolerance; the antigen‐presenting roles of dendritic (+/− cytokine co‐stimulation) and memory B cells in primary and secondary anti‐FVIII immune responses, respectively; the immune regulatory effect of CD4+, CD8+, CD4+/CD25+ T regulatory cells, specific T‐B cell co‐stimulatory interactions and apoptotic fibroblasts on these responses; as well as the respective roles of memory B and plasma cells and anti‐idiotype antibodies in ongoing anti‐FVIII antibody production are all now better understood (Waters & Lillicrap, ; Ettinger et al , ; Matsui et al , ; Kallas et al , ; Su et al , ; Reipert et al , ; van Helden et al , ; Gilles, ; Sule et al , ; Su et al , ; Sakurai et al , ; Pautard et al , ; Irigoyen et al , ).…”

Section: Haemophilia A: Immune Tolerance For Fviii Inhibitorsmentioning

confidence: 99%

Immune tolerance in haemophilia: the long journey to the fork in the road

DiMichele

2012

Br J Haematol

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SummaryAntibody eradication is the ultimate goal of inhibitor management. The only clinically proven strategy for achieving antigen-specific tolerance to factor VIII is immune tolerance induction (ITI). Our knowledge about ITI in haemophilia A and B was, historically, derived from small cohort studies and retrospective national and international ITI registries. Practice is now further influenced by prospective cohort data, and the results of a single prospective randomized international ITI trial. However, due to the low incidence of inhibitors in haemophilia B, there are few comparable data from which to develop a useful evidence-based approach to the prevention and eradication of factor IX inhibitors. The lack of an effective strategy is particularly problematic given the morbidity associated with the unique occurrence of allergic and anaphylactic reactions that often herald factor IX antibody development and preclude effective eradication. This paper will discuss our current understanding of immune tolerance outcome and outcome predictors for haemophilia A and B; review the current consensus practice recommendations for ITI; and summarize the emerging body of immunological science relating to antibody formation and tolerance. It will conclude by suggesting how our knowledge might inform the future investigative priorities impacting the therapeutic and preventative tolerance strategies of tomorrow.

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“…Finally, some evidence suggests that tolerance induction restores a -normal‖ balance of memory B cells. A recent report determined that the total population of CD19+CD27+ peripheral memory B cells was reduced in HA patients with inhibitors compared to healthy controls [60]. Importantly, restoration of this population correlated with successful response to ITI [60], perhaps reflecting the re-establishment of -normal‖ memory B cells.…”

Section: Effect Of Tolerance Induction On Memory B Cellsmentioning

confidence: 99%

“…A recent report determined that the total population of CD19+CD27+ peripheral memory B cells was reduced in HA patients with inhibitors compared to healthy controls [60]. Importantly, restoration of this population correlated with successful response to ITI [60], perhaps reflecting the re-establishment of -normal‖ memory B cells. Interestingly, non-class switched IgD+ B cells were prevalent among the remaining memory B cells in patients with inhibitors.…”

Section: Effect Of Tolerance Induction On Memory B Cellsmentioning

confidence: 99%

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

2014

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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.

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Severe haemophilia A patients have reduced numbers of peripheral memory B cells

Cited by 4 publications

References 25 publications

Abnormal frequency of the memory B cell subsets and plasmablasts in patients with congenital severe hemophilia A: correlation with “Inhibitor” formation

Abnormal frequency of the memory B cell subsets and plasmablasts in patients with congenital severe hemophilia A: correlation with “Inhibitor” formation

Immune tolerance in haemophilia: the long journey to the fork in the road

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

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