T cell–independent restimulation of FVIII-specific murine memory B cells is facilitated by dendritic cells together with toll-like receptor 7 agonist

Pordes, Aniko Ginta; Baumgartner, Christina K.; Allacher, Peter; Ahmad, Rafi; Weiller, Markus; Schiviz, Alexandra; Schwarz, Hans; Reipert, Birgit M.

doi:10.1182/blood-2011-02-336198

Cited by 15 publications

(11 citation statements)

References 39 publications

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“…12 Whether a T cell-independent immune response toward FVIII is evoked into producing FVIII-specific antibodies is not completely clear, but this could potentially be of relevance for the formation of nonneutralizing antibodies and/or low-affinity antibodies. 13 The neutralizing antibodies are mainly of the immunoglobulin (Ig) G1 and IgG4 subtypes and the epitopes recognized are located on both the light and heavy chains of FVIII with a preference for the A2 and C2 domains, 14 although several epitopes of both neutralizing and nonneutralizing types located outside these, some in the B domain, have also been described. 15,16 The main mechanism by which the antibodies neutralize the factor is by steric hindrance, but the formation of immune complexes and subsequent enhanced catabolism as well as hydrolysis have also been suggested.…”

Section: Immune Response To Fviiimentioning

confidence: 99%

FVIII inhibitors: pathogenesis and avoidance

Astermark

2015

Blood

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The pathogenesis of inhibitory antibodies has been the focus of major scientific interest over the last decades, and several studies on underlying immune mechanisms and risk factors for formation of these antibodies have been performed with the aim of improving the ability to both predict and prevent their appearance. It seems clear that the decisive factors for the immune response to the deficient factor are multiple and involve components of both a constitutional and therapy-related nature. A scientific concern and obstacle for research in the area of hemophilia is the relatively small cohorts available for studies and the resulting risk of confounded and biased results. Careful interpretation of data is recommended to avoid treatment decisions based on a weak scientific platform. This review will summarize current concepts of the underlying immunological mechanisms and risk factors for development of inhibitory antibodies in patients with hemophilia A and discuss how these findings may be interpreted and influence our clinical management of patients. (Blood. 2015;125(13):2045-2051 IntroductionUnderstanding of the pathophysiological mechanisms leading to the development of inhibitory anti-factor (F)VIII antibodies in patients with hemophilia A has improved considerably over the last 2 decades. It is clear that the process is multifactorial and involves cells, cytokines, and other immune regulatory molecules, the level and action of which are both genetically and nongenetically defined. Despite improvements in understanding, we remain unable to fully predict the immune response to the deficient factor and inhibitor risk at the onset of replacement therapy. There are several ongoing efforts aiming to achieve more accurate methods for prediction and others to develop nonimmunogenic hemostatic options, but these remain opportunities for the future. Findings continue to emerge regarding risk factors and potential immune mechanisms of significance for the outcome, but until new results have been sufficiently confirmed through replication and the mechanisms of action in humans better defined, the chances of withholding a beneficial treatment or administering one associated with an adverse outcome are increased. Efficacy and safety should be the guiding principles for all treaters in the environment of cost constraints in which they act. This review will summarize current data-based findings and interpretations of how and why inhibitory antibodies develop in patients with hemophilia A and explore how the findings may or may not influence our daily practice. Immune response to FVIIIThe initiation of an immune response and formation of high-affinity polyclonal antibodies toward FVIII requires endocytosis of the infused molecule by antigen presenting cells (APCs), eg, dendritic cells, macrophages, and/or B cells, processing intracellularly in the endosomes, and presentation of antigen-derived peptides via the HLA class II molecules on the cell surface to the CD4 1 T cells. In previously untreated patients, ie, patients...

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Section: Immune Response To Fviiimentioning

confidence: 99%

FVIII inhibitors: pathogenesis and avoidance

Astermark

2015

Blood

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“…Possibly the timing and T cell dependence of acute PB responses depends on the nature of the antigen and the engagement of pattern recognition receptors. In in vitro systems, TLR7 and 9 ligands are able to facilitate memory activation directly via TLR9 signaling in human memory B cells (Good et al, 2009) or indirectly via TLR7-mediated activation of dendritic cells in mice (Pordes et al, 2011) and via pDC-derived IFN-I in humans (Bekeredjian-Ding et al, 2005). It is thus possible that activation of memory B cells by viral infection is different from activation of memory B cells by recombinant vaccines.…”

Section: Timing Of Plasmablast Appearance In the Bloodmentioning

confidence: 99%

Origin and Function of Circulating Plasmablasts during Acute Viral Infections

Fink¹

2012

Front. Immun.

172

161

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Activated B cells proliferate and differentiate into antibody-producing cells, long-lived plasma cells, and memory B cells after immunization or infection. Repeated encounter of the same antigen triggers the rapid re-activation of pre-existing specific memory B cells, which then potentially enter new germinal center reactions and differentiate into short-lived plasmablasts or remain in the system as memory B cells. Short-lived class-switched IgG and IgA plasmablasts appear in the circulation transiently and the frequency of these cells can be remarkably high. The specificities and affinities of single plasmablasts in humans have been reported for several viral infections, so far most extensively for influenza and HIV. In general, the immunoglobulin variable regions of plasmablasts are highly mutated and diverse, suggesting that plasmablasts are derived from memory B cells, yet it is unclear which memory B cell subsets are activated and whether activated memory B cells adapt or mature before differentiation. This review summarizes what is known about the phenotype and the origin of human plasmablasts in the context of viral infections and whether these cells can be predictors of long-lived immunity.

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“…Multiple reports have demonstrated a critical role for CD4+ T cell help in this process [30][31][32][33][34][35][36]47]. On the other hand, recent experimental evidence suggests that T-independent activation of memory B cells specific for FVIII can occur by co-stimulation of TLR 9 or TLR 7 in the presence of dendritic cells [48,49]. As MZ B cells can respond to antigen via both T-dependent and T-independent mechanisms (reviewed in [50]), it is intriguing to speculate that this population may play an important role in maintenance of inhibitor antibody response in both congenital hemophilia patients and acquired hemophiliacs.…”

Section: Role Of Memory B Cells In Inhibitor Productionmentioning

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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T cell–independent restimulation of FVIII-specific murine memory B cells is facilitated by dendritic cells together with toll-like receptor 7 agonist

Cited by 15 publications

References 39 publications

FVIII inhibitors: pathogenesis and avoidance

FVIII inhibitors: pathogenesis and avoidance

Origin and Function of Circulating Plasmablasts during Acute Viral Infections

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

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