Persistence of exhaustion in cured hep C

Abstract

In this issue of Blood, Del Padre et al 1 evaluated the impact of eliminating chronic antigen exposure on B-cell exhaustion in the human therapeutic setting of directacting antiviral therapy for chronic hepatitis C virus infection (HCV) complicated by mixed cryoglobulinemia (MC). The phenotype of hepatitis C-related MC B cells has been previously demonstrated by this group and others 2 to include low-level CD21 expression (CD21 low ) and hypoproliferation in response to stimulation either through the B-cell receptor or Toll-like receptor 9, imperfectly termed "exhausted" or "anergic." At baseline, CD21 low B cells from HCVinfected patients expressed markers of chronic activation, with elevated and nearmaximal basal levels of phosphorylated extracellular signal-regulated kinase, and were also predisposed to apoptosis. During oral direct-acting antiviral therapy, the authors observed that by 4 weeks (at which point, most patients have no circulating HCV RNA), these basal abnormalities at least partially normalized. During longitudinal follow-up after patients were documented as cured, the overall frequency of CD21 low cells progressively declined from 50% to 30% of circulating B cells. However, the frequency of V H 1-69 1 B cells specific for HCVrelated MC generally remained stable, although some regained CD21 expression. Despite partial resolution of the exhaustion phenotype, surviving V H 1-69 1 B cells remained hypoproliferative upon Toll-like receptor 9 ligation, suggesting that the B-cell exhaustion phenotype is durably programmed into antigen-specific B cells during long-term extracellular antigen exposure. Mixed cryoglobulinemia is one of several B-cell proliferative disorders that may result from chronic hepatitis C infection, and it is thought to be driven by expansion of HCV envelope-specific B cells that preferentially use immunoglobulin gene segments V H 1-69 and V k [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]3 and to evolve rheumatoid factor activity through somatic hypermutation. 4Although MC is an infrequent complication of chronic hepatitis C infection, the technological ability to identify and isolate HCV-specific B cells via an anti-idiotype V H 1-69-specific antibody (G6) has made this condition an important model for studying humoral immune dysfunction during human chronic viral infection. Prior studies have identified that V H 1-69 1 B cells manifest genetic signatures of enhanced interferon-mediated responsiveness, apoptosis, and B-cell anergy; are phenotypically most commonly CD27

HBV induces inhibitory FcRL receptor on B cells and dysregulates B cell-T follicular helper cell axis

“…In this study, we demonstrate an abnormal expansion of atypical B cells in CHB infection, which are defective in generating HBs specific antibody secreting cells. A similar expansion of tissue-like memory or atypical “exhausted” B cells is shown for other chronic infections including HIV, HCV and malaria 12 , 14 , 15 . Since chronic antigen exposure is a plausible factor behind their expansion, normalization of these cells is expected with effective virus control.…”

“…During chronic HIV infection, abnormal expansion of CD19+ CD10−CD20+ CD27−CD21− tissue like memory B cells expressing inhibitory receptor FcRL4 occurs, although this expansion is normalized with effective antiretroviral therapy 12 . Similar increase in these so called exhausted B cells occur during chronic hepatitis C infection 13 , cure of HCV using DAA therapy does not however normalize these expanded cells 14 (and our unpublished data). Plasmodium falciparum infection results in similar increase in these defective B cells with impaired B cell receptor signaling and responses 15 .…”

Switching thrombopoietin receptor agonist treatments in patients with primary immune thrombocytopenia

“…13 In addition, eltrombopag may be able to bypass the interferon γ-mediated blockade of TPO-R signaling, which is thought to be involved in the loss of stem cells in aplastic anemia. 16 Based on preclinical evidence, the proinflammatory cytokine interferon γ forms neutralizing heterodimers with endogenous TPO that block the extracellular binding site of the TPO-R; however, owing to its unique transmembrane binding site, eltrombopag can evade this blockage. 16 If supported by clinical data, these findings could explain why eltrombopag is effective in aplastic anemia, in which endogenous TPO levels are significantly elevated, but also have important clinical implications for other hematologic disorders involving chronic inflammation.…”

“…16 Based on preclinical evidence, the proinflammatory cytokine interferon γ forms neutralizing heterodimers with endogenous TPO that block the extracellular binding site of the TPO-R; however, owing to its unique transmembrane binding site, eltrombopag can evade this blockage. 16 If supported by clinical data, these findings could explain why eltrombopag is effective in aplastic anemia, in which endogenous TPO levels are significantly elevated, but also have important clinical implications for other hematologic disorders involving chronic inflammation. 16,17 Independent of its TPO-RA activity, eltrombopag is also a strong iron chelator, able to decrease oxidative stress, and has shown antileukemic effects in preclinical studies.…”

Pharmacokinetics and Pharmacodynamics Modeling and Simulation Systems to Support the Development and Regulation of Liposomal Drugs

“…In a preclinical study, Vyxeos ® was demonstrated to selectively increase the exposure of daunorubicin and cytarabine in a fixed ratio in leukemia-laden bone marrow, thus resulting in a significantly prolonged effect with regard to leukemia suppression [40]. In clinical trials, it was shown to have superior efficacy and comparable toxicity to the standard combination of daunorubicin and cytarabine in patients with AML [41].…”