Hepatitis B core-specific memory B cell responses associate with clinical parameters in patients with chronic HBV

Vanwolleghem, Thomas; Groothuismink, Zwier M. A.; Kreefft, Kim; Hung, Magdeleine; Novikov, Nikolai; Boonstra, André

doi:10.1016/j.jhep.2020.01.024

Cited by 41 publications

(64 citation statements)

References 32 publications

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“…Since HBcAg-specific antibodies are generated during infection, this defect is selective to HBsAg-specific cells, potentially due to high levels of circulating HBsAg present in patients ( 27 ). Indeed, HBs specific but not HBc specific B cells show characteristics of impaired cells characterized by atypical memory phenotype and poor differentiation into antibody secreting cells ( 5 , 6 , 28 , 29 ). At the same time, T FH have dysregulated response to HBsAg that associates with HBV persistence ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Follicular Helper T (TFH) Cell Targeting by TLR8 Signaling For Improving HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients

et al. 2021

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Identifying signaling pathways that induce B cell response can aid functional cure strategies for chronic hepatitis B infection (CHB). TLR8 activation with ssRNA was shown to enhance follicular helper T cell (TFH) function leading to improved B cell responses in vitro. We investigated whether this mechanism can rescue an exhausted immune response in CHB infection. Effect of TLR8 agonism on supporting cytokines and TFH and B cells were evaluated using ex vivo and in vitro assays. The ability of an oral TLR8 agonist to promote TFH and B cell response was tested in samples from phase 1b clinical trial. TLR8 agonism induced TFH polarizing cytokine IL-12 in monocytes. Treatment of peripheral blood mononuclear cells (PBMCs) from CHB patients with TLR8 agonists induced cytokine IL-21 by TFH cells with enhanced IL-21+BCL-6+ and ICOS+BCL-6+ co-expression. Mechanistically, incubation of isolated naïve CD4+ T cells with TLR8 triggered monocytes resulted in their differentiation into IL-21+ICOS+BCL-6+ TFH in an IL-12 dependent manner. Furthermore, co-culture of these IL-21 producing TFH with autologous naïve B cells led to enhanced memory (CD19+CD27+) and plasma B cell generation (CD19+CD27++CD38+) and IgG production. Importantly, in TFH from CHB patients treated with an oral TLR8 agonist, HBsAg-specific BCL-6, ICOS, IL-21 and CD40L expression and rescue of defective activation induced marker (AIM) response along with partial restoration of HBsAg-specific B cell ELISPOT response was evident. TLR8 agonism can thus enhance HBV-specific B cell responses in CHB patients by improving monocyte-mediated TFH function and may play a role in achieving HBV functional cure.

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Section: Discussionmentioning

confidence: 99%

Follicular Helper T (TFH) Cell Targeting by TLR8 Signaling For Improving HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients

et al. 2021

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“…However, application of fluorescently labeled antigen‐bait systems was able to reveal for the first time that HBsAg‐specific B cells in fact persist at equivalent levels in patients with chronic or acute‐resolving infection and HBV‐vaccinated controls but are functionally defective, failing to produce detectable anti‐HBs upon stimulation in vitro 22,23 . Comparatively, HBcAg‐specific B cells are present at much higher frequencies than HBsAg‐specific B cells, 24 with their number associated with elevated liver inflammation and ongoing viral replication 25 . In stark contrast to HBsAg‐specific B cells, HBcAg‐specific B cells maintain an ability to secrete anti‐HBc antibodies upon IL‐2, IL‐21 and CD40 stimulation 24 .…”

Section: Antigen‐driven Determination Of Memory B Cell Programsmentioning

confidence: 99%

Human antiviral B cell responses: Emerging lessons from hepatitis B and COVID‐19

Burton¹,

Maini²

2021

Immunological Reviews

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Humoral immunity is a critical component of the coordinated response required to resolve viral infections and mediate protection following pathogen clearance or vaccination. A better understanding of factors shaping the memory B cell response will allow tailored development of efficient preventative vaccines against emerging acute viral infections, therapeutic vaccines, and immunotherapies for chronic viral infections. Here, we use recent data obtained by profiling antigen‐specific B cell responses in hepatitis B as a framework to explore lessons that can be learnt from different viral infections about the diverse influences on humoral immunity. Hepatitis B provides a paradigm where successful B cell responses in resolved or vaccinated individuals can be contrasted to the failed response in chronic infection, while also exemplifying the degree to which B cell responses within infected individuals can differ to two antigens from the same virus. Drawing on studies in other human and murine infections, including emerging data from COVID‐19, we consider the influence of antigen quantity and structure on the quality of the B cell response, the role of differential CD4 help, the importance of germinal center vs extrafollicular responses and the emerging concept that responses residing in non‐lymphoid organs can participate in B cell memory.

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“…As the humoral response to HBV is primarily directed towards HBcAg and this response closely follows the phases of infection [ 141 ], AHBc measurement shows efficacy for monitoring the natural history of HBV infection and the severity of liver disease. For example, AHBc levels were found to positively correlate with ALT levels (r = 0.559–0.663; p < 0.001), but not HBV viral load [ 142 , 143 ].…”

Section: Novel Hbv Biomarkersmentioning

confidence: 99%

Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management

Osiowy

2021

Viruses

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Even though an approved vaccine for hepatitis B virus (HBV) is available and widely used, over 257 million individuals worldwide are living with chronic hepatitis B (CHB) who require monitoring of treatment response, viral activity, and disease progression to reduce their risk of HBV-related liver disease. There is currently a lack of predictive markers to guide clinical management and to allow treatment cessation with reduced risk of viral reactivation. Novel HBV biomarkers are in development in an effort to improve the management of people living with CHB, to predict disease outcomes of CHB, and further understand the natural history of HBV. This review focuses on novel HBV biomarkers and their use in the clinical setting, including the description of and methodology for quantification of serum HBV RNA, hepatitis B core-related antigen (HBcrAg), quantitative hepatitis B surface antigen (qHBsAg), including ultrasensitive HBsAg detection, quantitative anti-hepatitis B core antigen (qAHBc), and detection of HBV nucleic acid-related antigen (HBV-NRAg). The utility of these biomarkers in treatment-naïve and treated CHB patients in several clinical situations is further discussed. Novel HBV biomarkers have been observed to provide critical clinical information and show promise for improving patient management and our understanding of the natural history of HBV.

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Hepatitis B core-specific memory B cell responses associate with clinical parameters in patients with chronic HBV

Cited by 41 publications

References 32 publications

Follicular Helper T (TFH) Cell Targeting by TLR8 Signaling For Improving HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients

Follicular Helper T (TFH) Cell Targeting by TLR8 Signaling For Improving HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients

Human antiviral B cell responses: Emerging lessons from hepatitis B and COVID‐19

Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management

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