B cells are increasingly recognized as playing an important role in the ongoing control of hepatitis B virus (HBV). The development of antibodies against the viral surface antigen (HBV surface antigen [HBsAgs]) constitutes the hallmark of resolution of acute infection and is a therapeutic goal for functional cure of chronic HBV (CHB). We characterized B cells directly ex vivo from the blood and liver of patients with CHB to investigate constraints on their antiviral potential. Unexpectedly, we found that HBsAg-specific B cells persisted in the blood and liver of many patients with CHB and were enriched for T-bet, a signature of antiviral potential in B cells. However, purified, differentiated HBsAg-specific B cells from patients with CHB had defective antibody production, consistent with undetectable anti-HBs antibodies in vivo. HBsAg-specific and global B cells had an accumulation of CD21^–CD27^– atypical memory B cells (atMBC) with high expression of inhibitory receptors, including PD-1. These atMBC demonstrated altered signaling, homing, differentiation into antibody-producing cells, survival, and antiviral/proinflammatory cytokine production that could be partially rescued by PD-1 blockade. Analysis of B cells within healthy and HBV-infected livers implicated the combination of this tolerogenic niche and HBV infection in driving PD-1^hiatMBC and impairing B cell immunity.

Chronic HBV (CHB) infection suppresses virus-specific T cells, but its impact on humoral immunity has been poorly analyzed. Here, we developed a dual-staining method that utilizes hepatitis B virus (HBV) surface antigens (HBsAg) labeled with fluorochromes as “baits” for specific ex vivo detection of HBsAg-specific B cells and analysis of their quantity, function, and phenotype. We studied healthy vaccinated subjects (n = 18) and patients with resolved (n = 21), acute (n = 11), or chronic (n = 96) HBV infection and observed that frequencies of circulating HBsAg-specific B cells were independent of HBV infection status. In contrast, the presence of serum HBsAg affected function and phenotype of HBsAg-specific B cells that were unable to mature in vitro into Ab-secreting cells and displayed an increased expression of markers linked to hyperactivation (CD21^lo) and exhaustion (PD-1). Importantly, B cell alterations were not limited to HBsAg-specific B cells, but affected the global B cell population. HBsAg-specific B cell maturation could be partially restored by a method involving the combination of the cytokines IL-2 and IL-21 and CD40L-expressing feeder cells and was further boosted by the addition of anti–PD-1 Abs. In conclusion, HBV infection has a marked impact on global and HBV-specific humoral immunity, yet HBsAg-specific B cells are amenable to a partial rescue by B cell–maturing cytokines and PD-1 blockade.

Background Liver involvement in sarcoidosis is variable and can occur in the absence of pulmonary disease. Data on the natural history of hepatic sarcoid and response to therapy are lacking. This study investigates hepatic dysfunction complicating lung disease and significant liver involvement presenting independent of pulmonary sarcoid. Patients and methods One hundred and eighty patients were included in the study. The minimum follow-up was 2 years. Results Fifty per cent of the study population had derangement of liver function attributable to hepatic sarcoid. Twenty-three patients (13%) had liver involvement without lung disease. Sixty-three patients were administered corticosteroids; approximately one-third had a complete clinical response, one-third a partial response and one-third showed no response. Fourteen patients (8%) were cirrhotic at presentation, and two progressed to cirrhosis despite steroid therapy. Sixteen patients received a second-line immunosuppressive agent; one-half of these showed a response to treatment augmentation (four patients azathioprine, three patients methotrexate, one patient both drugs). Six patients required liver transplantation, with disease recurrence in one recipient. In four patients, sarcoid as the aetiology of end-stage liver disease was diagnosed only on examination of the explanted liver. Conclusion Sarcoidosis can cause end-stage chronic liver disease, which is often unrecognized until examination of the explanted liver. Response to conventional immunosuppression is variable and unpredictable. Transplantation is feasible and safe in this population but recurrence is possible.

HBV DNA integration originally recognized as a non-functional byproduct of the HBV life cycle has now been accepted as a significant contributor to HBV pathogenesis and HDV persistence. Integrated HBV DNA is derived from linear genomic DNA present in virus particles or produced from aberrantly processed relaxed circular genomic DNA following an infection, and can drive expression of HBsAg and HBx. DNA integration events accumulate over the course of viral infection ranging from a few percent during early phases to nearly 100 percent of infected cells after prolonged chronic infection. HBV DNA integration events have primarily been investigated in the context of HCC development where they can activate known oncogenes and other growth promoting genes, cause chromosomal instability and presumably epigenetic alterations promoting tumor growth. More recent evidence suggests that HBsAg expression from integrated DNA might contribute to HBV pathogenesis by attenuating the immune response. Integrated DNA provides a source for envelope proteins required for HDV replication and hence represents a means for HDV persistence. Because integrated DNA is responsible for persistence of HBsAg in the absence of viral replication it impacts established criteria for the resolution of HBV infection which relies on HBsAg as a diagnostic marker. Integrated HBV DNA has been useful in assessing the turnover of infected hepatocytes which occurs during all phases of chronic hepatitis B including the initial phase of infection historically termed immune tolerant. HBV DNA integration was also shown to impact the development of novel therapies targeting viral RNAs.

Background & Aims: Studies have suggested that patients with chronic hepatitis B (CHB), either co-, or super infected, have more aggressive liver disease progression than those with the hepatitis delta virus (HDV). This systematic literature review and meta-analysis examined whether HDV RNA status is associated with increased risk of advanced liver disease events (ALDEs), in patients who are HBsAg and HDV antibody positive. Approach & Results: A total of 12 publications were included. Relative rates of progression to ALDE for HDV RNA+/detectable versus HDV RNA-/undetectable were extracted for analysis. Reported odds (OR) and hazard ratios (HRs) with 95% confidence intervals (CI) were pooled using the Hartung-Knapp-Sidik-Jonkman method for random-effects models. Presence of HDV RNA+ was associated with an increased risk of any ALDE (random effect [95% CI]: risk ratio (RR): 1.48 [0.93, 2.33]; HR: 2.62 [1.55, 4.44]). When compared to HDV RNA- patients, HDV RNA+ was associated with a significantly higher risk of progressing to compensated cirrhosis (RR 1.74 [1.24, 2.45]), decompensated cirrhosis (HR 3.82 [1.60, 9.10]), hepatocellular carcinoma (HR 2.97 [1.87, 4.70]), liver transplantation (HR 7.07 [1.61, 30.99]), and liver-related mortality (HR 3.78 [2.18, 6.56]). Conclusion: Patients with HDV RNA+ status have a significantly greater risk of liver disease progression than patients who are HDV RNA-. These findings highlight the need for improved HDV screening and linkage to treatment to reduce the risk of liver-related morbidity and mortality. Export