The balance of type 1 and type 2 immune responses in the contexts of hepatitis B infection and hepatitis D infection

Townsend, Elizabeth; Zhang, Grace Y; Ali, Rabab; Firke, Marian; Moon, Mi Sun; Han, Mingda; Fram, Benjamin; Glenn, Jeffrey S.; Kleiner, David E.; Koh, Christopher; Heller, Theo

doi:10.1111/jgh.14617

Cited by 17 publications

(18 citation statements)

References 42 publications

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“…Interestingly, TNF-a levels are higher in HDV patients and there is a close correlation between TNF-a and the severity of the disease. 36 Thus, taken together, these data indicate that TNF-a is involved in HDV-induced liver damage and suggest that anti-TNF-a might be a possible treatment aimed at attenuating liver damage in patients with chronic HDV infection and/or that it might be useful in cases of fulminant hepatitis associated with HDV infection. Studies to determine the source of TNF-a are ongoing.…”

Section: Discussionmentioning

confidence: 73%

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection

et al. 2020

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Background & Aims: HDV infection induces the most severe form of human viral hepatitis. However, the specific reasons for the severity of the disease remain unknown. Recently, we developed an HDV replication mouse model in which, for the first time, liver damage was detected. Methods: HDV and HBV replication-competent genomes and HDV antigens were delivered to mouse hepatocytes using adeno-associated vectors (AAVs). Aminotransferase elevation, liver histopathology, and hepatocyte death were evaluated and the immune infiltrate was characterized. Liver transcriptomic analysis was performed. Mice deficient for different cellular and molecular components of the immune system, as well as depletion and inhibition studies, were employed to elucidate the causes of HDV-mediated liver damage. Results: AAV-mediated HBV/HDV coinfection caused hepatocyte necrosis and apoptosis. Activated T lymphocytes, natural killer cells, and proinflammatory macrophages accounted for the majority of the inflammatory infiltrate. However, depletion studies and the use of different knockout mice indicated that neither T cells, natural killer cells nor macrophages were necessary for HDV-induced liver damage. Transcriptomic analysis revealed a strong activation of type I and II interferon (IFN) and tumor necrosis factor (TNF)-a pathways in HBV/HDV-coinfected mice. While the absence of IFN signaling had no effect, the use of a TNF-a antagonist resulted in a significant reduction of HDV-associated liver injury. Furthermore, hepatic expression of HDAg resulted in the induction of severe liver damage, which was T cell-and TNF-a-independent. Conclusions: Both host (TNF-a) and viral (HDV antigens) factors play a relevant role in HDV-induced liver damage. Importantly, pharmacological inhibition of TNF-a may offer an attractive strategy to aid control of HDV-induced acute liver damage.

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Section: Discussionmentioning

confidence: 73%

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection

et al. 2020

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“…However, to the best of our knowledge, there are no data on the cytokine profile during the acute phase of HDV superinfection in humans, and the data are also very limited for the chronic phase. In a recent study performed at a single time point in patients with chronic hepatitis D, the levels of IFN-␥ and IL-12 p70 did not differ compared to those of controls, whereas IL-17A, IL-10, CXCL9, and TNF-␣ were found to be increased (42). Moreover, it has been shown that circulating CD4 ϩ and CD8 ϩ T cells from patients with chronic hepatitis D express low levels of IFN-␥ and TNF-␣ upon in vitro activation (43).…”

Section: Discussionmentioning

confidence: 80%

Distinct Cytokine Profiles Correlate with Disease Severity and Outcome in Longitudinal Studies of Acute Hepatitis B Virus and Hepatitis D Virus Infection in Chimpanzees

Engle

Battista

Danoff

et al. 2020

mBio

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Historical studies conducted in chimpanzees gave us the opportunity to investigate the basis for the different severities of liver damage and disease outcome associated with infection with wild-type hepatitis B virus (HBV) versus a precore HBV mutant, HBV/hepatitis D virus (HDV) coinfection, and HDV superinfection. Weekly samples from 9 chimpanzees were studied for immune responses by measuring plasma levels of 29 cytokines in parallel with alanine aminotransferase (ALT) levels and viral kinetics. Comparison of classic acute hepatitis B (AHB) with severe or progressive AHB and HBV/HDV coinfection or superinfection identified distinct cytokine profiles. Classic AHB (mean ALT peak, 362 IU/liter) correlated with an early and significant induction of interferon alpha-2 (IFN-α2), IFN-γ, interleukin-12 p70 (IL-12 p70), and IL-17A. In contrast, these cytokines were virtually undetectable in severe AHB (mean ALT peak, 1,335 IU/liter), characterized by significant elevations of IL-10, tumor necrosis factor alpha (TNF-α), and MIP-1β. In progressive AHB (mean ALT peak, 166 IU/liter), there was a delayed and lower-magnitude induction of cytokines. The ALT peak was also delayed (mean, 23.5 weeks) compared to those of classic (13.5 weeks) and severe AHB (7.5 weeks). HBV/HDV coinfection correlated with significantly lower levels of IFN-α2, IFN-γ, and IL-17A, associated with the presence of multiple proinflammatory cytokines, including IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-15. Conversely, HDV superinfection induced the highest ALT peak (1,910 IU/liter) and was associated with a general suppression of cytokines. Our data demonstrate that the most severe liver damage, caused by an HBV precore mutant and HDV, correlated with restricted cytokine expression and lack of Th1 response, raising the question of whether these viruses are directly cytopathic. IMPORTANCE Studies performed in chimpanzees at the National Institutes of Health (NIH) demonstrated a significant difference in ALT levels during acute hepatitis of different viral etiologies, with a hierarchy in the extent of liver damage according to the infecting virus: the highest level was in HDV superinfection, followed by infection with a precore HBV mutant, HBV/HDV coinfection, and, lastly, wild-type HBV infection. Our study demonstrates that both the virus and host are important in disease pathogenesis and offers new insights into their roles. We found that distinct cytokine profiles were associated with disease severity and clinical outcome. In particular, resolution of classic acute hepatitis B (AHB) correlated with a predominant Th1 response, whereas HBV/HDV coinfection showed a predominant proinflammatory response. Severe AHB and HDV superinfection showed a restricted cytokine profile and no evidence of Th1 response. The lack of cytokines associated with adaptive T-cell responses toward the precore HBV mutant and HDV superinfection argues in favor of a direct cytopathic effect of these viruses.

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“…Cytokine secretion varies among subsets of Th2 and Treg cells. Notably, a Th2 bias in the Th1/Th2 cytokine balance is not conducive to a successful antiviral immune response [73,[170][171][172][173][174].…”

Section: Immune Checkpoints Affect Chronic Hepatitis Virus Infection mentioning

confidence: 99%

Immune Checkpoints in Viral Infections

Cai

Liu

Zhong

et al. 2020

Viruses

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As evidence has mounted that virus-infected cells, such as cancer cells, negatively regulate the function of T-cells via immune checkpoints, it has become increasingly clear that viral infections similarly exploit immune checkpoints as an immune system escape mechanism. Although immune checkpoint therapy has been successfully used in cancer treatment, numerous studies have suggested that such therapy may also be highly relevant for treating viral infection, especially chronic viral infections. However, it has not yet been applied in this manner. Here, we reviewed recent findings regarding immune checkpoints in viral infections, including COVID-19, and discussed the role of immune checkpoints in different viral infections, as well as the potential for applying immune checkpoint blockades as antiviral therapy.

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The balance of type 1 and type 2 immune responses in the contexts of hepatitis B infection and hepatitis D infection

Cited by 17 publications

References 42 publications

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection

Distinct Cytokine Profiles Correlate with Disease Severity and Outcome in Longitudinal Studies of Acute Hepatitis B Virus and Hepatitis D Virus Infection in Chimpanzees

Immune Checkpoints in Viral Infections

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