Abnormal Innate Immunity in Acute-on-Chronic Liver Failure: Immunotargets for Therapeutics

Abstract

Acute-on-chronic liver failure (ACLF) is a severe life-threatening condition with high risk of multiorgan failure, sepsis, and mortality. ACLF activates a multifaceted interplay of both innate and adaptive immune response in the host which governs the overall outcome. Innate immune cells recognize the conserved elements of microbial and viral origin, both to extort instant defense by transforming into diverse modules of effector responses and to generate long-lasting immunity but can also trigger a massive intrahepatic immune inflammatory response. Acute insult results in the activation of innate immune cells which provokes cytokine and chemokine cascade and subsequently initiates aggressive systemic inflammatory response syndrome, hepatic damage, and high mortality in ACLF. Dysregulated innate immune response not only plays a critical role in disease progression but also potentially correlates with clinical disease severity indices including Child-Turcotte-Pugh, a model for end-stage liver disease, and sequential organ failure assessment score. A better understanding of the pathophysiological basis of the disease and precise immune mechanisms associated with liver injury offers a novel approach for the development of new and efficient therapies to treat this severely ill entity. Immunotherapies could be helpful in targeting immune-mediated organ damage which may constrain progression toward liver failure and eventually reduce the requirement for liver transplantation. Here, in this review we discuss the defects of different innate immune cells in ACLF which updates the current knowledge of innate immune response and provide potential targets for new therapeutic interventions.

Increased Circulating T Follicular Helper Cells Induced via IL-12/21 in Patients With Acute on Chronic Hepatitis B Liver Failure

“…Systemic inflammatory response, including TNF, IL-8, IL-6, and IL-2, contributes to the transition from stable chronic liver disease to HBV-ACLF, which is associated with morbidity and mortality of hepatitis ( 32 ). These pro-inflammatory cytokines were up-regulated significantly in HBV-ACLF, consistent with both local and systemic acute inflammation during the development of HBV-ACLF.…”

Acute-on-Chronic Liver Failure: Pathophysiological Mechanisms and Management

“…Current advancements in the understanding of the pathophysiological basis suggest that hyperreactive systemic inflammatory response is a critical driver of tissue damage and organ injury in patients with acutely decompensated cirrhosis leading to the development of ACLF (13). Extensive production of inflammatory mediators including cytokines, chemokines, growth factors, bioactive lipid mediators, and expression of chemokine receptors by different immune cells induce systemic inflammation, immune-mediated tissue damage, and subsequently liver failure (14)(15)(16)(17)(18)(19). Activated immune cells release other mediators such as proteases, reactive oxygen species (ROS), prostaglandins, and leukotrienes that further aggravate tissue damage (16,20).…”

Role of immune dysfunction in drug induced liver injury

“…Reports have shown high levels of cytokines in patients with ACLF. This may be due to the activation of monocytes and macrophages in response to DAMPs, microbial toxins or drug adducts[ 19 , 75 , 76 ].…”

“…The trigger due to paracetamol toxicity can occur in two ways- the first is due to direct toxicity by paracetamol and the second due to immune response that is secondary to the hepatocellular damage due to the direct toxicity. The activation of innate immune response due to the paracetamol acute toxicity results in upregulation of cytokine and chemokine production that initiates severe systemic inflammation, liver damage and mortality[ 70 , 75 , 77 , 78 ].…”

“…Similar to the acute toxicity, immune activation in alcoholic liver disease results in activation of resident Kupffer cells and dendritic cells as well as the infiltrating immune cells- monocytes and neutrophils lead to progression towards fibrosis and cirrhosis. This disrupts the liver architecture and function setting stage for liver failure, that can be actuated by an acute trigger[ 75 , 78 , 79 ].…”