News From The Journal Of Clinical Investigation, July 6, 2009

Main Category: Liver Disease / Hepatitis
Also Included In: Eczema / Psoriasis;  Immune System / Vaccines;  Lung Cancer
Article Date: 08 Jul 2009 - 0:00 PDT

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HEPATOLOGY: Immune cells linked to severe infant liver disease

Very little is known about the cause of biliary atresia, a progressive liver disease in newborns. However, Jorge Bezerra and colleagues, at the University of Cincinnati College of Medicine, Cincinnati, have now linked immune cells known as NK cells to the initiation of biliary atresia in mice. Correlative evidence obtained by analysis of livers of infants with biliary atresia suggests that these cells are likely clinically relevant.

Biliary atresia occurs when the bile ducts (the channels and ducts that carry bile, a liquid that helps digest fat, from the liver to the gallbladder) outside the liver are obstructed. This causes bile to build up in the liver, which becomes progressively more and more damaged. The only treatments are surgery or liver transplantation, depending on the severity of the obstruction. In the study, activated NK cells were found in the livers of infants with biliary atresia and not in nondiseased infant livers. Consistent with these cells having a role in biliary atresia, NK cells were the most abundant immune cells in bile ducts outside the mouse liver at the time of obstruction in experimental biliary atresia and their depletion prevented bile duct injury and subsequent obstruction. The authors therefore suggest that NK cell-mediated damage to the bile duct initiates biliary atresia.

TITLE: Neonatal NK cells target the mouse duct epithelium via Nkg2d and drive tissue-specific injury in experimental biliary atresia https://www.the-jci.org/article.php?id=38879

DERMATOLOGY: Psoriasis-like inflammation: crucial role for the protein CCR6

Psoriasis, a chronic skin disorder caused by the immune system, affects 1%-2% of white individuals. Although there are a number of treatments, the chronic recurrent nature of the disorder means more efficient therapies are being sought. Work in a mouse model of psoriasis-like inflammation, by Joshua Farber and colleagues, at the National Institute of Allergy and Infectious Diseases, Bethesda, has provided new insight into the immune mechanisms that likely underlie psoriasis and identified a potential new drug target.

In the study, when the soluble immune molecule IL-23 was injected into the ears of normal mice the ears developed psoriasis-like inflammation. By contrast, no inflammation developed when IL-23 was injected into the ears of mice lacking the protein CCR6. As immune cells known as Th17 cells express CCR6, initial analysis focused on these cells. Consistent with a role for these cells in the IL-23-induced psoriasis-like inflammation, injection of the immune molecule IL-22 (which is produced by Th17 cells) into the ears of normal and CCR6-deficient mice induced equivalent inflammation. However, further analysis indicated that the IL-22 did not come from Th17 cells, rather it came from a non-T cell source. The authors therefore conclude that CCR6 is essential for IL-23-induced, IL-22-mediated psoriasis-like inflammation, which initially develops in a T cell-independent manner, and suggest that CCR6 might be a therapeutic target for the treatment of psoriasis.

TITLE: CCR6 is required for IL-23-induced psoriasis-like inflammation in mice https://www.the-jci.org/article.php?id=37378

IMMUNOLOGY: First natural target for regulatory T cells expressing CD8

Immune cells known as Tregs keep the immune system under control, preventing it from attacking the body and causing autoimmune diseases such as rheumatoid arthritis. However, Tregs have also been found to accumulate in tumors, where they suppress the antitumor immune response. These immune modulatory functions have made Tregs the focus of many researchers. Most concentrate on Tregs expressing the protein CD4 on their surface and comparatively little is known about those that express the protein CD8. But now, Mads Hald Andersen and colleagues, at Herlev University Hospital, Denmark, have carefully characterized a population of CD8-expressing Tregs that they identified in the blood and tumor tissue of patients with cancer.

In the study, CD8+ Tregs that recognized heme oxygenase-1, a protein involved in the late stages of inflammatory responses, were detected in the blood and tumor tissue of patients with cancer. Importantly, these cells were more efficient than CD4+ Tregs at preventing other immune cells from proliferating, producing immune effector molecules, and attacking other cells. Further analysis indicated that the heme oxygenase-1-specific CD8+ Tregs affected other immune cells, at least in part, by producing suppressive soluble factors. The authors therefore suggest that these potent regulatory cells act to control ongoing immune responses because they are active only when heme oxygenase-1 is available, i.e., in the late stages of inflammatory responses.

TITLE: Identification of heme oxygenase-1-specific regulatory CD8+ T cells in cancer patients https://www.the-jci.org/article.php?id=38739

ONCOLOGY: Marker protein causes poor outcome in lung cancer

Individuals with non-small cell lung cancer (NSCLC) expressing high levels of HIF2-alpha have a poor clinical outcome. However, whether HIF2-alpha actually causes the poor outcome or is simply a marker of this has not been determined. Evidence to suggest that high levels of HIF2-alpha contribute to poor clinical outcome in patients with NSCLC has now been provided by research conducted at the University of North Carolina, Chapel Hill, using a mouse model of lung cancer.

Mice engineered such that a mutant protein (KrasG12D) can be experimentally switched on in lung cells develop lung cancer many weeks after KrasG12D has been switched on. When the researchers, led by William Kim, further genetically modified the mice such that a nondegradeable form of HIF2-alpha was switched on in the lungs with KrasG12D, they found that the mice developed larger, more invasive tumors, and thus died sooner. The authors therefore conclude that HIF2-alpha promotes tumor growth and progression in a model of lung cancer and suggest that HIF2-alpha causes poor outcome in individuals with NSCLC.

TITLE: HIF2-alpha cooperates with RAS to promote lung tumorigenesis in mice https://www.the-jci.org/article.php?id=38443

METABOLISM: Linking energy production with energy requirements

Eric Berglund and colleagues, at Vanderbilt University Medical Center, Nashville, have provided new insight into the way the mouse liver couples metabolic pathways with energy requirements, a process critical for adapting to changing conditions such as fasting and exercise.

The energy state in a liver cell (i.e., the hepatic energy state), which is defined by levels of the different forms of adenine nucleotides, couples metabolic pathways with energy requirements. In the study, hepatic energy state was found to decrease markedly in mice following exercise, fasting, and exposure to other metabolic stressors. Further in vivo analysis indicated that the hormone glucagon, which stimulates energy consumption and is found in increased amounts in the blood during metabolic stress, mediated this reduction in hepatic energy state. Consistent with this, mice that do not mount a glucagon response when their blood glucose levels drop did not show a reduction in hepatic energy state when under metabolic stress, despite high levels of glucagon. The authors therefore suggest that the fall in hepatic energy state during exposure to acute metabolic stressors is a normal physiological response mediated by glucagon to increase energy production in the liver.

TITLE: Hepatic energy state is regulated by glucagon receptor signaling in mice https://www.the-jci.org/article.php?id=38650

Source:
Karen Honey
Journal of Clinical Investigation