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JCI table of contents: September 13, 2007

JCI Journals

EDITOR'S PICK: Understanding the NOXious cause of Lou Gehrig disease

There is no known cure for amyotrophic lateral sclerosis (ALS), often known as Lou Gehrig disease and motor neuron disease. ALS is a progressive, fatal, neurodegenerative disease caused by the degeneration of nerves that control voluntary muscle movement. New evidence generated in mice by John Engelhardt and colleagues at Iowa University, Iowa City, has provided insight into the mechanisms responsible for certain forms of the disease and has identified potential targets for the development of drugs to treat individuals with these forms of ALS.

In some individuals, ALS is caused by a mutation in their SOD1 gene. Mice overexpressing this mutant gene (SOD1G93A mice) develop ALS-like disease. In this study, the authors found that the rate of disease progression could be dramatically slowed and survival markedly improved if SOD1G93A mice lacked expression of either Nox1 or Nox2, although the effects were more dramatic in the absence of Nox2. The Nox1 and Nox2 genes are on the X-chromosome and female mice lacking just one copy of either gene showed delayed disease onset, indicating that even a 50% decrease in expression of these proteins provided some protection. These data have led to the suggestion that developing drugs to inhibit the Nox pathway might be of benefit to individuals with ALS.

TITLE: Redox modifier genes in amyotrophic lateral sclerosis in mice

AUTHOR CONTACT:

John F. Engelhardt
University of Iowa, Iowa City, Iowa, USA.
Phone: (319) 335-7744; Fax: (319) 335-7198; E-mail: john-engelhardt@uiowa.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31265


EDITOR'S PICK: What makes a fungus virulent? It's lipase

Infection with the fungus Candida parapsilosis is a major problem for individuals in intensive care units, as well as for premature infants and immunocompromised adults. Despite this, little is known about which of its genes account for its virulence. New insight into the virulence mechanisms of C. parapsilosis has now been provided by Attila Gacser and colleagues at the Albert Einstein College of Medicine, New York, who have developed a new way to eliminate genes in C. parapsilosis.

In the study, growth in lipid-rich media of C. parapsilosis engineered to lack lipase activity was shown to be dramatically reduced compared with the growth of normal C. parapsilosis. Furthermore, the mutant fungi were more easily destroyed in vitro by macrophage cell lines and were less virulent when used to infect human cells in vitro and mice in vivo. These data have demonstrated that C. parapsilosis lipase is an important virulence factor for this pathogen and led the authors to suggest that developing drugs that target this lipase might be of therapeutic benefit to individuals who become infected with C. parapsilosis.

TITLE: Targeted gene deletion in Candida parapsilosis demonstrates the role of secreted lipase in virulence

AUTHOR CONTACT:

Attila Gacser
Albert Einstein College of Medicine, Bronx, New York, USA.
Phone: (718) 430-2993; Fax: (718) 430-8968; E-mail: gacsera@gmail.com.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32294


VIROLOGY: Timing is everything when treating viral infections

A new study by Robert Mittler and colleagues from Emory University School of Medicine, Atlanta, has indicated that the timing of treatment with an immune-modifying drug, relative to when a mouse becomes infected with a virus, is crucial in determining whether the treatment is effective or not.

If mice were treated with an antibody that stimulates the molecule CD137 (also known as 4-1BB) before being infected, or within 48 hours of being infected, with the virus LCMV Armstrong the immune response failed to clear the virus. By contrast, if treatment was delayed until more than 72 hours after infection the immune response was enhanced and rapidly cleared the virus. Further analysis revealed that early treatment with CD137-specific antibody caused large numbers of immune cells known as CD4+ and CD8+ T cells to die by day 8 of the infection. These data have important implications for the development of CD137 agonists as vaccine adjuvants, something that is currently ongoing.

TITLE: Immune suppression or enhancement by CD137 T cell costimulation during acute viral infection is time-dependent

AUTHOR CONTACT:

Robert S. Mittler
Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: (404) 727-9425; Fax: (404) 727-8199; E-mail: rmittler@rmy.emory.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32426


PULMONARY: Two stimuli better than one at inducing mucus production

Individuals with cystic fibrosis (CF) are highly susceptible to both bacterial and fungal infection of their airways. In a new study, Jeffrey Wine and colleagues at Stanford University have provided a potential explanation for the vulnerability of individuals with CF to airway infections.

Although the airway glands of healthy individuals produce mucus when stimulated with either acetylcholine (ACh) or vasoactive peptide (VIP), the airway glands of individuals with CF produce mucus only when stimulated with ACh. The authors found that low levels of VIP and ACh were synergistic in their ability to induce the airway glands of healthy individuals to produce mucus; no synergy was observed for airway glands from individuals with CF. These data provide support for the hypothesis that low levels of VIP and ACh stimulate background levels of mucus secretion and that this is an important component of airway immune defense against bacterial and fungal infection that is absent in individuals with CF.

TITLE: Synergistic airway gland mucus secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis

AUTHOR CONTACT:

Jeffrey J. Wine
Stanford University, Stanford, California, USA.
Phone: (650) 725-2462; Fax: (650) 725-5699; E-mail: wine@stanford.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31992


NEPHROLOGY: TLR4 makes blood loss damaging to the kidney

During transplantation it is necessary that the organ being transplanted spends some time without a blood supply; that is, it finds itself in ischemic conditions. Upon reconnection of the blood supply in its new recipient the organ is subject to ischemia/reperfusion injury (IRI), something that negatively affects short- and long-term graft survival. Understanding the molecular mechanisms that trigger IRI are therefore an area of intensive investigation.

A new study in mice by Huiling Wu and colleagues at the University of Sydney, Australia, has indicated a central role for TLR4 in mediating IRI in the kidney. Ischemia in the kidney was shown to increase the expression of TLR4 on kidney tubule cells and infiltrating immune cells and mice lacking TLR4 were protected from kidney dysfunction following ischemia. Expression of TLR4 by kidney tubule cells had the dominant role in mediating kidney damage after ischemia. Signaling through TLR4 on kidney tubule cells induced the production of proinflammatory cytokines, leading the authors to conclude that TLR4-mediated signaling causes kidney damage after ischemia by initiating an inflammatory response.

TITLE: TLR4 activation mediates kidney ischemia/reperfusion injury

AUTHOR CONTACT:

Huiling Wu
University of Sydney, Sydney, New South Wales, Australia.
Phone: 61-2-9351-2898; Fax: 61-2-9351-8771; E-mail: huilingw@med.usyd.edu.au.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31008


INFLAMMATION: TREM-1 has the guts to mediate inflammation

In a new study, Christoph Mueller and colleagues at the University of Bern, Switzerland, have identified a crucial role for the cell surface protein TREM-1 in mediating chronic inflammation in the intestine of mice and humans.

Immune cells known as macrophages in the intestines of mice and humans do not normally express TREM-1. However, in this study, expression of TREM-1 by these cells was shown to be increased in individuals with inflammatory bowel disease (IBD) and in mice with colitis; levels of TREM-1 expression correlated directly with the severity of the intestinal inflammation in both IBD patients and mice with colitis. The severity of disease in mouse models of colitis was reduced by administration of a TREM-1 antagonist peptide either before or after clinical signs of the disease could be detected. These data led the authors to suggest that TREM-1 expression levels might provide a marker to assess disease activity in individuals with IBD and that TREM-1 might be a viable target for the development of therapeutics to treat individuals with chronic inflammatory diseases such as IBD.

TITLE: TREM-1–expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases

AUTHOR CONTACT:

Christoph Mueller
University of Bern, Bern, Switzerland.
Phone: 41-31-632-8904; Fax: 41-31-381-8764; E-mail: christoph.mueller@pathology.unibe.ch.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30602


CARDIOVASCULAR BIOLOGY: Keeping T cells in check limits atherosclerosis

Atherosclerosis is a chronic inflammatory disease that often leads to heart attacks and strokes. T cells have an important role in the development of atherosclerosis and new data produced by Andrew Lichtman and colleagues at Brigham and Women's Hospital, Boston, have identified one way in which proatherogenic T cells are kept in check in mice.

Mice susceptible to developing atherosclerosis (LDLR-deficient mice) that lacked the cell surface receptors PD-L1 and PD-L2 were observed to develop more severe atherosclerotic disease than normal LDLR-deficient mice. The number of T cells in the atherosclerotic lesions in these mice was also greater than in the lesions of normal LDLR-deficient mice. Further analysis indicated that PD-L1 and PD-L2 are required to limit T cell activation by immune cells known as antigen-presenting cells and led the authors to conclude that PD-L1 and PD-L2 interactions with their ligand PD-1 are crucial for dampening the proatherogenic T cell response.

TITLE: Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice

AUTHOR CONTACT:

Andrew H. Lichtman
Brigham and Women's Hospital, Boston, Massachusetts, USA.
Phone: (617) 525-4335; Fax: (617) 525-4333; E-mail: alichtman@rics.bwh.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31344


NEUROBIOLOGY: Breaking down the molecular pathway to a neuromuscular disease

Slow-channel myasthenic syndrome (SCS) is an inherited disease that causes progressive muscle weakness. It is caused by mutations in acetylcholine receptor (AChR) genes that lead to the AChR being open for too long. Although this is known to cause calcium levels at the junction between nerves and the muscle to be much higher than normal, the molecular pathway that leads from high levels of calcium to muscle weakness has not be clearly defined. Using a mouse model of SCS, Christopher Gomez and colleagues at the University of Chicago, have found that calpain, which is a calcium-activated protein, and caspase 3 have an important role in mediating disease. The authors therefore suggested that inhibiting both these proteins, which mediate their effects by degrading other proteins, might be of therapeutic use for the treatment of individuals with SCS.

TITLE: Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome

AUTHOR CONTACT:

Christopher M. Gomez
University of Chicago, Chicago, Illinois, USA.
Phone: (772) 702-6390; Fax: (773) 702-5670; E-mail: gomez001@uchicago.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30383

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