JCI table of contents: Oct. 1, 2007

Infection with West Nile Virus (WNV) can cause lethal encephalitis and there are currently no vaccines or specific therapeutics for use in humans. However, data generated by Erol Fikrig and colleagues at Yale University School of Medicine has provided evidence that the proinflammatory soluble factor MIF might provide a target for developing therapeutics to treat WNV encephalitis.

Infection with WNV was shown to increase the amount of MIF in the plasma and spinal fluid of humans and the amount of MIF found in the spleen and brain of mice. In mice, an absence of MIF activity increased survival after infection with WNV and in MIF-deficient mice this was associated with decreased viral load and decreased infiltration of immune cells into the brain in the early stages of encephalitic disease. As viral load and immune cell infiltration in the brain increased at later time points after infection with WNV, the authors suggested that delayed viral neuroinvasion in the absence of MIF allowed the virus to be cleared in the periphery and thus survival was enhanced.

TITLE: Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion

AUTHOR CONTACT:
Erol Fikrig
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-2453; Fax: (203) 785-7053; E-mail: erol.fikrig@yale.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32218

Age-related macular degeneration (AMD) is most common cause of blindness in the elderly in industrialized countries, but the molecular mechanisms behind the disease remain ill defined. Some insight into this has now been provided by a team of researchers in France, who showed that abnormal migration of microglial cells, due to a lack of expression of the cell surface protein CX3CR1, causes disease similar to AMD in mice. The potential clinical impact of these observations is discussed in the accompanying commentary by Lois Smith and colleagues from Harvard Medical School, Boston.

In the study, it was shown that as mice lacking CX3CR1 aged microglial cells accumulated in the subretinal space. These cells were filled with fat and their accumulation in the subretinal space was associated with retinal degradation. Similar subretinal accumulation of microglial cells was observed in individuals with AMD. As individuals who have a certain variant of the CX3CR1 gene, which was shown to impair microglial cell migration in vitro, were found to be more susceptible to AMD, the authors concluded that CX3CR1-dependent microglial cell accumulation in the subretinal space might be a molecular mechanism that drives AMD.

TITLE: CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration

AUTHOR CONTACT:

Florian Sennlaub
Centre de recherche des Cordeliers, Paris, France.
Phone: 33-1-40-46-78-63; Fax: 33-1-40-46-78-65; E-mail: sennlaub@idf.inserm.fr.

Christophe Combadière
INSERM U543, Faculté de Médecine Pitié-Salpétrière, Paris, France.
Phone: 33-1-40-77-98-92; Fax: 33-1-40-77-97-34; E-mail: combad@ccr.jussieu.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31692

ACCOMPANYING COMMENTARY
TITLE: Overstaying their welcome: defective CX3CR1 microglia eyed in macular degeneration

AUTHOR CONTACT:
Lois E. H. Smith
Children’s Hospital, Boston, Massachusetts, USA.
Phone: (617) 919-2529; Fax: (617) 730-0392; E-mail: lois.smith@childrens.harvard.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33513

Individuals who survive a heart attack are at high risk of developing chronic heart failure because the heart tissue is remodeled; that is, it undergoes changes in size, shape, and function. The death of heart muscle cells (cardiomyocytes) by a process known as apoptosis is thought to have an important role in cardiac remodeling following a heart attack.

In a new study using mice, Gerald Dorn and colleagues at the University of Cincinnati have provided evidence that apoptosis of cardiomyocytes outside the area of the heart affected by the heart attack is crucial for cardiac remodeling. Mice lacking the proapoptotic molecule Bnip3 were found to exhibit decreased cardiac remodeling after a heart attack compared with normal mice and therefore their heart function was improved. This was associated with decreased cardiomyocyte apoptosis around the edges of the region of the heart affected by the heart attack. The authors therefore suggested that targeting Bnip3 might be a good approach to preventing further damage to the heart after a heart attack. This sentiment is echoed in an accompanying commentary by Richard Kitsis and colleagues at the Albert Einstein College of Medicine, Bronx.

TITLE: Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice

AUTHOR CONTACT:
Gerald W. Dorn II
University of Cincinnati, Cincinnati, Ohio, USA.
Phone: (513) 558-3065; Fax: (513) 558-3438. E-mail: dorngw@ucmail.uc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32490

ACCOMPANYING COMMENTARY
TITLE: Nipping at cardiac remodeling

AUTHOR CONTACT:
Richard N. Kitsis
Albert Einstein College of Medicine, Bronx, New York, USA.
Phone: (718) 430-2609; Fax: (718) 430-8989; Email: kitsis@aecom.yu.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33706

Over 90% of the world’s population is infected with Epstein-Barr virus (EBV). Most individuals become infected in early childhood when it causes no symptoms. However, in adolescents and young adults infection with EBV often causes infectious mononucleosis, a disease that is characterized by fever, sore throat, muscle soreness, and fatigue. In a new study, Karen McAulay and colleagues from Edinburgh University, United Kingdom, have identified specific genetic markers close to the HLA class I genes that are associated with the development of infectious mononucleosis.

Analysis of two microsatellite markers and two single-nucleotide polymorphisms near the HLA class I locus indicated that certain alleles were more common in individuals with infectious mononucleosis than in individuals who were EBV-seronegative. As discussed in the accompanying commentary by Paul Farrell at Imperial College London, United Kingdom, these same HLA class I alleles are also risk factors for EBV-associated Hodgkin’s lymphoma (HL). Farrell therefore suggests that these data provide support for the idea that suffering from infectious mononucleosis predisposes an individual to developing HL and that developing a vaccine for EBV should be considered.

TITLE: HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection

AUTHOR CONTACT:
Karen A. McAulay
University of Edinburgh, Edinburgh, United Kingdom.
Phone: 44-131-650-7943; Fax: 44-131-650-7942; E-mail: kmcaulay@ed.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32377

ACCOMPANYING COMMENTARY
TITLE: Role for HLA in susceptibility to infectious mononucleosis

AUTHOR CONTACT:
Paul J. Farrell
Imperial College London, London, United Kingdom.
Phone: 44-020-7594-2005; Fax: 44-020-7594-3973; Email:p.farrell@imperial.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33563

Exactly why obesity is a risk factor for type 2 diabetes has not been determined, but it has been suggested that one factor that has an important role is the hormone leptin, which is produced by fat tissue. A new study using mice by Rohit Kulkarni and colleagues at the Joslin Diabetes Center, Boston, has provided support for this idea.

When fed a normal diet, mice lacking the receptor for leptin in the pancreas were found to produce more insulin than normal mice in response to glucose. This was because both the number and size of their insulin-producing cells, the beta-cells of the pancreas, was increased. However, when fed a high-fat diet, mice lacking the receptor for leptin in the pancreas produced less insulin than normal mice in response to glucose. This was because they failed to increase either beta-cell number or size. These data led the authors to suggest that altered leptin action in the pancreatic islets is an important factor that contributes to the onset of diabetes in individuals who are obese.

The similarities and differences between this study and the analysis of an independently generated strain of mice lacking the receptor for leptin in the pancreas, which was recently published in Cell Metabolism, is discussed in an accompanying commentary by Mark Magnuson and Kevin Niswender from Vanderbilt University School of Medicine, Nashville.

TITLE: Disruption of leptin receptor expression in the pancreas directly affects beta-cell growth and function in mice

AUTHOR CONTACT:
Rohit N. Kulkarni
Joslin Diabetes Center, Boston, Massachusetts, USA.
Phone: (617) 713-3460; Fax: (617) 713-3476; E-mail: Rohit.Kulkarni@joslin.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=30910

ACCOMPANYING COMMENTARY
TITLE: Obesity and the beta-cell: Lessons from leptin

AUTHOR CONTACT:
Mark A. Magnuson
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Phone: (615) 322-7006; Fax: (615) 322-7236; Email: mark.magnuson@vanderbilt.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33528

Tumor growth and metastasis requires the tumor develops its own network of blood vessels, a process known as neovascularization. Therapeutics targeting one factor produced by tumors to promote neovascularization, VEGF, have had some success in the clinic. However, tumors often produce several factors that promote neovascularization. A new study in mice by Yihai Cao and colleagues at the Karolinska Institute, Sweden, has demonstrated that there is cooperation between two factors produced by many tumors to promote neovascularization, FGF2 and PDGF-BB. The clinical implication of this study — that targeting more than one molecule might be necessary to successfully treat individuals with cancer — is discussed in the accompanying commentary by Jack Arbiser from Emory University School of Medicine, Atlanta.

TITLE: Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis

AUTHOR CONTACT:
Yihai Cao
Karolinska Institute, Stockholm, Sweden.
Phone: 46-8-5248-7596; Fax: 46-8-31-94-70; E-mail: yihai.cao@mtc.ki.se.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32479

ACCOMPANYING COMMENTARY
TITLE: Why targeted therapy hasn’t worked in advanced cancer

AUTHOR CONTACT:
Jack L. Arbiser
Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: (404) 727-5063; Fax: (404) 727-0923; Email: jarbise@emory.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33190

Loss of the protein Pten is observed in a high proportion of lung tumors known as adenocarcinomas. Its role in preventing lung adenocarcinomas has now been clarified in a new study in mice by Akira Suzuki and colleagues from Kyushu University, Japan.

The authors generated mice in which Pten could be eliminated in cells that line the airways (bronchioalveolar epithelial cells) by exposure to the antibiotic doxycycline. Most mice in which Pten was eliminated in bronchioalveolar epithelial cells in the womb died soon after birth of a lack of oxygen, indicating that Pten has a role in normal lung development. Any surviving mice, as well as most mice in which Pten was eliminated in the bronchioalveolar epithelial cells 3–4 weeks after birth, developed lung tumors, most of which were adenocarcinomas. Consistent with the idea that lung adenocarcinomas arise from bronchioalveolar stem cells (BASCs), mice in which Pten was eliminated in bronchioalveolar epithelial cells had increased numbers of BASCs compared with normal mice. These data led the authors to suggest that the Pten signaling pathway might provide a good target for the development of therapeutics to treat individuals with lung adenocarcinomas.

TITLE: Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice

AUTHOR CONTACT:
Akira Suzuki
Kyushu University, Fukuoka, Japan.
Phone: 81-92-642-6838, Fax: 81-92-632-1499; E-mail: suzuki@bioreg.kyushu-u.ac.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31854

The production of large amounts of reactive oxygen species (ROS) is important for combating infections but has the unwanted side effect of causing tissue damage. New data generated by Rikard Holmdahl and colleagues at Lund University, Sweden, has now indicated that in mice ROS can mediate protection against autoimmune diseases mediated by immune cells known as T cells.

Mice lacking p47phox have a reduced capacity to produce ROS and show increased susceptibility to T cell–mediated arthritis. In this study, it was shown that re-expression of p47phox in immune cells known as macrophages returned the level of susceptibility to T cell–mediated arthritis of p47phox-deficient mice to the level observed for normal mice. Further in vitro analysis revealed that macrophage produced ROS inhibited T cell activation and led to the conclusion that macrophage-derived ROS provide protection against autoimmunity by inhibiting T cell activation.

TITLE: Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species

AUTHOR CONTACT:
Rikard Holmdahl
Lund University, Lund, Sweden.
Phone: 46-46-2224607 ext. 3339; Fax: 46-46-2223110; E-mail: rikard.holmdahl@med.lu.se.

View the PDF of this article at: https://www.the-jci.org/article.phpid=31935