EDITOR'S PICK: The protein tPA provides protection for nerve cells
The protein tPA is best known for its role in breaking down blood clots that form in blood vessels and the heart. However, tPA is also found in nerve cells in the brain, where its function has not been clearly determined. Now, Manuel Yepes and colleagues, at Emory University School of Medicine, Atlanta, have generated data in mice indicating that tPA protects nerve cells in a region of the brain known as the hippocampus from death caused by a local reduction in blood flow, an event that occurs during stroke. Further analysis indicated several of the other molecules involved in the tPA-mediated protective process, leading the authors to propose two models for the protective effect of tPA in the hippocampus, both of which have implications for the development of therapeutic strategies to prevent nerve cell death in the clinic.
TITLE: Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus
AUTHOR CONTACT:
Manuel Yepes
Emory University School of Medicine, Atlanta, Georgia, USA.
Phone: 404.712.8358; Fax: 404.727.3728; E-mail: myepes@emory.edu.
View this article at: http://www.jci.org/articles/view/41722?key=99b7f213162c089e91a3
EDITOR'S PICK: Conquering a severe complication of celiac disease
One severe complication of celiac disease is enteropathy-associated T cell lymphoma, a high-grade invasive lymphoma with a very poor prognosis. Previous research has suggested that chronic exposure of immune cells in the walls of the small intestine, which are known as intraepithelial lymphocytes, to potent anti-death signals initiated by the soluble factor IL-15 contributes to the development of enteropathy-associated T cell lymphoma. A team of researchers, at INSERM U989, Université René Descartes, France, has now identified the survival signals delivered by IL-15 to freshly isolated human intraepithelial lymphocytes and to intraepithelial lymphocyte cell lines derived from patients with type II refractory celiac disease — a clinical state considered an intermediary step between celiac disease and enteropathy-associated T cell lymphoma. Importantly, treatment with an antibody directed at IL-15 caused intraepithelial lymphocytes to die and wiped out their accumulation in mice overexpressing human IL-15 in the lining of their gut. The team, led by Nadine Cerf-Bensussan and Bertrand Meresse, therefore suggests that IL-15 and its downstream survival signals might provide new targets for the treatment of type II refractory celiac disease.
TITLE: IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease–associated inflammation and lymphomagenesis
AUTHOR CONTACT:
Nadine Cerf-Bensussan
INSERM U989, Université René Descartes, Paris, France.
Phone: 33.140615302; Fax: 33.140615638; E-mail: nadine.cerfbensussan@inserm.fr.
Bertrand Meresse
INSERM U989, Université René Descartes, Paris, France.
Phone: 33.140615302; Fax: 33.140615638; E-mail: bertrand.meresse@inserm.fr.
View this article at: http://www.jci.org/articles/view/41344?key=e1dc4f9eec5f2e932a64
IMMUNOLOGY: How statins modulate immune function
Statins are a class of drug used to lower cholesterol levels in the blood. However, they also have many effects on the immune system, and it has been suggested that they might be useful for the treatment of inflammatory diseases mediated by immune cells known as T cells. Andrew Lichtman and colleagues, at the Brigham and Women's Hospital, Boston, have now provided new insight into the mechanisms by which statins reduce the inflammatory functions and disease-causing activities of T cells. Specifically, they find that statins work on T cells via a protein known as KLF2. As statin-treated T cells and KLF2-overexpressing T cells showed similar ability to reduce disease in a mouse model of T cell–mediated myocarditis (inflammation of the heart muscle), the authors suggest that the KLF2 pathway might provide a new therapeutic target for inflammatory diseases mediated by T cells.
TITLE: Statin-induced Kruppel-like factor 2 expression in human and mouse T cells reduces inflammatory and pathogenic responses
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 this article at: http://www.jci.org/articles/view/41384?key=47aa0f3129f3742aaeab
OPHTHALMOLOGY: One, two: counting the genes causing deafblindness in individual patients
Usher syndrome is a genetic disorder characterized by congenital deafness and gradual vision loss; it is the leading cause of deafblindness. Several genes have been linked with the condition, but many patients do not have mutations in any of these genes, suggesting that there might be other genes linked to it. Indeed, Hanno Bolz and colleagues, at the University of Cologne, Germany, have found that mutations in the PDZD7 gene contribute to Usher syndrome.
Although linked to Usher syndrome, the PDZD7 mutations were identified only in patients with mutations in other known Usher genes. Further analysis indicated that PDZD7 mutations can modify the severity of the vision loss suffered by patients with Usher syndrome and contribute to disease in combination with mutations in other Usher genes. These data challenge the prevailing view that Usher syndrome arises as a result of mutations in a single gene, suggesting that, at least in some instances, disease arises as a result of mutations in two genes.
TITLE: PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome
AUTHOR CONTACT:
Hanno J. Bolz
Bioscientia Center for Human Genetics, Ingelheim, Germany.
Phone: 49.6132.781.206; Fax: 49.6132.781.298; E-mail: hanno.bolz@bioscientia.de.
View this article at: http://www.jci.org/articles/view/39715?key=2d3213bbf587c963df37
VIROLOGY: Immune system going downhill fast with IL-10
Individuals chronically infected with viruses (e.g., individuals infected with HIV) develop progressively more dysfunctional immune systems. One thing thought to contribute to this is persistent high levels of the soluble immune factor IL-10, but the underlying mechanism(s) is not well understood. However, Galit Alter and colleagues, at Massachusetts General Hospital, Boston, have now identified one possible mechanism by which persistent high levels of IL-10 can cause progressive immune dysfunction.
In the study, IL-10 was found to make immune cells known as immature dendritic cells resistant to elimination by immune cells known as NK cells. Consistent with this in vitro data, partially "immature" dendritic cells were found to accumulate aberrantly in immune organs known as lymph nodes in individuals infected with HIV. As immature dendritic cells are poor inducers of immune responses, these data outline a mechanism by which persistent high levels of IL-10 could lead to progressive immune dysfunction.
TITLE: IL-10 induces aberrant deletion of dendritic cells by natural killer cells in the context of HIV infection
AUTHOR CONTACT:
Galit Alter
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: 617.724.0546; Fax: 617.726.5411; E-mail: galter@partners.org.
View this article at: http://www.jci.org/articles/view/40913?key=ce16fecd4fec7a357c39
IMMUNOLOGY: Immune cells learn how to dominate an immune response
A team of researchers, led by Nicole La Gruta, at the University of Melbourne, Australia, has generated data that should be helpful in developing vaccines that more efficiently maximize the anti-viral immune response.
One of the most important components of the anti-viral immune response is a population of immune cells known as CD8+ T cells. CD8+ T cell responses to viral infection are characterized in mice by the emergence of dominant and subdominant virus-targeting populations. Recent data have suggested that the number of precursors for a given T cell specificity determine whether it will become a dominant or subdominant responder. However, La Gruta and colleagues, have shown in mice that this is not the case. They found no consistent relationship between the frequency of T cell precursors targeting 4 different influenza virus peptides and the subsequent magnitude of the immune response. Rather, the extent of recruitment of a given precursor and its duration of expansion over the course of the infection determined the degree to which the T cell population dominated the anti-viral immune response. The authors hope these data will help promote the design of vaccines aimed at enhancing the magnitude and breadth of subdominant anti-viral immune responses, which are usually considered unimportant, eliciting efficient viral clearance.
TITLE: Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion
AUTHOR CONTACT:
Nicole L. La Gruta
University of Melbourne, Parkville, Victoria, Australia.
Phone: 61.3.8344.7962; Fax: 61.3.9347.1540; E-mail: nllg@unimelb.edu.au.
View this article at: http://www.jci.org/articles/view/41538?key=540a5cb216ba2e31a074
IMMUNOLOGY: Immune cell interplay in persistent viral infection
Individuals persistently infected with a virus often mount inefficient T cell immune responses to the virus. This is associated with the T cells expressing high levels of proteins that transmit inhibitory signals. One such protein is 2B4, but whether it has a role in T cell dysfunction has not been determined. Raymond Welsh and colleagues, at the University of Massachusetts Medical School, Worcester, have now provided new insight into its function through their analysis of mice persistently infected with lymphocytic choriomeningitis virus (LCMV).
In the study, persistent LCMV infection in mice lacking 2B4 led to reduced LCMV-targeted CD8+ T cell responses and prolonged viral persistence. However, these effects were not due to a lack of 2B4 on T cells. Rather, they were due to a lack of 2B4 on immune cells known as NK cells because the 2B4-deficient NK cells killed CD8+ T cells upon activation. These data provide unexpected insights into the T cell dysfunction that accompanies persistent virus infection, indicating that NK cells have a crucial regulatory role in apparently T cell–associated persistent infections.
TITLE: Absence of mouse 2B4 promotes NK cell–mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis
AUTHOR CONTACT:
Raymond M. Welsh
University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Phone: 508.856.5819; Fax: 508.856.5780. E-mail: Raymond.Welsh@umassmed.edu.
View this article at: http://www.jci.org/articles/view/41264?key=2efee2e3d4d7c11fc6e3
METABOLIC DISEASE: New regulator of beta-cell function and dysfunction in type 2 diabetes
Cells in the pancreas known as beta-cells produce the hormone insulin, which regulates blood glucose levels. These cells become dysfunctional in individuals with type 2 diabetes. A team of researchers, led by Jenny Gunton, at the Garvan Institute of Medical Research, Australia, has provided new insight into the regulation of normal mouse beta-cell function and identified a potential new target for the development of therapeutics to combat the beta-cell dysregulation that contributes to type 2 diabetes.
The protein HIF-1-alpha is best known for its key role in the response of a cell to low levels of oxygen. However, it has recently been suggested that HIF-1-alpha also has key functions in normoxic conditions. In the study, Gunton and colleagues detected low levels of HIF-1-alpha in mouse and human normoxic beta-cells and pancreatic islets. Furthermore, mice lacking HIF-1-alpha in their beta-cells failed to control blood glucose levels, while increasing HIF-1-alpha levels in ex vivo pancreatic islets from individuals with type 2 diabetes markedly improved their function. These data led the authors to suggest that HIF-1-alpha might provide a new target for the development of therapeutics to combat beta-cell dysregulation in individuals with type 2 diabetes.
TITLE: Hypoxia-inducible factor-1-alpha regulates beta-cell function in mouse and human islets
AUTHOR CONTACT:
Jenny E. Gunton
Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Phone: 011.61.2.9295.8474; Fax: 011.61.2.9295.8404; E-mail: j.gunton@garvan.org.au.
View this article at: http://www.jci.org/articles/view/35846?key=96d785bd9bc478e96b17
METABOLIC DISEASE: Promoting insulin secretion
The hormone insulin, which is secreted by pancreatic cells known as beta-cells, maintains normal levels of glucose in the blood. Impaired insulin secretion results in diabetes. A team of researchers, led by Nina Wettschureck, at the Max-Planck-Institute for Heart and Lung Research, Germany, has now provided new understanding of the signaling pathways that control insulin secretion by mouse beta-cells, potentially providing new targets for the development of approaches to promote insulin secretion in individuals with diabetes.
The release of insulin from beta-cells is largely controlled by levels of blood glucose, with high levels of glucose stimulating increased insulin secretion. However, the nervous system and other inputs also contribute to the control of insulin secretion. In the study, Wettschureck and colleagues found that mice lacking the signaling proteins Gq/G11 in their beta-cells failed to control blood glucose levels and failed to secrete normal levels of insulin. Importantly, these effects were a result of beta-cells not responding to glucose as well as to the nervous system and other stimulators of insulin secretion. Thus, Gq/G11-mediated signaling regulates beta-cell insulin secretion by integrating numerous input signals.
TITLE: The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice
AUTHOR CONTACT:
Nina Wettschureck
Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Phone: 49.6032.705.1214; Fax: 49.6032.705.1204; E-mail: Nina.Wettschureck@mpi-bn.mpg.de
View this article at: http://www.jci.org/articles/view/41541?key=2a174b0f4c89166a395b
Journal
Journal of Clinical Investigation