Harvard researchers have examined the factors that help spur the progression of colorectal cancer and identified the integrin [alpha]v[beta]6 as an important risk factor for development of early-stage disease. They further demonstrate that detection of high levels of this molecule is able to predict patient survival for colorectal cancer, a disease that kills over 55, 000 Americans each year. The study will appear online on January 20 in advance of publication in the February 1 print edition of the Journal of Clinical Investigation.
During embryonic development or wound repair, epithelial cells that line cavities within the body often undergo a change of shape and function in a process known as epithelial-mesenchymal transition (EMT). On occasion, this transition can result in the conversion of epithelial cells to tumor cells.
Richard Bates and colleagues, interested in determining what factors disrupt normal EMT and drive the development of tumor cells, examined the EMT process in colon carcinoma cells. They found that EMT involves activation of the protein integrin known as [alpha]v[beta]6 and this protein enhances the tumor-generating properties of these cells. Furthermore, analysis of almost 500 human colorectal carcinoma samples revealed that elevated levels of [alpha]v[beta]6 expression were associated with a significantly reduced survival time of patients in comparison with tumors that express little or low levels of this molecule.
The results define [alpha]v[beta]6 expression as an independent prognostic marker for colorectal cancer and, most significantly, one that is predictive of the outcome of early-stage disease.
TITLE: Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma
AUTHOR CONTACT:
Richard C. Bates
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: 617-667-2816; Fax: 617-975-5531; E-mail: rbates@caregroup.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/press/23183.pdf
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Antibody treatment partially reverses nerve damage in Alzheimer disease
Researchers from Washington University School of Medicine have shown that an antibody treatment administered to the brain surface in mice with Alzheimer disease is capable of rapidly reversing disease-related structural nerve damage. The study will appear online on January 20 in advance of print publication in the February 1 issue of the Journal of Clinical Investigation.
One of the many hallmarks of Alzheimer disease is the presence of deposits or "plaques" made up of amyloid-beta peptide (Abeta) in areas of the brain responsible for memory and cognition. While several approaches to decreasing Abeta production or increasing its clearance from the brain are being studied as potential treatments for Alzheimer disease, it is not known whether, upon clearance of Abeta, if significant structural damage to nerves is reversed, remains, or continues.
Using a mouse model of Alzheimer disease in which a subset of neurons and Abeta in the mouse brain express colored fluorescent proteins that can be visualized in the living animal under a microscope, David Holtzman and colleagues administered an anti- Abeta antibody treatment and monitored the structural changes to nerves within the mouse brains. They observed that following treatment of the brain surface, there was a significant decrease in the amount of structural nerve damage after only 3 days. The study suggests that Abeta deposition leads to ongoing nerve damage and that upon reducing buildup of Abeta in the brain, this structural damage is rapidly reversible.
The imaging technique used will also be a valuable tool for the study of the progression of Abeta deposition in the brain during experimental models of Alzheimer disease and to also assess the effectiveness of treatments including the anti-Abeta antibody treatment described here.
TITLE: Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice.
AUTHOR CONTACT:
David M. Holtzman
Department of Neurology, Washington University, St. Louis, Missouri, USA.
Phone: 314-362-9872; Fax: 314-362-2826; E-mail: Holtzman@neuro.wustl.edu.
View the PDF of this article at: https://www.the-jci.org/press/23269.pdf
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T cells target HIV in a relationship on the rebound
After a break in antiretroviral drug therapy in HIV-positive patients, the virus rebounds and begins to multiply. While this was feared to destroy, perhaps irreversibly, patient HIV-specific CD4+ T cells that are preferentially infected by the virus, it has now be shown to actually boost HIV-specific T cell production and activation, thereby boosting the immune response to the virus.
Scheduled interruption and resumption of antiretroviral treatment of HIV-positive patients has generated hopes of reducing drug toxicities, costs, and total treatment time. However there has been concern regarding how this on and off cycling of drug therapy effects viral replication and the patient's ongoing immune response to viral infection. While it was implied that even at high viral loads a small population of these HIV-specific CD4+ T cells remained, they have been difficult to quantify.
Rodney Phillips and colleagues from the University of Oxford developed a highly sensitive technique to visualize, quantify, and track the HIV-specific CD4+ T cell population in patients with early-stage HIV infection who were given a short, fixed course of antiretroviral therapy. They found that return of viral replication after cessation of treatment does not destroy this important T cell population – their numbers were in fact comparable to the numbers observed during therapy. Furthermore, the turnover of these virus-specific cells was increased and the CD4+ T cells were prompted to mature into what are known as effector cells, capable of exerting an immune function that helps coordinate other cells of the immune system to eliminate the virus.
The study will appear online on January 20 in advance of print publication in the February 1 edition of the Journal of Clinical Investigation.
TITLE: HIV-1–specific CD4+ T lymphocyte turnover and activation increase upon viral rebound.
AUTHOR CONTACT:
Rodney E. Phillips
University of Oxford, Oxford, United Kingdom.
Phone: 44-1865-281230; Fax: 44-1865-281890; E-mail: rodney.phillips@ndm.ox.ac.uk.
View the PDF of this article at: https://www.the-jci.org/press/23084.pdf
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T cell escape from thymic Alcatraz
The immune response must walk a fine line between mounting effective responses against foreign invaders without generating harmful immune responses to self. Just how T cells maintain this tolerance to self is not fully recognized. During T cell maturation, those cells that have a high affinity for self antigen and tissues are normally deleted before they escape the thymus. However some T cells only possess an intermediate affinity for self antigens and therefore escape deletion at this time. As a result, some regulatory mechanism must exist that limits the replication of these moderately self-reactive T cells. Hong Jiang and fellow researchers from Columbia University now describe one such mechanism of control, which involves Qa-1–dependent CD8+ T cells. The study demonstrates how the immune response has developed to safeguard self-tolerance yet also promote our capacity to deal with foreign invaders.
The study will appear online on January 20 in advance of print publication in the February 1 edition of the Journal of Clinical Investigation.
TITLE: An affinity/avidity model of peripheral T cell regulation.
AUTHOR CONTACT:
Hong Jiang
Department of Medicine, Columbia University, New York, New York, USA.
Phone: 212-305-9988; Fax: 212-305-4943; E-mail: hj4@columbia.edu.
View the PDF of this article at: https://www.the-jci.org/press/23879.pdf
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Researchers identify pathway that jumpstarts the autoimmune response in lupus
Patients with systemic lupus erythematosus (SLE) produce autoantibodies to their own proteins and DNA and the resultant inflammation can cause kidney damage, arthritis, and inflammation of the heart and blood vessels. Andrew Luster and colleagues from Harvard Medical School have shown that large aggregates of antibody–antigen complexes that contain DNA (known as DNA-containing immune complexes), isolated from the serum of lupus patients stimulate dendritic cells – cells that identify foreign invaders and jumpstart the immune response. This series of events is dependent on the molecule known as Toll-like receptor 9 (TLR9). Interestingly, serum or immune complexes isolated from patients with other autoimmune rheumatic diseases did not have this effect. The authors found that this stimulation requires the presence of DNA as well as what is known as the Fc part of immunoglobulin G, and that stimulation of dendritic cells in this manner caused the production of many proinflammatory factors that likely contribute to the development of SLE.
The study will appear online on January 20 in advance of print publication in the February 1 edition of the Journal of Clinical Investigation.
TITLE: Human lupus autoantibody–DNA complexes activate DCs through cooperation of CD32 and TLR9.
AUTHOR CONTACT:
Andrew D. Luster
Massachusetts General Hospital and Harvard University Medical School, Charlestown, Massachusetts USA.
Phone: 617-726-5710; Fax: 617-726-5651; E-mail: aluster@partners.org.
View the PDF of this article at: https://www.the-jci.org/press/23025.pdf
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Erratic lymphatics contribute to asthma
Excessive accumulation of fluid, known as edema, occurs in asthma and other inflammatory diseases when fluid drainage through lymphatic vessels is overwhelmed by the amount of plasma leaking from blood vessels. It is unclear to what extent new lymph vessels are able to grow from pre-existing ones – a process known as lymphangiogenesis – in order to compensate for this overload.
Donald McDonald and fellow researchers from University of California, San Francisco, examined mice infected with Mycoplasma pulmonis or in which a viral vector had been used to deliver to the mice the potential pro-lymphangiogenic factors known as VEGF-A, -C, or –D. The authors found extensive growth of new lymphatic vessels associated with airway inflammation after delivery of VEGF-C and –D. Surprisingly, while antibiotic therapy caused bronchial inflammation and blood vessels to regress, these new lymphatic vessels persisted. The study also showed that impaired growth of new lymphatics during airway inflammation may lead to bronchial lymphedema, which worsens the airway swelling, obstruction, and resultant wheezing that asthmatics, for example, experience. Correction of defective lymphangiogenesis may benefit the treatment of asthma and other inflammatory airway diseases.
The study will appear online on January 20 in advance of print publication in the February 1 edition of the Journal of Clinical Investigation.
TITLE: Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation.
AUTHOR CONTACT:
Donald M. McDonald
Department of Anatomy, University of California, San Francisco, California, USA.
Phone: 415-476-2118; Fax: 415-476-4845; E-mail: dmcd@itsa.ucsf.edu.
View the PDF of this article at: https://www.the-jci.org/press/22037.pdf
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An IL-6 sense balances pro- and anti-inflammatory effects during asthma
About 10% of the US population suffers from the chronic inflammation of their airways that we have come to know as allergic asthma. This inflammation is caused by the release from CD4+ T cells of proinflammatory molecules known as cytokines. Susetta Finotto and colleagues from the University of Mainz have examined the role of one such cytokine – interleukin-6 (IL-6) – and it's receptor in the development of allergic asthma. The IL-6 receptor can exist in multiple forms, including the membrane-bound (mIL-6R) or soluble (sIL-6R) forms. Finotto et al. found that the levels of sIL-6R were increased in the airways of asthmatic individuals and blockade of this receptor in mice suppressed airway inflammation. By contrast, blockade of mIL-6R led to an increase in the number of regulatory T cells, which help prevent an overactive inflammatory response and therefore suppress inflammation.
The study demonstrates that IL-6 signaling controls the balance between the production of pro- and anti-inflammatory factors in the airway during allergic airway inflammation. As such, drugs designed to block IL-6 signaling may represent a promising approach to the treatment of the inflammation associated with allergic asthma in humans.
The study will appear online on January 20 in advance of print publication in the February 1 edition of the Journal of Clinical Investigation.
TITLE: The IL-6R a chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo.
AUTHOR CONTACT:
Susetta Finotto
Laboratory of Cellular and Molecular Lung Immunology, University of Mainz, Mainz, Germany.
Phone: 49-06131-3933363; Fax: 49-06131-3933364; E-mail: finotto@mail.uni-mainz.de.
View the PDF of this article at: https://www.the-jci.org/press/22433.pdf
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With a little help from its friends, RANKL drives bone loss
Inflammation and the loss of calcium in bone are complications of rheumatoid arthritis and gum disease. The cell ultimately responsible for bone breakdown is the osteoclast, which is under the influence of a molecule known as RANKL. However our understanding of what triggers RANKL expression and its full effects on the osteoclast remains limited. Steven Teitelbaum and colleagues from Washington University now demonstrate, in mice, that tumor necrosis factor (TNF) induces bone marrow stromal cells to produce RANKL via an interleukin receptor-1 (IL-1)–dependent mechanism, which drives osteoclast production and subsequent bone breakdown. Furthermore, they show that IL-4 is able to block TNF and IL-1–induced RANKL signaling. The administration of IL-4 and/or the targeting of TNF, IL-1 or RANKL with appropriate drugs represent potential avenues of therapeutic development for diseases characterized by inflammation and loss of bone density.
The study will appear online on January 20 in advance of print publication in the February 1 edition of the Journal of Clinical Investigation.
TITLE: IL-1 mediates TNF-induced osteoclastogenesis.
AUTHOR CONTACT:
Steven L. Teitelbaum
Department of Pathology and Immunology. Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314-454-8463; Fax: 314-454-5505; E-mail: teitelbs@wustl.edu.
View the PDF of this article at: https://www.the-jci.org/press/23394.pdf
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Slain brain cells cause mental retardation syndrome
Researchers have created mice lacking the ATRX gene and show how mutations in this gene cause changes within the brain resulting in the severe mental retardation observed in patients with alpha-thalassemia X-linked mental retardation syndrome. Their observations also provide insight into the role of ATRX in normal development of the central nervous system. The study will appear online on January 20 in advance of print publication in the February 1 edition of the Journal of Clinical Investigation.
In their current study, David Picketts and colleagues from the Ottawa Health Research Institute show that loss of ATRX, a chromatin-remodeling protein, during the early stages of growth of the mouse embryo increases the rate of death of cells in the cortex of the mouse brain, resulting in a smaller forebrain and supporting the idea that ATRX is important for neuron survival in the cortex. This mechanism of neuron loss may contribute to the severe mental retardation observed in human patients with mutations in this gene.
TITLE: The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis.
AUTHOR CONTACT:
David J. Picketts
Ottawa Health Research Institute, Ottawa, Ontario, Canada.
Phone: 613-737-6750; Fax: 613-737-8803; E-mail: dpicketts@ohri.ca.
View the PDF of this article at: https://www.the-jci.org/press/22329.pdf
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