JCI table of contents: January 19, 2006EDITOR'S PICK
Vitamin D signals to prevent bone loss during osteoporosis
The risk of bone fracture resulting from falls increases as we age due to bone loss and osteoporosis. Physicians have routinely prescribed vitamin D and vitamin D–related drugs to retard bone loss, but until now, little was known about the specific targets of vitamin D in bone. In a study appearing online on January 19 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation, Kyoji Ikeda and colleagues from the National Center for Geriatrics and Gerontology in Japan examine mice with severe osteoporosis and show that oral vitamin D treatment inhibits the production of the protein c-Fos. As c-Fos plays a key role in the development of osteoclasts, which are the specialized cells responsible for bone breakdown and resorption, the authors also show that the vitamin D–mediated inhibition of c-Fos prevented bone loss through a suppression of osteoclast development. In addition, the authors used mice whose ovaries had been removed, in a more "human-like" model of osteoporosis, to screen for other vitamin D–like agents with c-Fos–suppressing activity. They identified a new vitamin D–related compound (DD281) that could prevent bone loss in these mice more potently than the natural vitamin D. These findings clarify how vitamin D helps limit bone resorption in conditions such as osteoporosis, and suggest that synthetic vitamin D analogs, including DD281, may warrant clinical trial to asses their potential in the treatment of osteoporosis and other related disorders of bone resorption.
TITLE: c-Fos protein as a target of anti-osteoclastogenic action of vitamin D, and synthesis of new analogs
National Center for Geriatrics and Gerontology, Obu, Japan
Phone: 81-562-46-8094; Fax: 81-562-46-8094; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=24742
Making new blood vessels: keeping the lines of sight open
The creation of new blood vessels, known as angiogenesis, is a process used to supply oxygen and nutrients at sites of tissue injury. Angiogenesis is known to be stimulated during hypoxia (low oxygen conditions, when new vessels are needed). However, the mechanisms by which hypoxia leads to new vessel formation is poorly understood. In the mouse retina specialized cells called astrocytes regulate angiogenesis by producing a structural support protein known as fibronectin during hypoxia, but until now it was unclear what triggered this pro-angiogenic event. In a new study appearing online on January 19 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation, Akiyoshi Uemura and colleagues from the RIKEN Center for Developmental Biology in Japan show that a nuclear protein called Tlx in pro-angiogenic astrocytes is regulated by oxygen levels. Mice that were genetically engineered so that they would not express Tlx (known as "Tlx knockout" mice) show a complete absence of retinal blood vessels even though other pro-angiogenic markers are expressed. To determine whether the astrocytes were altered, the authors analyzed fibronectin levels in normal and Tlx knockout mouse retinas. The Tlx knockout astrocytes did not form fibronectin matrices, thus explaining the failure of these mice to undergo retinal angiogenesis. The authors also discovered that Tlx is induced by low oxygen levels and that Tlx gene levels are downregulated during hyperoxia (too much oxygen), revealing that Tlx is an oxygen-sensing switch in retinal astrocytes. Together these studies demonstrate that oxygen-sensing Tlx plays an indispensable role in the development of healthy vascularized retinas via the regulation of formation of the fibronectin scaffold by pro-angiogenic astrocytes.
TITLE: Tlx acts as a pro-angiogenic switch by regulating extracellular assembly of fibronectin matrices in retinal astrocytes
RIKEN Center for Developmental Biology, Kobe, Japan
Phone: 81-78-306-1924; Fax: 81-78-306-1895; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=25964
TLR2 both triggers and tames the immune response
It is an established premise that invading pathogens release antigens that bind to Toll-like receptors (TLR ligands) on the surface of various cells of the immune system. This event stimulates specialized immune cells to release secreted proteins that activate other immune cells, such as T cells, to join the fight to destroy invading bacteria or fungi. The proliferation and activity of T cells is carefully controlled by a subset of cells known as regulatory T cells (Tregs). Treg depletion may allow an overzealous immune response to turn against the body's own tissues, resulting in autoimmune disorders such as arthritis and diabetes, while overactive Tregs can hinder the immune response against a foreign pathogen. In a study in mice appearing online on January 19 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation, Gosse Adema and colleagues at the Radboud University Nijmegen Medical Centre in The Netherlands, reveal that the type 2 TLR (TLR2) lies at the center of how Tregs know when to suppress and when not to suppress the immune response. The authors show that during infection of mice with the fungus Candida albicans, TLR2 ligands bind directly to TLR2 on Tregs and promote Treg proliferation. Interestingly, this binding also temporarily inhibits the suppressive activity of these Tregs, preventing them from suppressing the ongoing immune response, and thus ensuring clearance of the infection. Once the fungus is cleared by the immune system, the source of the TLR2 ligand is no longer present, and the Tregs regain their suppressive capabilities. This explains how TLR2 can directly control Treg function and allows Tregs to behave differently before, during, and after infection. This control mechanism contributes to the balance between the mounting of an effective immune response and the development of autoimmunity.
TITLE: Toll-like receptor 2 controls expansion and function of regulatory T cells
Gosse J. Adema
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Phone: 31-24-361-7600; Fax: 31-24-354-0339; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=25439
Clues to rare immunodeficiency disorder identified
Patients who suffer from the rare, often fatal X-linked proliferative disease (XLP) have a severe deficiency of special immune cells called CD27+ (or memory) B cells, and are highly susceptible to infection with Epstein Barr Virus (EBV). XLP patients are characterized by hypogammaglobulinemia, infectious mononucleosis, and/or lymphoma. It was previously shown that XLP CD27+ cells also express a marker of naïve B cells (IgM+) and it was unclear whether these IgM+CD27+ B cells in XLP patients could produce immunoglobulin (Ig) or function as normal memory B cells. New research by Stuart Tangye and colleagues at the Centenary Institute of Cancer Medicine and Cell Biology in Sydney, Australia demonstrates that these cells are indeed functional memory B cells. Their study, appearing online on January 19 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation, analyzed 17 XLP patients from 11 different families. The authors carefully assessed several features of the spleen, blood, and tonsils and show that although the germinal centers (GCs, where activated B cells mature) were infrequent and poorly formed in XLP patients, the production of IgM by IgM+CD27+ B cells was similar to that of normal individuals. These results show that the IgM+CD27+ memory B cells in XLP patients are not completely devoid of immune function. In fact, although XLP patients are highly susceptible to EBV infection they demonstrate normal resistance to other pathogens, which the authors suggest may be due to the mature IgM that is ultimately produced by these IgM+CD27+ B cells.
TITLE: Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype–switched, memory B cells in X-linked lymphoproliferative disease
Stuart G. Tangye
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, New South Wales, Australia
Phone: 61-2-9565-6127; Fax: 61-2-9565-6103; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=25720
Mouse study suggests a risk of serious side effects with peptide vaccines
A new study in mice appearing online on January 19 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation sheds light on the reasons some vaccines may be more harmful than the diseases they prevent. The work, performed by researchers at the Scripps Research Institute in La Jolla, California, has implications for vaccine design. The group, lead by J. Lindsay Whitton, was looking to understand the role of T cells in clearing viral infections. The authors show that the administration of synthetic peptide vaccines, designed to induce strong immune responses, can trigger serious, and sometimes lethal, shock by stimulating special T cells, known as CD8+ T cells, that recognize epitope(s) contained within the vaccine. These CD8+ T cells are central to clearing primary viral infections and are involved in protecting the body from subsequent infection. As a result these CD8+ T cells have become important targets of stimulation in the design of peptide vaccines. The authors injected mice with one of two different types of virus and subsequently immunized them with the cognate synthetic peptides. The animals rapidly developed severe hypothermia, and many died within hours. The main signaling molecule responsible for these effects was found to be a toxic protein known as tumor necrosis factor (TNF), produced by CD8+ T cells. The authors suggest that care must be taken when administering powerful immunogens such as peptide vaccines to individuals who may have a large pre-existing pool of epitope-specific CD8+ T cells.
TITLE: Peptide vaccination of mice immune to LCMV or vaccinia virus causes serious CD8+ T cell–mediated, TNF-dependent immunopathology
J. Lindsay Whitton
The Scripps Research Institute, La Jolla, California, USA
Phone: 858-784-7090; Fax: 858-784-7380; E-mail: [email protected]
View the PDF of this article at: https://www.the-jci.org/article.php?id=25608
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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