JCI table of contents -- June 1, 2007

June 01, 2007


Pregnant mom's exposure to flu vaccine kick-starts fetal immune system

Some researchers have hypothesized that the fetus can be exposed to and mount an immune response against allergens to which the mother has been exposed, and this may have an effect on the development of allergic sensitivity (e.g. eczema and asthma) later in an infant's life. However this hypothesis has remained controversial because of an inability to detect antigen-specific T cells in cord blood. Recently, a newly developed technique known as MHC tetramer staining has facilitated the detection of antigen-specific T cells.

In the June 1 issue of the Journal of Clinical Investigation, a team of researchers led by Rachel Miller from Columbia University used this technique to study cord blood B and T cell immune responses following maternal vaccination against influenza with Fluzone during pregnancy. The vaccination of pregnant women against influenza is considered safe and is recommended by the Centers for Disease Control and Prevention. The authors detected anti-Fluzone antibodies in approximately 40% of cord blood specimens examined. These results and further data reported in the study establish that B and T cell responses to antigens occur in utero following maternal vaccination against influenza, supporting the theory that the human neonatal immune system is not deficient or incompetent but, rather, capable of responding to environmental exposures. These conclusions have important implications for determining when immune responses to environmental exposures begin.

TITLE: Antigen-specific immune responses to influenza vaccine in utero


Rachel L. Miller

Columbia University College of Physicians and Surgeons, New York, New York, USA.

Phone: (212) 305-7759; Fax: (212) 305-2277; E-mail: rlm14@columbia.edu

Craig LeMoult

Communications & External Relations

Columbia University Medical Center, New York, New York, USA.

Phone: (212) 305-0820; Fax: (212) 305-4521; E-mail: cel2113@columbia.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=29466


Dietary supplementation with enzyme reverses some kidney disease

In the June 1 issue of the Journal of Clinical Investigation, Marjan Huizing and colleagues from the National Human Genome Research Institute report the first kidney disease caused by a genetic defect in the production of sialic acid. Remarkably, they show that, in mice, disease symptoms can be reversed by addition of a precursor of sialic acid, raising the intriguing possibility that dietary supplementation in this manner may have therapeutic benefit for patients with certain forms of kidney disease.

Humans with mutations in the GNE gene suffer from a neuromuscular disorder known as hereditary inclusion body myopathy (HBIM), in which sialic acid biosynthesis is disrupted and for which there is currently no effective therapy. In the current study, the investigators sought to develop a mouse model to test whether dietary supplementation of sialic acid or its precursor, uridine diphospho-N-acetylmannosamine (ManNAc), could reverse the defect.

In mice, the Gne/Mnk gene encodes ManNAc kinase (GNE/MNK), a key enzyme in sialic acid biosynthesis. In the current study the authors found that mice carrying one of the most common mutations observed in patients with HBIM - a mutation in Gne/Mnk - produced lower amounts of sialic acid, had blood and excess protein levels in their urine, and had structural defects in the glomerulus (a bundle of capillaries in the kidney that are actively involved in the filtration of blood). The authors show that these effects were caused by a reduction in the number of sialic acid residues on critical glomerular proteins such as podocalyxin, which was associated with a breakdown of the glomerular basement membrane and surrounding structures. This breakdown allows red blood cells and proteins that are normally retained in the glomerulus, to pass into the urine. They went on to show that dietary supplementation with ManNAc improved the structure of this membrane and prolonged the life of these animals.

In an accompanying commentary, Susan Quaggin from the University of Toronto comments that "based on the dramatic effects of dietary ManNAc supplementation...along with the simplicity and tolerability of this intervention, it seems plausible that this pathway might be used as a more general therapeutic approach for glomerular diseases of many causes." This is especially attractive as current therapies are associated with significant side effects and are often ineffective.

TITLE: Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine


Marjan Huizing

National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

Phone: (301) 402-2797; Fax: (301) 480-7825; E-mail: mhuizing@mail.nih.gov

Raymond MacDougall

Associate Director for Communications

National Human Genome Research Institute, Bethesda, Maryland, USA.

Phone: (301) 402-0911; Fax: 301-402-4831; E-mail: macdougallr@mail.nih.gov

View the PDF of this article at: https://www.the-jci.org/article.php?id=30954


TITLE: Sizing up sialic acid in glomerular disease


Susan E. Quaggin

The Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.

Phone: (416) 586-4800 ext. 2859; Fax: (416) 586-8588; E-mail: quaggin@mshri.on.ca

View the PDF of this article at: https://www.the-jci.org/article.php?id=32482


Don't judge a book by its cover: Interleukin-1beta turns out to be helpful in Alzheimer's disease

Individuals with Alzheimer's disease (AD) suffer from the formation of amyloid plaques, made up of the peptide amyloid beta (Abeta), in brain tissue. The role, if any, of inflammation in AD remains somewhat of a mystery. Although the levels of some proinflammatory proteins are elevated in AD brain tissue, whether these proteins have negative or positive effects is still unclear. In the June 1 issue of the Journal of Clinical Investigation, M. Kerry O'Banion and colleagues from University of Rochester Medical Center examined a mouse model of AD and found that overexpression of the proinflammatory molecule interleukin-1beta (IL-1beta) in the hippocampus resulted not in the expected worsening of Abeta deposition common to AD, but instead in the lessening of plaque formation in brain tissue.

In an accompanying commentary, Cynthia A. Lemere from Harvard Medical School comments that "the IL-1beta results reported here provide much food for thought and will undoubtedly encourage much-needed future investigation into a positive role for inflammation in neurodegenerative diseases, including AD. Manipulation of the immune system may be a potential therapeutic approach to protect against AD, although further studies are needed to understand all of the downstream effects of this manipulation."

TITLE: Sustained hippocampal IL-1beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology


M. Kerry O'Banion

University of Rochester Medical Center, Rochester, New York, USA.

Phone: (585) 275-5185; Fax: (585) 756-5334; E-mail: kerry_obanion@urmc.rochester.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=31450


TITLE: A beneficial role for IL-1beta in Alzheimer disease"


Cynthia A. Lemere

Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Phone: (617) 525-5214; Fax: (617) 525-5252; E-mail: clemere@rics.bwh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=32356


HIF provides a link between blood and bone development

The network of blood vessels throughout the body provides many essential elements to growing bone, including early forms of bone building cells known as osteoblasts as well as nutrients critical to bone mineralization. However, little remains known about how the vasculature integrates and conveys signals during bone development. In the June 1 issue of the Journal of Clinical Investigation, a report by the research team led by Thomas Clemens from the University of Alabama at Birmingham report significantly advances our understanding of bone-vascular coupling by establishing a critical role for osteoblast hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha in long bone formation in mice. They show that bone formation is controlled by osteoblast HIF-alpha signaling coupled to new blood vessel formation, and this process is dependent on the growth factor VEGF.

In an accompanying commentary, Dwight Towler from Washington University School of Medicine discusses these data and concludes that in addition to examining the contributions of bone-building osteoblasts and bone-resorbing osteoclasts to bone formation and loss, researchers must also consider the contributions of endothelial cells that line blood vessels in their study of bone formation and breakdown.

TITLE: The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development


Thomas L. Clemens

University of Alabama at Birmingham, Birmingham, Alabama, USA.

Phone: (205) 934-2726; Fax: (205) 934-0043; E-mail: tclemens@uab.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=31581


TITLE: Vascular biology and bone formation: hints from HIF


Dwight A. Towler

Washington University School of Medicine, St. Louis, Missouri, USA.

Phone: (314) 454-7434; Fax: (314) 454-8434; E-mail: dtowler@im.wustl.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32518


Inhibiting thrombin may protect against risks of thickened and hardened arteries

In atherosclerotic cardiovascular disease, arteries thicken and harden to such a severe degree that they may become clogged, causing the formation of a clot (thrombosis). The protein thrombin is a known trigger of thrombosis and researchers have wondered whether thrombin contributes to longer-term structural changes in the arterial wall that promote narrowing and clotting. In the June 1 issue of the Journal of Clinical Investigation, Toshio Matsumoto and colleagues from The University of Tokushima Graduate School of Health Biosciences, Japan, argue that it can. They show that a partial loss of heparin cofactor II (HCII), which is capable of inhibiting thrombin, exacerbates the formation of arterial lesions following arterial injury or in response to abnormally elevated levels of lipids in the blood in mice. They suggest that this possibly occurs through excessive thrombin signaling through protease-activated receptors. They go on to show that these symptoms were improved by supplementation of human HCII to HCII-deficient animals, which suggests that HCII may be of potential therapeutic use against atherosclerosis.

In an accompanying commentary, Eric Camerer from the Cardiovascular Research Institute at the University of California, San Francisco, discusses the effects of thrombin generation on unblocked arteries and avenues of future research with respect to potential therapies that inhibit thrombin action.

TITLE: Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II-deficient mice


Toshio Matsumoto

The University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan.

Phone: 81-88-633-7119; Fax: 81-88-633-7407; E-mail: toshimat@clin.med.tokushima-u.ac.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=27095


TITLE: Unchecked thrombin is bad news for troubled arteries


Eric Camerer

Cardiovascular Research Institute, University of California San Francisco, USA.

Phone: (415) 476-6172; Fax: (415) 476-8173; E-mail: eric.camerer@ucsf.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=32473


Anti-inflammatory effects of adiponectin in the circulation

Adiponectin is a protein hormone excreted into the bloodstream by fatty tissue and it plays a role in the suppression of inflammation-associated metabolic disorders that may result in type 2 diabetes, obesity, and atherosclerosis. In the June 1 issue of the Journal of Clinical Investigation, Rosario Scalia and colleagues from Thomas Jefferson University studied the vascular protective actions of adiponectin in mice. The authors found that adiponectin-deficient (Ad-/-) mice possessed high levels of nitric oxide and a 5-fold increase in the adhesion of leukocytes to the blood vessel wall. This effect could be blocked and reversed by the addition of the recombinant globular adiponectin domain (gAd). Importantly, prior administration of gAd was also shown to protect healthy mice against the induction of leukocyte-endothelium interactions. The study demonstrates a clear role for normal levels of adiponectin in the regulation of leukocyte-endothelium interactions in mice. The data also suggest that gAd may serve as a potential pharmacological treatment of abnormal endothelial dysfunction occurring in pathological conditions associated with adiponectin deficiency.

TITLE: Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo


Rosario Scalia

Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Phone: (215) 503-6409; Fax: (215) 503-2073; E-mail: Rosario.Scalia@jefferson.edu

Barry J. Goldstein

Jefferson Medical College, Philadelphia, Pennsylvania, USA.

Phone: (215) 503-1272; Fax: (215) 923-7932; E-mail: Barry.Goldstein@jefferson.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=29623

JCI Journals

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