JCI early table of contents for April 23, 2012

(Press-News.org) EDITOR'S PICK Vitamin D: a double-edged sword in the fight against osteoporosis? | Back to top Vitamin D is renowned for its role in creating strong bones and is a key regulator of serum calcium levels. Calcium is primarily obtained through diet and absorbed through the intestine and into the blood stream. In addition to building bone, calcium is required for a variety of important physiological processes. Vitamin D, which is detected by receptors in bone and intestinal cells, regulates the level of calcium in the blood stream and determines how much should be stored in the skeleton. Several recent clinical trials have examined the effects of vitamin D supplements on the prevention of bone fractures in the elderly; however, the results of these trials have not offered a consensus on the efficacy of these supplements.

In this month's issue of JCI, Dr. Geert Carmeliet and colleagues at the University of Leuven in Leuven, Belgium, investigated how vitamin D affects the skeleton when serum calcium levels are depleted. Using mice that lack the intestinal vitamin D receptor, the researchers showed that the mice still had normal serum calcium levels even when given a low-calcium diet. Additional experiments demonstrated that vitamin D stimulated bone cells to produce factors that removed calcium from bone in a process known as bone resorption in order to maintain normal serum calcium levels. Thus, while vitamin D is important for maintaining serum calcium levels, it can also promote bone density loss.

In an accompanying article, Dr. Cathleen Colón-Emeric and Dr. Kenneth Lyles of Duke University Medical Center in Durham, North Carolina, discuss the clinical implications of this investigation as well as how these findings may explain clinical trial results where vitamin D supplements failed to prevent fractures in elderly patients and, in some cases, were correlated with increased fracture rates.

TITLE:

Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D–induced inhibition of bone mineralization

AUTHOR CONTACT:

Geert Carmeliet

K.U.Leuven, Leuven, BEL

Phone: 32-16-33.07.31; Fax: +32-16-345934; E-mail: geert.carmeliet@med.kuleuven.be

View this article at: http://www.jci.org/articles/view/45890?key=0ad3937749a19a2cec9b

ACCOMPANYING THE ATTENDING PHYSICIAN

TITLE:

How much vitamin D should I take?

AUTHOR CONTACT:

Kenneth Lyles

Duke University, durham, NC, USA

Phone: 919-660-7520; Fax: ; E-mail: kenneth.lyles@duke.edu

View this article at: http://www.jci.org/articles/view/62966?key=16fdb710d185acc126b5

GENE THERAPY Inadvertent changes: how engineered viruses disrupt normal gene expression Gene therapy holds the promise of treating genetic conditions by restoring normal gene function. The field has developed slowly over the last several decades with high importance placed on safety to reduce the chance that introduced genes cause problems. Gene therapy often relies on engineered viruses that use viral machinery to deliver the desired gene product in cells. Two recent studies – led by Fulvio Mavilio of the Istituto Scientifico H. San Raffaele and Eugenio Montini at the San Raffaele Scientific Institute in Milan, Italy – examine how virus integration impacts gene expression with the hope of improving viral vectors used in gene therapy.

When genes are expressed a primary mRNA transcript is spliced so that sequences that do not encode for protein are eliminated. Using different strategies, both research teams identified that integration of viral vectors into the genome can disrupt normal gene splicing, which could impact gene expression and cellular functions. They further showed that cryptic splice sites in the viral vector accounted for many of the changes in gene expression, and that eliminating these site dramatically reduced aberrant transcript formation. Their results provide an effective strategy for modifying viral vectors to reduce unintended consequence and improve safety.

TITLE:

Lentiviral vector integration in the human genome induces alternative splicing and generates aberrant transcripts

AUTHOR CONTACT:

Fulvio Mavilio

University of Modena and Reggio Emilia, Modena, , ITA

Phone: 0039 059 2058076; E-mail: fulvio.mavilio@unimore.it

View this article at: http://www.jci.org/articles/view/61852?key=a9fed7ef30e38cd97362

ACCOMPANYING ARTICLE

TITLE:

Whole transcriptome characterization of aberrant splicing events induced by lentiviral vector integrations

AUTHOR CONTACT:

Eugenio Montini

San Raffaele Scientific Institute - San Raffaele Telethon Institute for Gen, Milan, UNK, ITA

Phone: +39 02 2643 3869; E-mail: montini.eugenio@hsr.it

View this article at: http://www.jci.org/articles/view/62189?key=b2860dc6022b03be1278

ACCOMPANYING COMMENTARY

TITLE:

Gene therapy: too much splice can spoil the dish

AUTHOR CONTACT:

Didier Trono

Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, , CHE

Phone: +41 21 693 17 51; Fax: +41 21 693 95 38; E-mail: didier.trono@epfl.ch

View this article at: http://www.jci.org/articles/view/63066?key=5251bf3db5ea6f45c566

IMMUNOLOGY Novel vaccination strategy improves response to fungal antigens in immunocompromised mice The fungus Aspergillus fumigatus is a major health concern for immune compromised individuals, including sufferers of chronic granulomatous disease. In immune-suppressed patients, transplanting immune cells known as T cells that specifically recognize A. fumigatus provides protection, although the mechanisms promoting long-term anti-fungal T cell memory remain largely unexplored. Dr. Luigina Romani at the University of Perugia sought to define the role of antigen presentation by dendritic cells (DCs) in the generation of T cell memory. Romani's group found in a mouse model of chronic granulomatous disease mice that injection of a purified fungal protein protected animals from A. fumigatus better than immunization with fungal spores. T cell immunity to A. fumigatus following fungal spore immunization depended on CD8 T cells whereas mice immunized with the purified fungal protein required CD4 T cells for protection. Not only did the response of T cells in adaptive immunity vary, but also the mode of antigen presentation by dendritic cells in the innate immune system. Fungal spore immunization relied on dendritic cells presenting antigens through the MHC class I presentation system, while purified protein immunization relied on MHC class II antigen presentation. In the mouse model of chronic granulomatous disease, fungal spore immunization failed to induce a processing step called autophagy that is required to present antigens by the MHC class I system, thus explaining the lack of T cell memory in these animals in response to immunization. In his accompanying commentary, Dr. George S. Deepe, Jr. noted that general induction of autophagy may enhance memory responses in humans. This study highlights several mechanisms by which the innate immune response fine tunes the adaptive that may prove invaluable for vaccine design.

TITLE:

CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease

AUTHOR CONTACT:

Luigina Romani

University of Perugia, Perugia, , ITA

Phone: 0039 75 5857411; Fax: 0039 75 5857411; E-mail: lromani@unipg.it

View this article at: http://www.jci.org/articles/view/60862?key=07522567c196e031e8d3

ACCOMPANYING COMMENTARY

TITLE:

NADPH oxidase regulates efficacy of vaccination in aspergillosis

AUTHOR CONTACT:

George Deepe

University of Cincinnati College of Medicine, Cincinnati, OH, USA

Phone: 513-558-4704; Fax: 513-558-2089; E-mail: george.deepe@uc.edu

View this article at: http://www.jci.org/articles/view/63417?key=5117db6cff99c63c36c4

ALLERGY AND ASTHMA Scratching below the surface of allergic contact dermatitis Skin comes in contact with multiple materials, such as jewelry and perfume, on a daily basis. Most people are able to tolerate this contact; however the immune system of those with allergic contact dermatitis misinterprets these materials as allergenic, leading to a rash. Dr. Bertrand Dubois and colleagues at the Université de Lyon have investigated how skin cells establish tolerance towards these potential allergens. They found that a special cell type, called Langerhans cells, play an important role. It is known that T cells are responsible for the tolerant immune response in healthy individuals, as well as the allergic response for those with allergic contact dermatitis. Here the Dubois group shows that it is the Langerhans cells that bring small pieces of the potential allergen to T cells in mice, initiating tolerance toward the material. Langerhans cells ensure that tolerance is achieved by inactivating the T cells that would mount an allergenic response, and stimulating T cells that will elicit tolerance. Understanding how skin tolerates contact with potential immune activators may lead to the development of a better treatment for the many who suffer with allergic contact dermatitis.

TITLE:

Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8+ T cells and activating Foxp3+ regulatory T cells

AUTHOR CONTACT:

Bertrand Dubois

INSERM-U851, Lyon, UNK, FRA

Phone: 33 437 282 456; Fax: 33 437 282 391; E-mail: bertrand.dubois@inserm.fr

View this article at: http://www.jci.org/articles/view/59725?key=d8e0ba65c88aa94ca7a8

ACCOMPANYING COMMENTARY

TITLE:

Epidermal Langerhans cells tune skin reactivity to contact allergens

AUTHOR CONTACT:

Mark Udey

Dermatology Branch, Bethesda, MD, USA

Phone: 301 496-2481; Fax: 301 496-5370; E-mail: udeym@mail.nih.gov

View this article at: http://www.jci.org/articles/view/63190?key=a4162b9769ee99d282e2

HIV/AIDS Enhancing Immune Responses to Limit Chronic Immune Activation During SIV The persistent immune activation that is typical of HIV-1 and SIV infection results in exhaustion and dysfunction of T and B cells; in T cells, this is marked by increased expression and signaling through the inhibitory receptor programmed death𔂿 (PD-1). Targeting this exhaustion pathway could result in improved antiviral immune responses, but there have been concerns that it would also lead to increased inflammation and immunopathology. In this issue of the JCI, Dyavar Shetty et al. demonstrate that blocking PD-1 actually reduced proinflammatory responses and improved immunity in the gut of SIV-infected rhesus macaques, suggesting that this might have therapeutic potential to prevent opportunistic infections in HIV-infected patients.

TITLE:

Enhancing Immune Responses to Limit Chronic Immune Activation During SIV

COMMENTARY AUTHOR CONTACT:

Jacob D. Estes

NCI/SAIC Frederick Inc., Frederick, MD, USA

Phone: 301-846-7641; Fax: 301-846-5588; E-mail: estesj@mail.nih.gov

View this article at: http://www.jci.org/articles/view/63389?key=d2495c39a1b5485dfa06

ACCOMPANYING RESEARCH ARTICLE

TITLE:

PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques

AUTHOR CONTACT:

Rama Rao Amara

The Yerkes National Primate Research Center, Atlanta, GA, USA

Phone: 404 727 8765; Fax: 404 727 7768; E-mail: ramara@emory.edu

View this article at: http://www.jci.org/articles/view/60612?key=255b24fdc405fab74135