JCI online early table of contents: Sept. 14, 2009

EDITOR'S PICK: What happens when immune cells just won't die? X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency most commonly caused by deficiency in the protein SAP. Following infection with the common virus that causes infectious mononucleosis (also known as mono or glandular fever), boys with XLP often develop an extreme, usually fatal, accumulation of activated immune cells known as cytotoxic T lymphocytes; but the mechanistic link between this and SAP deficiency has not been determined. However, Michael Lenardo and colleagues, at the NIH, Bethesda, have now found that T cells from individuals with XLP are resistant to cell death triggered by repeated stimulation of a cell surface protein complex known as the TCR. As repeated TCR stimulation normally constrains T cell expansion during immune responses, the authors propose that this makes the T cells susceptible to uncontrolled expansion upon infection.

TITLE: Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency

AUTHOR CONTACT:
Michael J. Lenardo
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Phone: (301) 496-6754; Fax: (301) 480-7352; E-mail: lenardo@nih.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=39518

EDITOR'S PICK: The making of mucus in common lung diseases

In the lung, mucus is produced by cells known as goblet cells, which are present in small numbers in the walls of the lungs and airways. Many inflammatory stimuli, including allergens, cigarette smoke, and chronic infections, increase the number and activity of these goblet cells. This leads to mucus hyperproduction and subsequent airway obstruction and contributes to symptoms in several common lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). New research, by Jeffrey Whitsett and colleagues, at Cincinnati Children's Hospital Medical Center, has now determined that a molecular regulatory network controlled by the protein SPDEF governs allergen-induced goblet cell differentiation and mucus production in the lungs of mice. As evidence that the same network is active in goblet cells lining the airways of patients with chronic lung diseases, the authors suggest that SPDEF regulates a molecular network that controls the goblet cell differentiation and mucus hyperproduction associated with common lung disease, including asthma, COPD and CF.

TITLE: SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production

AUTHOR CONTACT:
Jeffrey A. Whitsett
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: (513) 803-2790; Fax: (513) 636-7868; E-mail: jeff.whitsett@cchmc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=39731

EDITOR'S PICK: New function for the protein Bcl-xL: it prevents bone breakdown

In blood cells, the protein Bcl-xL has a well-characterized role in preventing cell death by a process known as apoptosis. However, its function(s) in osteoclasts, cells that slowly breakdown bone (a process known as resorption), has not been determined. In addressing this issue, Sakae Tanaka and colleagues, at The University of Tokyo, Japan, have discovered that not only does Bcl-xL prevent osteoclast apoptosis in mice, it also negatively regulates the bone-resorbing activity of osteoclasts.

To determine the function of Bcl-xL in osteoclasts, the researchers generated mice lacking Bcl-xL only in osteoclasts. As in blood cells, Bcl-xL was shown to promote the survival of osteoclasts. Unexpectedly, however, the mutant mice exhibited marked osteopenia at one year of age. Further analysis indicated that the reduced bone mass was caused by increased osteoclast-mediated bone resorption and identified a potential underlying mechanism. Specifically, Bcl-xL was found to decrease the production of extracellular matrix proteins, which bind cell surface integrin molecules, leading to the activation of c-Src signaling pathways that are already known to promote osteoclast-mediated bone resorption. Thus, in the absence of Bcl-xL, increased production of extracellular matrix proteins leads to increased osteoclast-mediated bone resorption.

TITLE: The antiapoptotic protein Bcl-xL negatively regulates the bone-resorbing activity of osteoclasts in mice

AUTHOR CONTACT:
Sakae Tanaka
The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Phone: 81-3-3815-5411 ext 33376; Fax: 81-3-3818-4082; E-mail TANAKAS-ORT@h.u-tokyo.ac.jp

View the PDF of this article at: https://www.the-jci.org/article.php?id=39819

VIROLOGY: How to distinguish HIV-1 from its relatives

TITLE: The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses

AUTHOR CONTACT:
Frank Kirchhoff
Institute of Virology, University of Ulm, Ulm, Germany.
Phone: 49-731-50065109; Fax: 49-731-50065131; E-mail: frank.kirchhoff@uniklinik-ulm.de

View the PDF of this article at: https://www.the-jci.org/article.php?id=38994

ONCOLOGY: Two drugs are better than one when targeting some lung tumors

TITLE: Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer

AUTHOR CONTACT:
William Pao
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
Phone: (615) 936-3831; Fax: (615) 343-7602; E-mail: william.pao@vanderbilt.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38746

PULMONARY: The inflammatory factor TNF-alpha does a little remodeling in the lungs

TITLE: TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice

AUTHOR CONTACT:
Peter Baluk
University of California at San Francisco, San Francisco, California, USA.
Phone: (415) 476-2118; Fax: (415) 476-4845; E-mail: peter.baluk@ucsf.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=37626

MUSCLE BIOLOGY: Two requirements for muscle wasting to occur in disease situations

TITLE: Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice

AUTHOR CONTACT:
William E. Mitch, M.D.
Baylor College of Medicine, Houston, Texas, USA.
Phone: (713) 798-8350; Fax: (713) 798-5010; E-mail: mitch@bcm.edu.

Jie Du, Ph.D.
Baylor College of Medicine, Houston, Texas, USA.
Phone: (713) 798-2032; Fax: (713) 798-5010; E-mail: jdu@bcm.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=38770

Source: Journal of Clinical Investigation