JCI table of contents: May 10, 2007

Patients with the syndrome leukocyte adhesion deficiency (LAD) III suffer from recurrent infections and an increased tendency to bleed. The exact defect responsible for this disease remains unclear. In a study appearing online on May 10 in advance of publication in the June print issue of the Journal of Clinical Investigation, Denisa Wagner and colleagues from Harvard Medical School show that mice engineered to lack the gene CalDAG-GEFI have a combination of defects in their leukocytes and platelets, similar to those observed in LAD-III patients.

In response to injury of the blood vessel lining, blood platelets adhere to fibrin, endothelial cells lining the vessel wall, and to each other via adhesion receptors known as integrins, to form what is often referred to as a blood clot. Wagner and colleagues evaluated the role of CalDAG-GEFI in integrin activation. They observed significant defects in beta1- and beta2-integrin–mediated adhesion of CalDAG-GEFI–deficient neutrophils, which impaired the response of these cells to injury and inflammation. In addition, they found that CalDAG-GEFI was essential for the activation of beta1 integrins on the surface of platelets and that CalDAG-GEFI-/- mice were unable to form blood clots. The data indicate that CalDEG-GEFI regulates beta integrin function and suggests that this gene may be defective in patients with LAD-III.

TITLE: Mick lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III

AUTHOR CONTACT:
Denisa Wagner
CBR Institute for Biomedical Research and Harvard Medical School, Boston, Massachusetts, USA.
Phone : (617) 278-3344; Fax : (617) 278-3368; E-mail : wagner@cbr.med.harvard.edu

Wolfgang Bergmeier
CBR Institute for Biomedical Research and Harvard Medical School, Boston, Massachusetts, USA.
Phone : (617) 278-6617; Fax : (617) 278-3368; E-mail : bergmeier@cbrinstitute.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=30575

Enlargement or overgrowth of heart cells known as cardiomyocytes – cardiac hypertrophy – is a common event in many heart diseases, and occurs in an effort to restore stresses on the heart wall to normal levels. A protein called ST2 that is produced by cardiomyocytes is a potentially useful biomarker in heart diseases, however its role in heart disease has been unclear. In a study appearing online on May 10 in advance of publication in the June print issue of the Journal of Clinical Investigation, Richard Lee and colleagues from Harvard Medical School show that ST2 and its recently identified ligand IL-33 work together to protect the heart in times of cardiac stress.

The authors showed that deletion of ST2 in mice increased cardiac hypertrophy as well as the thickening and scarring of heart tissue, and decreased survival of these animals in response to cardiac stress. Administration of IL-33, which is made by cells called fibrbroblasts, improved pathological changes and survival in response to cardiac stress in mice with intact ST2, but not in ST2-/- mice. The study suggests that IL-33/ST2 signaling is a crucial mechanism for protecting the heart and shows that cardiomyocytes and cardiac fibroblasts signal to each other in times of cardiac stress.

TITLE: IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system

AUTHOR CONTACT:
Richard Lee
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone : (617) 768-8272; Fax: (617) 768-8270; E-mail: rlee@partners.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30634

Glucocorticoids are widely used as drugs to treat inflammatory conditions such as arthritis or dermatitis and they act in part by suppressing T cell function. In a study appearing online on May 10 in advance of publication in the June print issue of the Journal of Clinical Investigation, Carlo Riccardo and colleagues from the University of Perugia show how the protein glucocorticoid-induced leucine zipper (GILZ) mediates the effects of the glucocorticoid dexamethasone.

Using a variety of biochemical and cellular approaches, the authors show that GILZ interacts directly with the signaling molecule Ras and forms a trimeric complex with Ras and another signaling protein Raf. Ras normally activates a number of signaling pathways involved in cell growth and survival, however the authors found that GILZ diminished the activation of Ras/Raf and in turn inhibited Ras- and Raf-dependent T cell proliferation. When GILZ was inactivated the antiproliferative effects of dexamethasone were inhibited, resulting in increased T cell proliferation. Together, the data indicate that GILZ acts as a negative regulator of Ras- and Raf-induced cell proliferation and as an important mediator of the antiinflammatory effects of glucocorticoids.

TITLE: GILZ mediates the antiproliferative activity of glucocorticoids by negative regulation of Ras signaling

AUTHOR CONTACT:
Carlo Riccardi
University of Perugia, Italy.
Phone : 39-075-5857467 ; Fax: 39-075-5857405 ; E-mail: riccardi@unipg.it.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30724

Common variable immunodeficiency (CVID) encompasses a varied group of immunodeficiency syndromes characterized by B cell defects, low immunoglobulin levels, and recurrent bacterial infections. Recently, Raif Geha and colleagues from Harvard Medical School reported that the gene TNFRSF13B, which encodes a protein known as TACI, is mutated (a C104R missense mutation) in about 10% of CVID patients. However, just how this TACI mutation causes CVID remained unknown. In a study appearing online on May 10 in advance of publication in the June print issue of the Journal of Clinical Investigation, these same authors provide insight into the molecular mechanisms of how TACI mutations cause CVID.

TACI is a cell surface receptor and is mainly expressed on B cells. The authors examined mice carrying a C76R TACI mutation (the equivalent of the human C104R mutation) and found that mutated TACI is unable to bind ligand. Both the human and mouse TACI mutants were shown to pre-associate with normal TACI, independent of ligand, indicating that the mutation was acting in a dominant-negative manner. More importantly, the human TACI mutant can interfere with signaling by normal TACI without interfering with the surface expression of normal TACI or its ability to bind ligand. Thus, ligand-independent preassociation of C104R TACI mutants with normal TACI mutants provides a potential explanation for how the C104R mutation may disrupt TACI signaling in B cells and impair the ability of B cells from CVID patients to produce immunoglobulin.

TITLE: Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID)

AUTHOR CONTACT:
Raif Geha
Children’s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA.
Phone : (617) 919-2482; Fax : (617) 730-0528; E-mail: raif-geha@childrens.harvard.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=31023