JCI Table of Contents, June 15 2006

June 15, 2006

EGF receptor activation prevents microbes from going more than skin deep

Our skin not only serves as a physical barrier against infection but skin cells themselves can mount an immune response to kill invading microbes by producing antimicrobial polypeptides (AMPs). As overt infection in the skin is a rare event, researchers have theorized that AMPs must not only help fight infection, but play a role in preventing infection from developing in the first place. In a study appearing online on June 15 in advance of print publication in the July issue of the Journal of Clinical Investigation, Ole Sorensen and colleagues from Lund University, Sweden, investigated what triggers AMP production in human skin. Interestingly, they found that AMPs were produced in human skin after sterile wounding of the skin surface, illustrating that exposure to invading microbes is not the sole trigger for the immune response in skin.

The authors went on to show that AMP was produced through activation of the epidermal growth factor receptor (EGFR), which is known to play a role in the normal wound-healing process. The authors found that the antibacterial activity of the skin against the potential skin pathogen Staphylococcus aureus was increased by activation of EGFR, and that the concentrations of AMPs in the epidermis of wounded skin exceeded those necessary to suppress or prevent the growth of foreign microbes. The results of this study demonstrate that wounding of the skin alone, without the presence of microbes, is sufficient to activate defense mechanisms in the skin that can prevent microbial growth and related harmful skin infections.

TITLE: Injury-induced innate immune response in human skin is mediated by transactivation of the epidermal growth factor receptor

AUTHOR CONTACT:
Ole E. Sorensen
Lund University, Lund, Sweden.
Phone: 46-46-222-4472; Fax: 46-46-155-7756; E-mail: Ole_E.Sorensen@med.lu.se.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28422

Combination therapy with a monocloncal antibody and a vaccine leads to tumor rejection

Effector T cells (Teff cells) are involved in activating and directing other immune cells, while regulatory T cells (Tregs) act to curb the over-aggressive responses of the T cell population. Researchers continue to work on devising ways to mobilize anti-tumor Teff cells in order to better shape the immune response to tumors. Previously, James Allison and colleagues from Memorial Sloan-Kettering Cancer Center, New York, demonstrated that an anti-CTLA4 monocloncal antibody used in combination with a vaccine expressing GM-CSF (Gvax) was able to eradicate skin and breast cancer in mice. In a new study appearing online on June 15 in advance of print publication in the July issue of the Journal of Clinical Investigation, this same research group investigated the effects of CTLA4 blockade on the balance between Teff cells and Tregs during tumor rejection.

The authors show that when cancer develops in mouse skin cells, Tregs accumulate in tumors, yet CD8+ Teff cells are underrepresented. They go on to demonstrate that blockade of CTLA4 lifts the inhibition of T cell proliferation and allows both Tregs and Teff cells to proliferate in response to exposure to self-antigen. Interestingly, combination of CLTA4 blockade with Gvax selectively primes the anti-tumor Teff cells for action. This led to greater infiltration of Teff cells into the tumor, and eventually to tumor rejection. Importantly, the authors report that chronic exposure to anti- CLTA4 or to the Gvax/anti-CTLA4 combination therapy does not deplete the number of Tregs, nor their regulatory activity, which suggests that upon completion of this therapy these cells would still be able to control possible adverse immune responses.

TITLE: CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effectors and regulatory T cells

AUTHOR CONTACT:
James P. Allison
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: 212-122-6971; Fax: 212-717-3212; E-mail: allisonj@mskcc.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=27745

Neutrophils in rheumatoid arthritis: how to lessen inflammation but still fight infection

Neutrophils, which quickly congregate at the sites of infection and inflammation, are capable of ingesting microorganisms or other particles. They do this by a process known as "respiratory burst". This involves activation of an NADPH oxidase enzyme, which produces large quantities of superoxide, a reactive form of oxygen that generally kills the ingested organism.

In a study appearing online on June 15 in advance of print publication in the July issue of the Journal of Clinical Investigation, Jamel El-Benna and colleagues from INSERM in Paris examine neutrophils from the joint fluid of rheumatoid arthritis patients and show that GM-CSF and TNF-alpha induce the phosphorylation of a serine residue at position 345 on a component of NADPH oxidase. This event, which occurs via ERK1/2 and MAPK signaling pathways, "primes" the enzyme for action at sites of inflammation. The authors suggest that using drugs that inhibit this phosphorylation step might prevent the exaggerated neutrophil response in inflammatory conditions like rheumatoid arthritis, yet still preserve the ability of neutrophils to fight infection.

TITLE: A specific p47phox-serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites

AUTHOR CONTACT:
Jamel El-Benna
INSERM, Paris, France.
Phone: 33-140-25-85-21; Fax: 33-144-85-62-07; E-mail: benna@bichat.inserm.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=27544

IL-21 receptor plays an essential role in the Th2 immune

During the immune response cells known as Th2 cells express a variety of cytokines (e.g. interleukin-4, -5, and -13), many of which stimulate B cells to proliferate and produce antibodies. This reaction is known as a Th2 immune response. In a study appearing online on June 15 in advance of print publication in the July issue of the Journal of Clinical Investigation, Thomas Wynn and colleagues from the National Institute of Allergy and Infectious Diseases in Maryland, investigated the role of a newly discovered cytokine receptor, the IL-21 receptor (IL-21R), in the Th2 response. To do this they infected mice that lacked IL-21R with 2 parasites known to induce the Th2 response: Schistosoma mansoni and Nippostrongylus brasiliensis. They found that inflammation and liver fibrosis were significantly reduced in infected IL-21R-deficient mice compared to normal infected mice. The authors determined that IL-21R has an essential role in the development of pathogen-induced Th2 immune responses and is an important amplifier of alternative macrophage activation. These findings may have relevance for the understanding and treatment of both inflammatory and chronic fibrotic diseases.

TITLE: The IL-21 receptor augments Th2 effector function and alternative macrophage activation

AUTHOR CONTACT:
Thomas A. Wynn
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Phone: 301-496-4758; Fax: 301-480-5025; E-mail: twynn@niaid.nih.gov.

View the PDF of this article at: https://www.the-jci.org/article.php?id=27727
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