Antimicrobial peptides research suggests novel tx of chronic skin conditions

San Diego - Research shows that human skin plays a proactive role in the body's immune defense, with small peptides having essential antimicrobial functions that protect against injury and insult.

Investigation of peptides suggests potential avenues for therapy in treating chronic skin conditions, including atopic dermatitis, and injuries, such as burns.

"Antimicrobial peptides represent an important part of our immune defense against skin and wound infections, and help to prevent skin bacteria spreading to other parts of the body to produce deeper-seated infection," says Victor Nizet, M.D., associate professor of pediatrics and pharmacy, University of California, San Diego.

Cathelicidins, defensins

Two major families of peptides, cathelicidins and defensins, have been the focus of much research. These defense molecules are not produced in high levels at baseline in normal skin. Instead, resident and infiltrating cells synthesize the peptides when the skin suffers injury or infection, and the peptides also appear in sweat.

Recent findings show the human cathelicidin LL-37 is upregulated in keratinocytes during chronic conditions including psoriasis, lupus erythematosus and contact dermatitis. The defensins hBD-2 and hBD-3 are also induced in keratinocytes of inflamed psoriatic lesions.

Researchers say the expression of the peptides in these conditions correlates with their low rate of secondary infection. Interestingly, however, the expression of LL-37 and hBD-2 are not upregulated in people with atopic dermatitis, who are highly susceptible to secondary bacterial and viral infections.

"The overexpression of antimicrobial peptides in psoriasis might explain the lack of infectious complications in this condition," Dr. Nizet says. The expression could, in fact, play a causative role in the inflammation of psoriasis itself, he adds.

"Since some antimicrobial peptides, such as cathelicidins, have important immunomodulatory properties, a baseline genetic problem leading to antimicrobial peptide overexpression could somehow contribute to skin inflammation of psoriasis."

Infection risk

Meanwhile, the suppression of the peptide in AD could explain that condition's heightened risk of infection.

"The defect in antimicrobial peptide production in the skin (reported in Ong et al, New England Journal of Medicine, 2002) likely explains the high susceptibility of AD to superinfection with staph, strep and HSV (herpes virus), as well as the increased risk of AD patients to having a bad reaction to the vaccinia (smallpox) vaccine," Dr. Nizet says.

In other skin conditions highly susceptible to infection, such as burn wounds and blisters, hBD-2 is dramatically decreased. The mechanism for the peptide loss in such wounds is still unknown.

Certain microbes have evolved their own counter-defenses to our antimicrobial peptides, Dr. Nizet says.

"I believe that relative resistance to antimicrobial peptides might be an important virulence feature of many human bacterial pathogens (e.g., Staph aureus, Group A strep)," he says.

Understanding how these bugs resist being destroyed by antimicrobial peptides might help identify new targets for antibiotic therapy, he says. Further, this "could render the organisms once more susceptible to our innate defense."

Bacteria resistance

In considering other pharmaceutical applications of antimicrobial peptides, creating more resistance in some bacteria concerns some experts. Dr. Nizet suggests identifying and overcoming various obstacles that interfere with normal antimicrobial peptide expression.

"I think a highly promising therapeutic approach would be to learn how antimicrobial peptide production is regulated, and support their expression in the natural context of cells that normally produce them.

"This could be useful in a variety of difficult infectious disease conditions, such as those that are resistant to standard antibiotics, or in prophylaxis patients during high-risk windows for infection, such as cancer chemotherapy, burns and post-surgery."

Research study

In a study published this year, Richard Gallo, M.D., found that vitamin D₃ appears to play an important role in stimulating antimicrobial peptide expression in the skin in response to inflammatory stimuli (J Clin Invest. 2007;117:803-811).

"We demonstrate what we believe to be a previously unexpected role for vitamin D₃ in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection," the study states.