Immune system protein LL-37 critical in controlling replication of vaccinia virus

Scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), have identified a defect in the immune response of people with the skin condition atopic dermatitis that puts them at risk of developing serious complications following smallpox vaccination.

Led by Donald Y.M. Leung, M.D., Ph.D., of the National Jewish Medical and Research Center in Denver, the researchers used laboratory-grown human skin cells to show that an immune system protein called LL-37 is critical in controlling replication of vaccinia virus, the live virus that is the key component in standard smallpox vaccine.

The investigators are part of NIAID's Atopic Dermatitis and Vaccinia Network, which was created in 2004 to integrate clinical and animal research aimed at reducing the risk of eczema vaccinatum, a potentially deadly complication of smallpox vaccination. Eczema vaccinatum occurs almost exclusively in people who have a history of atopic dermatitis, a common, non-contagious skin disorder also known as eczema.

"This new research, the first to be published by Atopic Dermatitis and Vaccinia Network scientists, illuminates one potential mechanism leading to eczema vaccinatum and improves our understanding of the immune responses to smallpox vaccine of people with atopic dermatitis," says NIAID Director Anthony S. Fauci, M.D.

Published in the March 2006 issue of Immunity, the study details how the overproduction in skin cells of inflammation-promoting molecules called interleukin-4 and interleukin-13 (IL-4 and IL-13) hampers LL-37 activity in people with atopic dermatitis. LL-37, a small protein produced in skin cells, is part of the body's first line of defense against invaders. Earlier research by Dr. Leung and his colleagues suggested that LL-37 is critical in controlling the spread of vaccinia virus.

In the current study, the investigators used skin samples taken from people with atopic dermatitis (as well as samples taken from healthy volunteers without skin disease and from people with another skin condition called psoriasis) to further investigate how dysfunctions in the immune response of people with eczema set the stage for eczema vaccinatum. When exposed to vaccinia virus, the skin samples from healthy volunteers and from those with psoriasis reacted by producing more LL-37. As a result, the replication of the virus was controlled and eventually halted. In contrast, LL-37 production was minimal in skin samples from people with atopic dermatitis and vaccinia replication was poorly controlled. Next, the scientists exposed skin samples from people with atopic dermatitis to vaccinia, and then added LL-37. With the LL-37 supplement, the skin cells successfully controlled the viral replication.

Dr. Leung and his group then looked more closely at why vaccinia infection fails to induce LL-37 production in atopic dermatitis skin. Comparing immune responses of skin cells grown in the lab from healthy volunteers and from people with atopic dermatitis, the researchers found that the latter skin samples produced excessive amounts of IL-4 and IL-13. Adding IL-4 and IL-13 to skin cells from healthy volunteers prior to vaccinia exposure reduced levels of LL-37 production. Conversely, when the scientists applied IL-4- and IL-13-neutralizing antibodies to skin samples from people with atopic dermatitis, LL-37 production increased significantly.

Together, these findings suggest a rationale for new treatment approaches to eczema vaccinatum, notes Dr. Leung. One approach involves developing drugs to mimic the action of LL-37 or developing LL-37-containing creams that could be applied to the skin in order to boost its ability to contain vaccinia virus infection. Another approach could be to develop agents to neutralize IL-4 and IL-13. Although no such drugs are currently marketed, compounds that can neutralize IL-4 and IL-13 are under study as possible asthma and allergy treatments, Dr. Leung says, and might also be applied to eczema vaccinatum treatment.

Smallpox vaccine, which is made with live vaccinia virus (a close relative of the virus that causes smallpox), has not been routinely given in the United States since the early 1970s. But recent concerns about the possibility of a bioterrorist attack using smallpox virus prompted authorities to reinstate voluntary smallpox vaccination for specific groups, such as military personnel. In the first five months of 2003, the U.S. Department of Defense vaccinated more than 450,000 personnel against smallpox. During this period, the majority of those who deferred vaccination cited atopic dermatitis or other skin conditions as the main reason.