Infection: Innate immune response is systemic, not localized

March 1, 2008

First study in humans finds that the innate immune response is systemic, not localized. It bolsters hopes for stimulating this response to better protect against infection.

Key Points

International report - The innate immune response to infection in skin appears to be systemic rather than localized, according to a new study from the Duke University Medical Center. It is believed to be the first time the nature of that response has been demonstrated in humans.

The research focused on two endogenous antimicrobial peptides (AMPs) with broad, potent antimicrobial activity - cathelicidin and human beta-defensin-2 (HBD-2). Decreased expression of AMPs in skin has been associated with increased susceptibility to infection in both animal models and humans.

Researchers chose infective cellulitis because "with a wound, you have trauma, and that could affect expression" of cell signaling proteins, according to lead author Martin E. Stryjewski, M.D, M.H.S. He is affiliated with the Duke Clinical Research Institute in Durham, N.C., and Centro de Educación Médica e Investigaciones Clínicas "Norberto Quimo" (CEMIC), Buenos Aires, Argentina.

The working hypothesis was that an active infection would stimulate expression of AMPs in more distant regions and limit the spread of that infection to those sites.

There is no good baseline data on what constitutes the normal range of expression of these AMPs in humans, so researchers chose to state their findings in terms of a ratio relative to expression in healthy skin from a single control subject, Dr. Stryjewski tells Dermatology Times.

The mean cathelicidin mRNA relative expression was 1.32 in the healthy skin of the controls. It soared to 39.46 in sites with active cellulitis, and remained highly elevated (21.41) at distal normal-appearing sites in those same patients. HBD-2 mRNA levels were 11.65, 20,844 and 201.1, respectively.

The mean serum level of interleukin (IL)-6 was significantly elevated in patients with cellulitis compared with the level in healthy subjects (2867.7 pg/mL vs. 12.4 pg/mL); as were serum levels of IL-8 (27.39 pg/mL vs. 4.91 pg/mL) and IL-10 (75.59 pg/mL vs. 0.51 pg/mL).

Cytokines communicate

"The most important finding is the fact that the skin works as a whole organ," Dr. Stryjewski says.

The AMPS "are overexpressed in cellulitis, but also in other areas of the skin that do not show evidence of cellulitis. The cytokines are communicating these messages, a first alert, so that other skin cells are prepared to defend against bacterial infections," he says.

The study had a single time point for measurement, so it is unclear how these chemical messages are being transmitted. It might be direct cell-to-cell signaling radiating out from the site of infection; systemic signaling through the blood circulatory system; or a combination of the two.

There was surprising variability among the study patients. While most generated expression of HBD-2 at the site of cellulitis that was at least twofold higher than the distal sites, three patients generated higher levels of HBD-2 at the distal sites than at the site of infection. There was an even greater intrapatient variability with expression of cathelicidin, with one patient expressing high levels at the distal site and none at the site of infection.

Dr. Stryjewski is not surprised by that data. The answer may lie in the genetic variability of humans; perhaps other AMPS are responding to the challenge of infection, he says.

"The only thing we can say so far is that there is variability, as shown in many other human fields. We need to do more research," he says.

Future work should focus on the response extended to other epithelial barriers such as the respiratory and gastrointestinal tracts, he says.

For more information:
Stryjewski ME, Hall RP, Chu VH, et al. Expression of antimicrobial peptides in the normal and involved skin of patients with infective cellulitis. (J Infect Dis. 2007 Nov 1;196(9):1425-1430. Epub 2007 Sep 27).