In a series of lab experiments, they identified LL37 as the key ingredient in psoriatic tissue that activates the dendritic cells. The peptide is a member of a family of antimicrobial peptides long known to defend against infection through their ability to directly destroy bacteria and viruses.
The team then demonstrated that LL37 activates the dendritic cells by binding to the self-DNA to form a structure that allows it into the dendritic cells, as if it were an invading microbe.
The complex is taken up inside a walled-off chamber in the pDCs called an endosome, where it connects to a sensitive internal receptor that launches production of interferon-alpha, setting off the immune response.
We think LL37s normal job is to alert the immune system to tissue damage and stimulate a temporary inflammatory response that enhances resistance to infection and initiates wound healing, Gilliet says.
When tissue is injured, cells are destroyed and they spill DNA into the areas surrounding the cells. LL37, released by epithelial cells, binds this extracellular DNA, which is then taken up by the pDCs to launch the protective inflammatory immune response, Gilliet says.
But in the case of autoimmune disease, LL-37 remains persistently produced, well beyond the temporary jolt needed to dampen infection and promote healing.
Gilliet says follow-up research to better understand the pathway and to exploit it to treat autoimmune disease and cancer is under way.
|Contact: Scott Merville|
University of Texas M. D. Anderson Cancer Center