LL37 binds to self-DNA, which allows it to enter pDCs thus triggering the production of interferon-alpha.
A peptide that acts as a natural antibiotic against invading microbes can also bind to the body’s own DNA and trigger an immune response in the absence of an infection, reports scientists at The University of Texas M. D. Anderson Cancer Center.
The scientists found that the peptide, LL37 or CAMP, drives autoimmunity in psoriasis. They believe that it may also play a role in other autoimmune disorders, as the peptide is heavily expressed in such maladies as inflammatory bowel disease and rheumatoid arthritis.
Previously, the researchers had accumulated evidence of a connection between skin damage with release of self-DNA and plasmacytoid dendritic cell (pDC) activation in psoriatic skin leading to disease formation. pDCs are highly specialized to recognize viral and other microbial infections. These cells engulf a virus and set off an immune system cascade to fight the infection by producing interferons.
In the current study, the M. D. Anderson team identified LL37 as the key ingredient in psoriatic tissue that activates the dendritic cells. They demonstrated that LL37 does so by binding to the self-DNA to form a structure that allows it into the dendritic cells, just as if it were an invading microbe. The complex is taken up inside the endosomes of the pDCs, where it connects to a sensitive internal receptor that launches production of interferon-alpha, setting off the immune response.
“We think LL37’s 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,” says senior author, Michel Gilliet, M.D., assistant professor in the departments of Immunology and Melanoma Medical Oncology. In the case of autoimmune disease, however, LL-37 remains persistently produced, well beyond the temporary jolt needed to dampen infection and promote healing, the team explains.
The research is reported in an early online publication in Nature.