A human 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, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports in an early online publication in Nature.
“This combination of the peptide and self-DNA activates the same immune response pathway as a virus does,” says senior author Michel Gilliet, M.D., assistant professor in M. D. Anderson’s Departments of Immunology and Melanoma Medical Oncology.
Researchers believe this response is both a likely key driver of autoimmune disease and an integral part of an early warning system that flags tissue damage to launch a protective inflammatory response to injury.
“We show that this pathway may drive autoimmunity in psoriasis, a chronic inflammatory skin disease,” Gilliet says. But the key peptide, called both LL37 and CAMP, is also heavily expressed in other autoimmune diseases such as inflammatory bowel disease and rheumatoid arthritis.
LL37 provides a new potential target to block in the treatment of chronic inflammatory diseases and a possible component for vaccines against infectious diseases and cancers, the authors note.
The team tracked down this new pathway by studying the activation of important immune defense cells in psoriasis. Plasmacytoid dendritic cells (pDCs) are highly specialized to recognize viral and other microbial infections.
They engulf a virus and set off an immune system cascade to fight the infection by producing interferons. Gilliet and colleagues previously showed that pDC activation in psoriatic skin drives the development of human psoriasis.
“These dendritic cells normally do not respond to self-DNA,” Gilliet explains. This unresponsiveness prevents the cells from launching an attack on the body’s own tissue.
However, researchers had accumulated evidence of a connection between skin damage with release of self-DNA and pDC activation in psoriatic skin leading to disease formation. They lacked a molecular mechanism connecting these factors.
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 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,” 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.
A grant from the M. D. Anderson Cancer Foundation funded the project, while part of the work was supported by grants from the Deutsche Forschungsmemeinschaft.