From American Academy of Dermatology, Summer Conference, August, 2012

Today's date: October 28, 2012

Researcher discovers ‘killer bees’ spawning alopecia areata

Angela M. Christiano, PhD

Alopecia areata is like a swarm of bees in the form of killer CD8 T cells attracted by NKG2D ligands. So concluded Angela M. Christiano, PhD, during her presentation, "Genetics of Alopecia Areata: What's All the Buzz About?" for Friday's Hot Topics session.

"We wanted to learn whether we could use modern genetic techniques to dissect the genetic architecture of alopecia areata and to understand the genes that control those interactions that go wrong between the hair follicle and the immune system," said Dr. Christiano, professor, departments of dermatology and genetics and development, Columbia University, New York.

Alopecia areata results from the collapse of the immune privilege of the hair follicle, she noted. The disease has a high heritability among family members, with a 10-fold increased risk for first-degree relatives of affected individuals.

"It has taken us 15 months to go from finding the genes to actually talking about drug targets," Dr. Christiano said.

Common pathways in other autoimmune diseases (rheumatoid arthritis, celiac disease, and type 1 diabetes) involve NK ligands in target organs. In alopecia areata, research has discovered an overexpression in the hair follicle of the ULBP3 gene, which encodes the NKG2D ligand.

"The aberrant expression of NK-activating ligands in genetically predisposed individuals may induce or exacerbate disease," Dr. Christiano said.

In mouse studies, she and fellow researchers wanted to test the presence and define the nature of these alopecia areata killer bees — NKG2D ligands — in mice. In mice with alopecia areata, they found the skin and lymph nodes loaded with these NKG2D ligand killer bees, while the control mice had none. Also, these NKG2D ligand killer bees are "armed and dangerous with IL-15 receptors."

"As a biomarker, we want to see these killer bees go down to zero," Dr. Christiano said. "The question came up about whether we could cut off the fuel supply for these killer bees, so one thing that has been very well defined about these immune cells is that they require IL-15 as fuel for their growth."

Previous research has found that the blockade of IL-15 appears effective in treating rheumatoid arthritis, psoriasis, and celiac disease, so she and fellow researchers initiated additional mouse studies to determine the effectiveness of anti-IL-15R (beta) blockade in preventing alopecia areata. What they discovered is that anti-IL-15R (beta) eliminates NKG2D ligand killer bees from the blood.

"We are very interested in IL-15 blockade either in infusion or topical form," Dr. Christiano said. "Downstream, from IL-15 are a number of kinases, particularly kinases JAK1 and JAK2, and there are drugs in development, particularly topicals, for those targets."

She also addressed how the existing drug, abatacept, targets CTLA4-Ig, which has proven to prevent onset of alopecia areata in the C3H-HeJ mouse model. These findings, she noted, provide essential pre-clinical data supporting the efficacy of CTLA4-Ig.

This research "is just a flavor of how we can use genetics and genomics to dissect these complicated diseases at a very fine level and think about ways of intervening at every step," Dr. Christiano said.