A research team led by St. Jude Children’s Research Hospital immunologists has revealed a previously unknown immune machinery that goes awry to trigger the inflammatory disease neutrophilic dermatosis. Neutrophilic dermatoses are a heterogeneous group of autoinflammatory skin disorders that include Sweet’s syndrome, pyoderma gangrenosum, and subcorneal pustular dermatosis and may occur with cancers such as leukemia as well as infections or inflammatory bowel disease.

Mapping the biological machinery underlying the disease’s inflammation is important because there are no drugs that specifically target the wide array of similar autoinflammatory diseases. Autoinflammatory diseases occur when the hyperactive innate immune system attacks the body.

Currently, the only treatments for such disorders are strong immunosuppressive drugs that also render patients susceptible to infection.

The study was led by Thirumala-Devi Kanneganti, Ph.D., a member of the St. Jude Department of Immunology. The findings appear today in the journal Immunity. First authors were Prajwal Gurung, Ph.D., a postdoctoral fellow in the Kanneganti laboratory, and Gaofeng Fan, Ph.D., of Cold Spring Harbor Laboratory.

Abnormalities in the PTPN6 gene have been implicated in human diseases such as pyoderma gangrenosum, multiple sclerosis, leukemia and psoriatic arthritis.

The researchers used a strain of gene-altered mouse in which the activity of a protein encoded by the Ptpn6 gene was “dialed down.” The mice developed inflammatory skin disease similar to neutrophilic dermatosis in humans. Like humans with the disorder, the mice appear normal when first born, but as they age, they developed the inflammatory disease.

How does disease ensue in the Ptpn6 mutant mice? What are the key pathways that are regulated by the Ptpn6 gene? Kanneganti and her colleagues previously discovered in a seminal study published in Nature that IL-1 alpha is the key master regulator that provokes uncontrolled immune response in the Ptpn6 mutant mice. But the machinery linking Ptpn6 and IL-1 alpha was a “black box,” Kanneganti said.