Clues to autoimmune conditions – and what may protect against them – are revealed by genomic analysis of a blistering skin disease

BUFFALO, N.Y. – Researchers studying a rare, blistering skin condition have made a novel discovery:  they have identified a protective mechanism among genetically susceptible individuals who nevertheless remain healthy. The research is providing new clues to why some individuals who carry genetic risk factors for developing autoimmune diseases, do not go on to develop them.

The paper was published in late August in Genes and Immunity, a Nature Publishing Group journal, by researchers at the University at Buffalo’s Clinical and Translational Research Center. The study of the skin condition Pemphigus vulgaris (PV), is the first genome-wide transcriptional analysis of the disease, which allows for a comprehensive survey of disease-related genes.

“Our findings introduce a potentially paradigm-shifting concept of how autoimmunity in general might be kept at bay in genetically susceptible individuals,” explains Animesh A. Sinha, MD, PhD, Rita M. and Ralph T. Behling Professor and Chair of Dermatology in the UB School of Medicine and Biomedical Sciences and lead author on the paper.

PV is an autoimmune skin disorder that results in the often painful blistering of the skin and mucous membranes. Generally treated with corticosteroids and other immunosuppressive agents, the condition is life-threatening if untreated.

According to Sinha, PV is an excellent model for the study of organ-specific human autoimmune disease.

The research, which was initiated at Weill Medical College of Cornell University/New York Hospital and completed at UB, involved the microarray screening of more than 54,000 genes in the blood of 13 patients with active PV, 8 patients in remission and 10 healthy controls. A subset of controls expressed proteins  in their blood previously identified by Sinha to be PV risk factors, but they exhibited no autoimmune symptoms.

Sinha described the goals of the study. “We wanted to establish genetic signatures relevant to the disease in order to define new molecular markers for diagnosis and prognosis, highlight biological pathways involved in the development of the disease, discover novel targets for therapy and try to pinpoint disease susceptibility genes,” he explains.

“It turns out that healthy individuals with a genetic risk factor for developing PV but who are symptom-free, have down-regulated expression of a set of genes in their blood that we found is up-regulated in patients with PV,” he explains.

“This suggests a ‘protection signature’ in healthy individuals carrying these genetic risk elements,” he says.

“We believe that this is the first time that such a protection signature has been identified for any autoimmune condition,” says Sinha. “Eventually, we might be able to leverage information contained within this ‘natural response’ of the immune system against autoimmunity in order to develop entirely new strategies to block disease.

“With this knowledge, it may be possible to identify genes and immune pathways that can be manipulated in patients and at-risk individuals to prevent, or even reverse, the development of autoimmunity,” he concludes.

The research also may make possible the development of more individually-tailored treatments in an era of personalized medicine, he adds.

Co-authors with Sinha are Rama Dey-Rao,PhD, post-doctoral associate and Kristina Seiffert-Sinha, MD, research assistant professor, both of the UB Department of Dermatology.  

The research was funded by the Colleck Research Fund, UB’s Behling Dermatology Fund and UB.