Researchers discover genetic basis for eczema, new avenue to therapies

Dec. 21, 2012 — Researchers at Oregon State University have announced the discovery of an underlying genetic cause of atopic dermatitis, a type of eczema most common in infancy that also affects millions of adults around the world with dry, itchy and inflamed skin lesions.

The findings were just published in PLoS ONE, a professional journal, and may set the stage for new therapeutic approaches to this frustrating syndrome, which is difficult to treat and has no known cure. Eczema is also related to, and can sometimes cause asthma, a potentially deadly immune dysfunction.

Pharmaceutical scientists at OSU found in laboratory studies that eczema can be triggered by inadequate Ctip2, a protein and master regulator that affects other genetic functions. They have identified two ways in which improper function of Ctip2 can lead to eczema.

In a recent publication, they found that Ctip2 controls lipid biosynthesis in the skin, the fats that are needed to help keep skin healthy and hydrated. In the new study, they discovered that Ctip2 suppresses TSLP, a cytokine protein produced by skin cells that can trigger inflammation.

Levels of this inflammatory TSLP, which is ordinarily undetectable in human skin, were found to be 1,000 times higher in laboratory animals that had been genetically modified to have no Ctip2 production in their skin.

"In these studies, we've basically shown that inadequate Ctip2 is reducing the lipids in skin that it needs to stay healthy, protect itself and perform its function," said Arup Indra, an associate professor in the OSU College of Pharmacy. "At the same time this can allow unwanted formation of proteins that trigger inflammation. The skin's ability to resist inflammation is going down just as the amount of inflammation is going up, and the underlying reason is that Ctip2 is not doing its job."

"Either or both of these problems can lead to eczema," Indra said.

Atopic dermatitis is associated with a dysfunctional immune response, but researchers have never understood the underlying cause. Existing treatments use moisturizers to try to protect skin, and in difficult cases powerful steroid drugs can help, but they often have significant unwanted side effects, especially in long-term use.

"With a better understanding of just what is causing eczema on a genetic basis, we should be able to personalize treatments, determine exactly what each person needs, and develop new therapies," Indra said. "This might be with topical compounds that increase Ctip2 expression in skin cells, or customized treatments to restore an individual person's lipid profile. In the future, systemic epigenetic modification might even be possible."

The creation at OSU of the laboratory model to study this issue is also of considerable importance, Indra said. There's evidence it could be used to screen for drugs with potent anti-inflammatory activities.

Eczema is a persistent skin rash that can be fairly common in infants or youth, which some research indicates may be linked to food or pollen allergens. Most people outgrow it as they reach adulthood, but some suffer from the debilitating condition their entire life.

"Our skin is the largest organ in the human body and one of the most important," Indra said. "It's our first barrier of defense, is in a constant battle against external insults, is influenced by both genetics and the environment, and has to be finely tuned to do many jobs. In eczema, this process begins to break down."

Eczema allows significant loss of fluids through the skin, allows allergens to penetrate, and in severe cases can cause a systemic inflammatory response.

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The above story is reprinted from materials provided by Oregon State University.

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Journal Reference:

Zhixing Wang, Ling-juan Zhang, Gunjan Guha, Shan Li, Kateryna Kyrylkova, Chrissa Kioussi, Mark Leid, Gitali Ganguli-Indra, Arup K. Indra. Selective Ablation of Ctip2/Bcl11b in Epidermal Keratinocytes Triggers Atopic Dermatitis-Like Skin Inflammatory Responses in Adult Mice. PLoS ONE, 2012; 7 (12): e51262 DOI: 10.1371/journal.pone.0051262

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Skin cells reveal DNA's genetic mosaic

Nov. 18, 2012 — The prevailing wisdom has been that every cell in the body contains identical DNA. However, a new study of stem cells derived from the skin has found that genetic variations are widespread in the body's tissues, a finding with profound implications for genetic screening, according to Yale School of Medicine researchers.

Published in the Nov. 18 issue of Nature, the study paves the way for assessing the extent of gene variation, and for better understanding human development and disease.

"We found that humans are made up of a mosaic of cells with different genomes," said lead author Dr. Flora Vaccarino, the Harris Professor of Child Psychiatry at the Yale Child Study Center. "We saw that 30 percent of skin cells harbor copy number variations (CNV), which are segments of DNA that are deleted or duplicated. Previously it was assumed that these variations only occurred in cases of disease, such as cancer. The mosaic that we've seen in the skin could also be found in the blood, in the brain, and in other parts of the human body."

The longstanding belief has been that our cells have the same DNA sequence and this blueprint governs the body's functions. The Yale team's research challenges this dogma. Some scientists have hypothesized that during development, when DNA is copied from mother to daughter cells, there could be deletions, duplications and changes in the sequence of the DNA, and an entire group of genes could be affected. This premise has been incredibly difficult to test, but Vaccarino and colleagues have done so in this new study.

The team used whole genome sequencing to study induced pluripotent stem cells lines (iPS), which are stem cells developed from a mature-differentiated cell. The team grew cells taken from the inner upper arms of two families. The team spent two years characterizing these iPS cell lines and comparing them to the original skin cells.

While observing that the genome of iPS cells closely resembles the genome of skin cells from which they originated, the team could identify several deletions or duplications involving thousands of base pairs of DNA. The team then performed additional experiments to understand the origin of those differences, and showed that at least half of them pre-existed in small fractions of skin cells. These differences were revealed in iPS cells because each iPS line is derived from one, or very few, skin cells. Vaccarino said these iPS lines could act as a magnifying glass to see the mosaic of genomic differences in the body's cells.

"In the skin, this mosaicism is extensive and at least 30 percent of skin cells harbor different deletion or duplication of DNA, each found in a small percentage of cells," said Vaccarino. "The observation of somatic mosaicism has far-reaching consequences for genetic analyses, which currently use only blood samples. When we look at the blood DNA, it's not exactly reflecting the DNA of other tissues such as the brain. There could be mutations that we're missing."

"These findings are shaping our future studies, and we're doing more studies of the developing brains of animals and humans to see if this variation exists there as well," Vaccarino added.

Vaccarino worked with a team of researchers from several laboratories, including those of Mark Gerstein, Sherman Weissman, Alexander Eckehart Urban, working together under the auspices of the Program in Neurodevelopment and Regeneration. Other authors on the study include Alexej Abyzov, Jessica Mariani, Dean Palejev, Ying Zhang, Michael Seamus Haney, Livia Tomasini, Anthony Ferrandino, Lior A. Rosenberg Belmaker, Anna Szekely, Michael Wilson, Arif Kocabas, Nathaniel E. Calixto, Elena L. Grigorenko, Anita Huttner, and Katarzyna Chawarska.

The study was funded by NIH/NIMH, the Simons Foundation, and the State of Connecticut.

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The above story is reprinted from materials provided by Yale University. The original article was written by Karen N. Peart.

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Journal Reference:

Alexej Abyzov, Jessica Mariani, Dean Palejev, Ying Zhang, Michael Seamus Haney, Livia Tomasini, Anthony F. Ferrandino, Lior A. Rosenberg Belmaker, Anna Szekely, Michael Wilson, Arif Kocabas, Nathaniel E. Calixto, Elena L. Grigorenko, Anita Huttner, Katarzyna Chawarska, Sherman Weissman, Alexander Eckehart Urban, Mark Gerstein, Flora M. Vaccarino. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature, 2012; DOI: 10.1038/nature11629

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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