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zoom RSS アトピー性皮膚炎・湿疹の原因遺伝子

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画像 湿疹やアトピーの原因は最近の研究で、皮膚の保湿作用をするフィラグリンという蛋白の遺伝子異常からおきているという。
 慢性湿疹はアレルギー疾患であるとされてきたが、最近の遺伝研究から、湿疹の半数は皮膚のバリアが不完全あることからくるとわかった。
 2006年にアーウィンマクレーン(スコットランドのダンディー大学の遺伝学者)とアランアービン博士(ダブリンの小児科の皮膚科学者)がfilaggrinフィラグリン(自然の保湿作用を持つ皮膚たんぱく質)の遺伝子異常によると報告した。中等症以上の湿疹患者では1/3〜1/2で異常がみられ、小児喘息の発症リスクが2倍になるという。
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A New View on the Roots of Itchy Skin
By INGFEI CHEN
http://health.nytimes.com/ref/health/healthguide/esn-eczema-ess.html?ref=health

画像Eczema can affect various parts of the body, including the eyelid.
Dr. P. Marazzi/Photo Researchers, Inc.

In Brief:
The prevailing theory that chronic eczema is primarily an allergic disease has been challenged in recent years.

Genetic studies suggest that a defective, leaky skin barrier is the initial cause in up to half of eczema cases seen by doctors.

Topical drugs that reduce inflammation are still the mainstay of treating rashes, but new genetic findings highlight the importance of keeping the skin barrier intact by frequent use of moisturizers.

For millions of people who suffer from chronic eczema, life can become a hellish existence in which patches of dry skin become red and inflamed and constantly cry out: scratch me!

“It’s like having poison oak or poison ivy 24 hours a day, seven days a week, forever,” said Vicki Kalabokes, chief executive of the nonprofit National Eczema Association in San Rafael, Calif.

The best treatments, like prescription creams and ointments that tamp down inflammation, can provide some relief. Antihistamines may aid nighttime sleep, and a good skin-care routine of slathering on moisturizers and avoiding irritating soaps also helps. But for many patients who still scratch through the night and hide crusted, oozing infections under long sleeves and pants, the medical world has little more to offer.

That could change, thanks to recent research that has led to new thinking about why chronic eczema happens. In a sort of chicken-versus-egg turnabout, researchers have challenged the prevailing dogma that chronic eczema is mainly an allergic disease that leads to skin dryness and rashes. Instead, a growing number of experts believe that a structural defect of the skin is the primary culprit, instigating the immunologic problems seen in patients.

For decades, allergists embraced the idea that eczema arose from an immune overreaction inside the body, leading to inflammation and cracked, itchy skin. Skin cracking, in turn, let in more allergens, irritants and microbes that further fueled the cycle. The theory was supported by the observation that eczema sufferers show high blood levels of an immune defense protein called IgE and often develop immune-related ailments like asthma, food allergies and hay fever.

Many dermatologists, on the other hand, have argued that allergies do not cause chronic eczema. Over the last decade, some proposed that an intrinsic defect of the skin occurs first and then causes immunological weirdnesses. In other words, trouble develops from the outside in.

The major breakthrough came in 2006, when Irwin McLean, a geneticist at the University of Dundee in Scotland, and Dr. Alan Irvine, a pediatric dermatologist at Our Lady’s Hospital for Sick Children in Dublin, Ireland, reported that chronic eczema was rampant among families carrying a defective gene for filaggrin, a skin protein that serves as a natural moisturizer. Without it, the usually impervious barrier formed by the skin is compromised by cracking.

“Our work has really said, ‘Look, it’s not all just about the immune system,’ ” Dr. Irvine said.

The flawed gene fails to produce filaggrin, which normally pulls together protein filaments and flattens out dead cells to form the skin’s outermost layer. The molecule also holds water in, moisturizing the barrier.

About one-third to half of all children and adults with moderate to severe chronic eczema have a nonfunctioning filaggrin gene, Dr. Irvine said. Researchers have identified nearly 40 filaggrin mutations, including variations specific to Asian populations. And evidence suggests that the risk of childhood asthma is nearly doubled in those who inherit one of these mutations, but only after eczema arises first.

With a dry, filaggrin-deficient barrier, almost anything on the patient’s skin ― dust mites, pollen, food proteins or bacteria ― can easily get through, said Dr. Jon M. Hanifin, a dermatologist at Oregon Health & Science University in Portland who was not involved in the genetic work. The new thinking is that the foreign intrusions activate immune cells to respond and crank out IgE, causing the inflamed skin lesions. That process may also prime the immune system to overreact to specific allergens, leading eventually to asthma, hay fever and food allergies.

The genetic findings could help explain why chronic eczema has grown increasingly common in industrialized countries in the past two decades, Dr. Irvine said. Environmental factors like increases in pollutants or use of soaps, air conditioning and central heating may dry out or irritate a defective skin barrier.

But debate rages on over how much of eczema may still originate from allergic disease. It is unclear whether a leaky skin barrier is always the initial culprit. Many people who do not have a filaggrin mutation still get eczema, and eczema does not occur in everyone who carries the genetic defect, noted Dr. Donald Leung, an immunologist at the National Jewish Medical and Research Center in Denver.

While a genetic skin barrier defect is important, he said, the immune and environmental factors also play key contributing roles in this complex disease. Dr. Leung’s own research has revealed that inflammation itself can reduce filaggrin levels in the skin.

On the other hand, mutations in additional skin barrier genes may yet be discovered.

It may be possible to create eczema drugs enhancing filaggrin production. For now, the genetic studies magnify the need to protect the dry, damaged skin barrier ― and keep out irritants and allergens ― by hydrating it and keeping it intact. That means that along with using anti-inflammatory medications, it is crucial for eczema patients to follow the basic advice on moisturizing to prevent flare-ups, Dr. Hanifin said.

For infants, the research even raises the possibility of prevention.

“It points up to us that maybe we can reduce the impact of asthma and allergic rhinitis by treating the skin in kids with eczema early,” he said, “by moisturizing right from day one.”

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Nature Genetics 38, 337 - 342 (2006)
Published online: 29 January 2006; | doi:10.1038/ng1743
Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris

Frances J D Smith1, Alan D Irvine2, Ana Terron-Kwiatkowski1, Aileen Sandilands1, Linda E Campbell1, Yiwei Zhao1, Haihui Liao1, Alan T Evans3, David R Goudie4, Sue Lewis-Jones5, Gehan Arseculeratne5, Colin S Munro6, Ann Sergeant6, Gráinne O'Regan2, Sherri J Bale7, John G Compton7, John J DiGiovanna8, 9, Richard B Presland10, 11, Philip Fleckman11 & W H Irwin McLean1

1 Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

2 Department of Paediatric Dermatology, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland.

3 Pathology, Tayside University Hospitals NHS Trust, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

4 Clinical Genetics, Tayside University Hospitals NHS Trust, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

5 Dermatology, Tayside University Hospitals NHS Trust, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

6 Department of Dermatology, South Glasgow University Hospitals NHS Trust, Glasgow, G51 4TF, UK.

7 Gene Dx, Gaithersburg, Maryland 20877, USA.

8 Division of Dermatopharmacology, Department of Dermatology, Brown Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA.

9 Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

10 Oral Biology, School of Dentistry, University of Washington, Seattle, Washington 98195, USA.

11 Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
Correspondence should be addressed to W H Irwin McLean w.h.i.mclean@dundee.ac.uk
Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren1. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approx4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

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Nature Genetics 38, 441 - 446 (2006)
Published online: 19 March 2006; | doi:10.1038/ng1767
Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Colin N A Palmer1, 15, Alan D Irvine2, 15, Ana Terron-Kwiatkowski3, Yiwei Zhao3, Haihui Liao3, Simon P Lee1, David R Goudie4, Aileen Sandilands3, Linda E Campbell3, Frances J D Smith3, Gráinne M O'Regan2, Rosemarie M Watson2, Jo E Cecil5, Sherri J Bale6, John G Compton6, John J DiGiovanna7, 8, Philip Fleckman9, Sue Lewis-Jones10, Gehan Arseculeratne10, Ann Sergeant11, Colin S Munro11, Brahim El Houate12, Ken McElreavey12, Liselotte B Halkjaer13, Hans Bisgaard13, Somnath Mukhopadhyay13 & W H Irwin McLean3

1 Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.

2 Department of Paediatric Dermatology, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland.

3 Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.

4 Clinical Genetics, Tayside University Hospitals NHS Trust, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

5 The Bute Medical School, University of St. Andrews, St. Andrews, Fife, Scotland, UK.

6 GeneDx, Gaithersburg, Maryland 20877, USA.

7 Division of Dermatopharmacology, Department of Dermatology, Brown Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA.

8 Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

9 Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.

10 Dermatology, Tayside University Hospitals NHS Trust, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

11 Department of Dermatology, South Glasgow University Hospitals NHS Trust, Glasgow G51 4TF, UK.

12 Reproduction, Fertility and Populations, Institut Pasteur, 75724 Paris, France.

13 Danish Paediatric Asthma Centre, Copenhagen, University Hospital, DK-2900 Gentofte, Copenhagen, Denmark.

14 Children's Asthma and Allergy Research Unit, Maternal and Child Health Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.

15 These authors contributed equally to this work.
Correspondence should be addressed to W H Irwin McLean w.h.i.mclean@dundee.ac.uk
Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades1 and now affects approx20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable2. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated3. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approx9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

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