Elias Delivers Dohi Memorial Lecture to Japanese Dermatology Association

On Saturday, June 15, 2013 Dr.  Peter Elias delivered the Dohi Memorial Lecture at the annual meeting of the Japanese Dermatological Association in Yokohama, Japan.  This invited lectureship is the highest honor accorded each year by the JDA.  The title of his presentation: “Treating Atopic Dermatitis at the Source: Correctve Barrier Repair Based upon New Pathogenic Insights.”

Elias Awarded Honorary Membership in Japanese Society

Following his invited lectureship on June 15, 2013,  Dr. Elias was awarded an honorary membership in the Japanese Dermatological Association at its 112th annual meeting.

Featured in Allure May 2013 Issue

Allure-Kindle-Cover-May-2013Our work on antihistamines and the skin also featured in the May 2013 issue of Allure magazine.  This work demonstrates that these commonly used drugs are applied directly to the skin they can improve the function of the skin barrier and also have potent anti-inflammatory effects.  This work holds promise for the development of new treatments for common skin disorders like atopic dermatitis and psoriasis.

Our Research on Antihistimines and the Skin Barrier Featured on Allure.com

A new treatment for common skin diseases like psoriasis and eczema (or atopic dermatitis), or other skin conditions with a defective skin barrier, is the hope raised by recent work from the Elias laboratory and featured in Allure this month.  These studies demonstrate that when antihistamines are applied topically to the skin, they improve the skin barrier.  This suggests that creams or ointments containing anithistamines of the type that do not cause sedation as a side effect could provide a safe and effective way to treat inflammatory skin disorders caused in part by a defective skin barrier, like eczema and psoriasis.

Antihistamines and the Skin Barrier

Publication: Topical antihistamines display potent anti-inflammatory activity linked in part to enhanced permeability barrier function.
Lin TK, Man MQ, Santiago JL, Park K, Roelandt T, Oda Y, Hupe M, Crumrine D, Lee HJ, Gschwandtner M, Thyssen JP, Trullas C, Tschachler E, Feingold KR, Elias PM.
J Invest Dermatol. 2013 Feb;133(2):469-78. . Epub 2012 Sep 27.

Synopsis and Significance: Usually, antihistamines are given by mouth to reduce itch.  Although they also have potent anti-inflammatory activity in tissue culture, this has not been observed when they are taken orally.  Because we have  identified high levels of histamine receptors in the epidermis, we hypothesized that they might be more effective if administered directly to the skin. We show here that topical antihistamines not only improve skin barrier function, but they also display potent anti-inflammatory activity in mouse models of several different skin diseases, such as atopic dermatitis.  These studies could lead to a paradigm shift in the ways that antihistamines are used to treat skin disorders in the future (i.e., as topical rather than internally-administered agents).  This work was recently feature on an Allure post.

Histamine and the Skin Barrier

Allergy Magazine January 2013Publication: Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model.

Gschwandtner M, Mildner M, Mlitz V, Gruber F, Eckhart L, Werfel T, Gutzmer R, Elias PM, Tschachler E.  Allergy. 2013 Jan;68(1):37-47. Epub 2012 Nov 15.

Synopsis and Significance:  Histamine is another neurotransmitter, classically associated with allergic responses. We demonstrate here that it also binds to two receptors that are present in abundance in the outer part of skin, the epidermis. While it is known to mediate  itch arising deeper in the skin, in epidermis it decreases the production of critical proteins that form the cells of the stratum corneum.  In other words, histamine is ‘bad’ for the skin’s permeability barrier, and antihistamines can improve barrier function.

Evolution of Skin Pigmentation

Publication: Re-appraisal of current theories for the development and loss of epidermal pigmentation in hominins and modern humans.
Elias PM, Williams ML. J Hum Evol. 2013 Mar 8. [Epub ahead of print]

Synopsis and Significance: In this paper we propose that the evolution of dark skin pigmentation in human ancestors was driven by their need to preserve body water in the hot and dry climate of the equatorial African savannah. This, the most critical function of skin, is provided by the skin’s permeability barrier. Dark pigmentation generates a superior barrier and allowed these hominins to leave the forest and hunt on the hot, dry savannahs with a lesser risk of dehydration.

We further propose that this theory is in greater concordance with reproductive fitness and with skin biology than the more widely espoused theories for the evolution of pigmentation, such as protection from genotoxic effects of sunlight and/or from photodegradation of folic acid.

Contrary to the prevailing hypothesis that pigment was subsequently lost to allow more sunlight to penetrate and to stimulate vitamin D3 production by the skin, we note that modern humans, who left Africa for northern climes, no longer needed the effects of melanin on their skin barrier competence, because they now resided in colder and moister habitats. We propose that production of melanin was reduced over time as a form of metabolic conservation – to save energy for more urgent needs.

Ceramides and Generation of the Skin’s Barrier

cover exper dermatolPublication: Ceramides stimulate caspase-14 expression in human keratinocytes.
Jiang YJ, Kim P, Uchida Y, Elias PM, Bikle DD, Grunfeld C, Feingold KR.
Exp Dermatol. 2013 Feb;22(2):113-8. doi: 10.1111/exd.12079.

Synopsis and Significance:

Ceramides are a key family of lipids, made by the epidermis, that are  required for the normal  function of the skin’s permeability barrier.  They also serve as cellular signals to trigger epidermal differentiation, resulting in formation of the permeability barrier.

Caspase 14 is an epidermal protease that regulates key events leading to barrier formation, including the breakdown of profilaggrin to filaggrin, a step in the formation of the corneocyte (or stratum corneum cell). Here, we identify a potential ‘feed-forward’ regulatory mechanism, whereby ceramides, destined for the lipid-based water barrier, also increase caspase-14 production and thereby enhance the formation of the cells that too are critical components of the skin’s barrier.

Stress and Innate Immunity of the Skin

mole cell biol feb 2013 coverPublication: A novel role of a lipid species, sphingosine-1-phosphate, in epithelial innate immunity.
Park K, Elias PM, Shin KO, Lee YM, Hupe M, Borkowski AW, Gallo RL, Saba J, Holleran WM, Uchida Y. Mol Cell Biol. 2013 Feb;33(4):752-62. Epub 2012 Dec 10.

Synopsis and Significance: The antimicrobial peptide, LL-37, a cathelicidin, is a critical component of the skin’s innate immune defense against infectious organisms. It’s production by epidermal cells, ‘keratinocytes’, is known to be regulated by vitamin D3 through the vitamin D receptor.  Here we  identify a new signaling molecule, sphingosine-1-phospate.  It increases production of  LL-37 when the epidermis is under stress; e.g., following ultraviolet light exposure, during wound healing, or under attack by pathogenic micro-organisms. Conversely, vitamin D  does not stimulate LL-37 production when the epidermis is stressed in this manner, but only under normal, baseline conditions.  Identification of this new signaling mechanism will allow the development of new topical compounds, both synthetic and natural, that could be used to enhance epidermal innate immunity and antimicrobial defense, when the skin is under microbial attack from the outside.

Skin Cancer and Atopic Dermatitis

Publication: Letter to the Editor in response to the commentary, ‘Does a History of Eczema Predict a Future Basal Cell Carcinoma?
Elias PM, Williams ML.  J Invest Dermatol. 2013 Jan 22.  [Epub ahead of print] No abstract available.  PMID: 23340733

Synopsis and Significance:  Recently, a large Veterans Administration study showed an unexpected association between basal cell carcinoma, the most common ultraviolet-induced skin cancer, and a prior or current history of atopic dermatitis. In an accompanying commentary, it was suggested that the link could be the result of the patients’ prior treatments for eczema,  which often involves the topical use of immune suppressing drugs.  Systemic immune suppression is known to increase risk of skin cancer, particularly in individuals who have received organ transplants.

In our letter,  we note, however, that sun-induced cancers tend to occur at different sites than those most commonly involved with eczema, which might have been previously treated with topical anti-inflammatory agents.  In addition, we note that atopic dermatitis is highly associated with an inherited defect in a protein required for skin barrier function, called filaggrin. This association of atopic dermatitis with filaggrin deficiency is strongest for persons of Northern European ancestry – the same population at highest risk for skin cancer.

We also note that loss of filaggrin results in downstream depletion of a molecule called urocanic acid. This molecule is the most important filter of ultraviolet light in outermost layer of skin, the stratum corneum.  Hence, deficiency of urocanic acid would allow more damaging rays of light to enter the skin, and could account for the association between basal cell skin cancers and a history of atopic dermatitis.

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