Editors’ Picks from Experimental Dermatology


After a brief hiatus, we welcome back Editors' Picks from Experimental Dermatology.  Enjoy the latest discoveries!

 

 

Identification of HLA-E as susceptibility lucus of pemphigus vulgaris: One more step towards a genetic understanding of the disease

Pemphigus vulgaris (PV) is a devastating and potentially life-threatening autoimmune skin blistering disease (AIBD). In PV autoantibodies directed against desmoglein 3 (Dsg) and, in some cases, Dsg 1, cause intraepidermal blister formation above the basal layer of keratinocytes (1). The availability of antibody-transfer PV animal models (2) has contributed to a more detailed understanding of the events that lead to blister formation in the skin. In contrast, little is known regarding mechanisms leading to the loss of tolerance to Dsg 1 and 3 in patients with PV. Transfer of Dsg-reactive T cells has proven the crucial contribution of T cells to autoantibody production (3), and several HLA loci have been reported to be associated with PV (4). In addition, the first genome-wide association study recently identified ST18 as the first gene outside the HLA locus to be associated with PV (5). Collectively, this points towards a strong contribution of the genome to PV susceptibility. In the study by Bhanusali et al (6) a possible association of PV with HLA-E was investigated. The HLA-E genetic region is located between the classical class I genes HLA-C and HLA-A on chromosome 6p21 in humans, and there have not been any reports regarding HLA-E alleles and PV. In a cohort of 52 PV patients and 51 healthy controls Bhanusali et al document an association of HLA-E*0103X with susceptibility to PV (6). This novel observation further extends our understanding of the genetic control of PV. The identification of PV susceptibility loci may in the future help to identify individuals at risk to develop the disease. Furthermore, unraveling of the pathways encoded by these susceptibility loci may also help to identify novel therapeutic targets for this still difficult-to treat condition. In my personal opinion, this may be best approached by combined analysis of the so far existing patient cohorts collected by several groups.

REFERENCES:

(1) Stanley JR, Amagai M. Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. N Engl J Med. 2006;355(17):1800-10.

(2) Bieber K, Sun S, Ishii N, Kasperkiewicz M, Schmidt E, Hirose M, Westermann J, Yu X, Zillikens D, Ludwig RJ. Animal models for autoimmune bullous dermatoses. Exp Dermatol. 2010 Jan;19(1):2-11. doi: 10.1111/j.1600-0625.2009.00948.x

(3) Ujiie H, Shimizu H. Evidence for pathogenicity of autoreactive T cells in autoimmune bullous diseases shown by animal disease models. Exp Dermatol. 2012; Dec;21(12):901-5. doi: 10.1111/exd.12011

(4) Sinha AA. The genetics of pemphigus. Dermatol Clin. 2011;Jul;29(3):381-91, vii. doi: 10.1016/j.det.2011.03.020.

(5) Sarig O, Bercovici S, Zoller L, Goldberg I, Indelman M, Nahum S, Israeli S, Sagiv N, Martinez de Morentin H, Katz O, Baum S, Barzilai A, Trau H, Murrell DF, Bergman R, Hertl M, Rosenberg S, Nöthen MM, Skorecki K, Schmidt E, Zillikens D, Darvasi A, Geiger D, Rosset S, Ibrahim SM, Sprecher E. Population-specific association between a polymorphic variant in ST18, encoding a pro-apoptotic molecule, and pemphigus vulgaris. J Invest Dermatol. 2012; Jul;132(7):1798-805. doi: 10.1038/jid.2012.46.

(6) Bhanusali DG, Sachdev A, Rahmanian A, . Gerlach JA, Tong JC, Seiffert-Sinha K and  Sinha AA, HLA-E*0103X is associated with susceptibility to Pemphigus vulgaris. Exp Derm. 2013, Feb;22(2):108-12. doi: 10.1111/exd.12077

Selected by Ralf J. Ludwig, Lübeck, Germany

 

 

Are therapeutic effects of anti-acne agents mediated by activation of FoxO1 and inhibition of TORC1?

Acne pathogenesis has recently been linked to decreased nuclear FoxO1 levels and increased mTORC1 activity. Melnik and Schmitz (2013) presented an interesting hypothesis: anti-acne agents either enhance nuclear FoxO-activity or inhibit mTORC1. Their arguments are based on the more or less well-known effects of some acne treatments. Tetracyclines inhibit NFκB activation and TNFα secretion, and their suppression of IKKβ/mTORC1 signaling may attenuate sebaceous lipogenesis. It is believed that isotretinoin increases nuclear FoxO1 levels. Azelaic acid-mediated mitochondrial ROS-release may upregulate FoxO expression and inhibit mTORC1, effects which are similar with benzoyl peroxide.  Androgen-mediated stimulation of mTORC2 and consecutive mTORC2-mediated activation of Akt inhibits FoxO1 activity and stimulates androgen receptor transcriptional activity. The hypothesis of a common mode of action of anti-acne agents as either FoxO-enhancers or mTORC1-inhibitors provides an approach of potential great clinical importance for the development of new anti-acne agents, such as FoxO-enhancers or synthetic and natural mTORC1-inhibitors, like resveratrol and epigallocatechin-3-gallate.

REFERENCES:

Melnik BC, Schmitz G Are therapeutic effects of anti-acne agents mediated by activation of FoxO1 and inhibition of TORC1? Exp Dermatol. 2013 Jul;22(7):502-4. doi: 10.1111/exd.12172.

Selected by L. Emtestam, Stockholm, Sweden

 

 

Pretreatment of epidermal growth factor promotes primary hair recovery via the dystrophic anagen pathway after chemotherapy-induced alopecia

Several treatments for chemotherapy-induced alopecia (CIA) have been reported, including scalp tourniquet, scalp cooling, and administration of ammonium trichloro(dioxoethylene-o,o')tellurate, minoxidil, or vitamin D3. Many agents have been reported to effectively prevent CIA in animal models including interleukin-1, fibroblast growth factors, keratinocyte growth factors, cyclin-dependent kinase inhibitors, caspase-3 inhibitors, N-acetylcysteine, parathyroid hormone receptor antagonists, and laminin-511. However, many treatments and agents are not definitively effective against CIA, such as epidermal growth factor (EGF). Although its protective effect was demonstrated by Jimenez JJ et al. in 1992, the associated mechanism remains obscure.

Seung Hwan Paik et al. (2013) reported that topical EGF application decreased the chemotherapy-induced apoptosis of keratinocytes in the hair matrix. Additionally, EGF retarded the progression of CIA and promoted primary recovery after CIA via the dystrophic anagen pathway, suggesting that treatments that promote the dystrophic anagen pathway may decrease chemotherapy-induced damage to hair follicles.

Although topical EGF application is very effective in the treatment of CIA, drug cost may need to be addressed. It is also possible that topical EGF application may promote tumor development if the blood concentration of EGF increases. Nevertheless, CIA treatment using EGF may become a new, effective alopecia-protection strategy.

REFERENCES:

Paik SH, Yoon JS, Ryu HH, Lee JY, Shin CY, Min KH, Jo SJ, Kim KH, Kwon O.  Pretreatment of epidermal growth factor promotes primary hair recovery via the dystrophic anagen pathway after chemotherapy-induced alopecia.  Exp Dermatol. 2013 Jul;22(7):496-9. doi: 10.1111/exd.12182.

Selected by H. Imanishi, D. Tsuruta, Osaka, Japan.

 

 

Ozone – and its impact on epidermal keratinocytes

Because the skin is an interface between the body and the environment it is chronically exposed to several forms of stress among which ozone (O3) has been shown to be one of the most toxic. It is generally understood that, although O3 is not a radical species per se, the toxic effects of O3 are mediated through free radical reactions and they are achieved either directly by the oxidation of biomolecules to give classical radical species (hydroxyl radical) or by driving the radical-dependent production of cytotoxic, nonradical species (aldehydes) (FRBM, Pryor W, 1994).

The work by McCarthy et al provides evidence that the effect of ozone on human keratinocytes  -- besides the well-established induction of lipid peroxidation cascade -- can also affect mitochondria sirtuin expression, specifically, SIRT3. This study first confirms the presence of SIRT3 in keratinocytes and then shows for the first time that SIRT3 levels decreased after ozone exposure. As SIRT3 has been shown to regulate SOD activity, an enzyme that catalyzes the dismutation of superoxide (O2−) into oxygen and hydrogen peroxide, this study adds a new insight on the possible sources of oxidative stress detected after O3 exposure, and it might explain the increased levels of H2O2 induced by O3. In addition, based on the authors' previous work (Dong et al, 2012), it could be interesting to understand whether SIRT4, which is also located in the mitochondria, can be modulated by ozone and whether its expression is inversely related to SIRT3, as demonstrated for UV exposure.

REFERENCES:

McCarthy JT, Pelle E, Dong K, Brahmbhatt K, Yarosh D, Pernodet N. Effects of ozone in normal human epidermal keratinocytes. Exp Dermatol. 2013 May;22(5):360-1. doi: 10.1111/exd.12125

Dong K, Pelle E, Yarosh DB, Pernodet N.  Sirtuin 4 identification in normal human epidermal keratinocytes and its relation to sirtuin 3 and energy metabolism under normal conditions and UVB-induced stress. Exp Dermatol. 2012 Mar;21(3):231-3. doi: 10.1111/j.1600-0625.2011.01439.x.

Selected by G. Valacchi, Ferrara, Italy

 

 

Towards a molecular understanding of comorbidity in psoriasis

Patients with psoriasis are not only burdened by their chronic cutaneous inflammation but also suffer from metabolic disorders such as obesity and cardiovascular disease. So far, it has been unclear if this comorbidity is caused by psoriasis, causative of psoriasis, or observed by chance. As susceptibility to complex diseases such as psoriasis and its associated diseases results from an interplay of genetic and environmental factors, it seems plausible that the comorbidity of psoriasis with other diseases indicates common genetic controls.

Unexpectedly, however, two studies independently showed very little genetic overlap of psoriasis with its associated comorbid entities (1, 2). This points towards the environment controlling the observed metabolic and cardiovascular comorbidity of psoriasis. This assumption has now been experimentally addressed by Xue and colleagues (3): In large patient / control cohorts Xue et al. (i) demonstrate that  obesity is a risk factor for psoriasis, (ii) detect an increased cutaneous expression of leptin in psoriatic skin, and (iii) show a functional relevance of this increased leptin expression.

Leptin is a bioactive product released by adipose tissue to regulate weight, and it is increased in obesity, as confirmed by Xue et al (3). In addition, this paper nicely demonstrates that leptin increases the proliferation of keratinocytes and enhances the secretion of pro-inflammatory cytokines independent of other stimuli (3), two hallmarks of psoriasis.

Collectively, this study identifies leptin as a molecular link between obesity and psoriasis, and it underscores how important it is to systematically explore the role of leptin in skin biology and pathology (4). Taking into account the new Xue et al. study and the missing genetic association, diet seems to be a good candidate to be causative for both psoriasis and psoriasis-associated metabolic and cardiovascular comorbidity.

REFERENCES:

(1) Lu Y, Chen H, Nikamo P et al. Association of cardiovascular and metabolic disease genes with psoriasis. J Invest Dermatol. 2013 Mar;133(3):836-9. doi: 10.1038/jid.2012.366.

(2) Gupta Y, Möller S, Zillikens D, Boehncke WH, Ibrahim SM, Ludwig RJ. Genetic control of psoriasis is relatively distinct from that of metabolic syndrome and coronary artery disease. Exp Dermatol 2013 Aug;22(8):552-3. doi: 10.1111/exd.12192

(3) Xue K, Liu H, Jian Q, Liu B, Zhu D, Zhang M, Gao L and Li C, Leptin induces secretion of pro-inflammatory cytokines by human keratinocytes in vitro – a possible reason for increased severity of psoriasis in patients with a high body mass index Exp Dermatol.2013 Jun;22(6):406-10. doi: 10.1111/exd.12162.

(4) Poeggeler B, Schulz C, Pappolla MA, Bodó E, Tiede S, Lehnert H, Paus R. Leptin and the skin: a new frontier. Exp Dermatol. 2010 Jan;19(1):12-8. doi: 10.1111/j.1600-0625.2009.00930.x.

 

Selected by Ralf J. Ludwig, Lübeck, Germany

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