Alopecia areata: Hope for humans from helpful mice

Mouse with hairless patches

Cytotoxic T cells (CD8+NKG2D+) produce cytokines that interfere with human hair follicles, producing hair loss. Alopecia areata (AA) has been known in man for centuries. An appropriate and spontaneous natural mouse genetic model for AA was discovered a few decades ago in mice at Bar Harbor Laboratories in Maine, and it has been incredibly useful, as documented in several publications in the Journal of Investigative Dermatology and other journals. The mouse model is especially important as new therapies for this disease are contemplated. The cytotoxic T cells produce high levels of certain cytokines from JAK signaling. In the mouse model both systemic and topical JAK inhibitors, approved by the FDA for treating myelofibrosis, effectively inhibited AA and restored hair growth (Xing et al, 2014). In three humans with moderate to severe AA hair growth as “near complete” after 3-5 months of oral therapy with the JAK inhibitor ruxolitinib. This exciting beginning of a new therapeutic era will no doubt be followed by further studies of whether alopecia recurs when treatment is stopped, optimum treatment regimens, side effects, combined therapy with corticosteroids, and whether other JAK kinase inhibitors will work, etc.

This is a very important step for AA research and AA patients since this disease, which is often considered an orphan disease, should receive more attention from the pharmaceutical industry. Much of the basic and clinical research in AA which has allowed this progress has been supported by the NIH — especially NIAMS, and the National Alopecia Areata Foundation. The editor is on an advisory board for the latter.


Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nature Medicine advance online publication 17 Aug 2014 (doi:10.1038/nm.3645).


Image credit:  BMC Genetics 14:40, 2013; used with permission from Springer

Editors’ Picks from Experimental Dermatology

The dark side of type XVII collagen

Gostynski et al. identified a so far unrecognized function of type XVII collagen (COL17). Based on detailed clinical observations, the authors demonstrated that in human skin, melanocytes’ supply to the epidermis depends on COL17 expression (Gostynski et al, 2014).

This striking discovery was found by the clinical observation of revertant skin in patients with epidermolysis bullosa (EB), characterized by genetic deficiency of type XVII collagen (COL17), laminin-332, or type VII collagen (COL7). In addition to correction to a healthy phenotype, hyperpigmentation (compared to non-revertant skin of the patients) was often observed in the revertant skin. A more detailed investigation showed that hyperpigmentation only occurred in patients with an underlying deficiency of COL17. In these patients, revertant skin showed not only hyperpigmentation but also an increase in melanocyte density. In contrast, neither hyperpigmentation nor an increase in melanocyte density was observed in patients with deficiency in either laminin-332 (LAMB3 gene) or COL7 (COL7A1 gene), in whom revertant skin could be identified by the healthy phenotype only.

Taken together, these data strongly point towards a new role for COL17, namely controlling melanocyte numbers and function. Albeit further work is required to unravel the precise molecular mechanism of this phenomenon, this paper nicely highlights the function of matrix proteins beyond being a mere static framework for cell-cell / cell-matrix adhesion. In my opinion there is another reason why this paper is interesting for dermatology research: The discoveries presented here were initiated by a clinical observation. This is a perfect example of translational research, and I wish I would see more papers like this!

Gostynski A, Pasmooij AMG, Del Rio M et al. Pigmentation and melanocyte supply to the epidermis depend on type XVII collagen. Exp Dermatol. 2014 Feb;23(2):130-2. doi: 10.1111/exd.12304.


By Ralf J. Ludwig, Dept. of Dermatology, University of Lübeck, Germany




Mesenchymal stem cell therapy for immune-modulation: the donor, the recipient, and the drugs in-between

Krisztian Nemeth’s excellent publication, “Mesenchymal stem cell therapy for immune-modulation: the donor, the recipient, and the drugs in-between,” highlights several timely and key considerations regarding the use of mesenchymal stem cells (MSCs) for immune based therapy. While the manuscript focuses primarily on the immune modulatory properties of MSCs, the principles discussed are important considerations in all clinical efforts using MSCs. Although many properties have been assigned to these specialized cells, little has been discussed about the variability of MSCs derived from different sources. Donor demographics, tissue origin, processing of cells in culture, and passage number are among numerous inconsistencies found within the literature, which can impact MSC function. The authors provide a rational argument that differences in immune suppressive properties between MSC preparations, as well as donor MSC response to medications given recipients, could significantly affect clinical outcome. Other functional differences in MSCs may also have significant impact on regenerative medicine applications. Further investigation is needed to develop more specific testing that can characterize differences between MSC preparations and provide a better functional match between donors and recipients.

Nemeth K. Mesenchymal stem cell therapy for immune-modulation: the donor, the recipient, and the drugs in-between Exp Dermatol. 2014 May 26. doi: 10.1111/exd.12459.

By Evangelos Badiavas, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA




Leucine-rich glioma inactivated protein 3: Not only a crucial molecule in neuronal development but also in the regulation of skin pigmentation

Over the last decade it has become apparent that Leucine-rich glioma inactivated proteins (LGI 1-4) are essential molecules for the development and function of the vertrebrate nervous system, as they modulate synaptic transmission and myelination (Kegel et al, 2013). LGI1-4 possess a leucine rich repeat domain and a so-called epilepsy-associated domain, and both structures are responsible for protein–protein interactions. The first LGI gene to be identified, LGI1, was detected in a glioma cell line, and it has been suggested that loss of LGI1 contributes to the malignant progression of glial tumors. Moreover, LGI1, 2 and 4 may function in synaptic remodelling and myelination of axons. Mutations in the LGI1,2 and 4 genes are associated with diverse pathological conditions such as epilepsy and psychiatric disorders. In contrast, mutations in the LGI3 gene have not been connected with a pathological phenotype. But it has been suggested that the LGI3 protein is essential for diverse functions in the nervous system, such as neuronal exocytosis and the uptake of amyloid proteins by astrocytes. Recently, it has been revealed that LGI3 plays not only a central function in the brain but also in the skin. LGI3 is highly expressed in human skin and secreted from UVB-irradiated keratinocytes (Lee et al, 2012). But the physiological role of LGI3 in the skin has not been fully understood. The present study by Jeong et al. (2014) now indicates that LGI3 stimulates melanin synthesis in melanocytes. Thus, it seems likely that LGI3 is a crucial paracrine cytokine, released from keratinocytes, that regulates skin pigmentation in response to UVB irradiation (Jeong et al, 2014).

Kegel, L., Aunin, E., Meijer, D., and Bermingham, J. R. (2013) LGI proteins in the nervous system, ASN Neuro 5, 167-181.doi: 10.1042/AN20120095.

Lee, S. H., Jeong, Y. M., Kim, S. Y., Jeong, H. S., Park, K. C., Baek, K. J., Kwon, N. S., Yun, H. Y., and Kim, D. S. (2012) Ultraviolet B-induced LGI3 secretion protects human keratinocytes, Exp Dermatol 21, 716-718.doi: 10.1111/j.1600-0625.2012.01550.x

Jeong, H. S., Jeong, Y. M., Kim, J., Lee, S. H., Choi, H. R., Park, K. C., Kim, B. J., Baek, K. J., Kwon, N. S., Yun, H. Y., and Kim, D. S. (2014) Leucine-rich glioma inactivated 3 is a melanogenic cytokine in human skin, Exp Dermatol.2014 Jun 6. doi: 10.1111/exd.12462.


By Burkhard Kleuser, Department of Toxicology, University of Potsdam, Germany



SMAD inhibition attenuates epithelial to mesenchymal transition by primary keratinocytes in vitro

Epithelial to mesenchymal transition (EMT) is a crucial step in many pathologic conditions, from fibrotic disease to invasive cancer (Yan et al, 2010; Nakamura et al, 2011). The molecular background triggering this highly complex process, however, is organ-specific and only partially understood.

O’Kane and colleagues investigated how the chemokines TGF-β and TNF-α initiate EMT in cultured cutaneous keratinocytes in an attempt to model conditions encountered in scleroderma and other connective tissue diseases (2014). Chemokine stimulation led to the characteristic spindle-shaped mesenchymal cell morphology, accompanied by E-Cadherin and Zo-1 loss as well as increased Fibronectin and Vimentin on the protein level. This shift was paralleled by secretion of metalloproteases MMP-2/-9. Shortly after chemokine addition, elevated levels of phosphorylated SMAD-2, -3, and p38 were observable, suggesting a mode of action via their (TGF-β and TNF-α) canonical signaling pathways. Importantly, inhibition of the TGF-β signaling cascade and, to a minor extent, p38, prevents EMT in keratinocytes and is even capable of reversing an already established mesenchymal phenotype.

In conclusion, the authors suggest that SMAD inhibition may revert EMT by targeting TGF-β signaling and seting the stage for a novel therapeutic approach in cutaneous fibrotic diseases.


Nakamura M, Tokura Y. (2011) Epithelial-mesenchymal transition in the skin. J Dermatol Sci. 61:7-13. doi: 10.1016/j.jdermsci.2010.11.015.

O’Kane D et al (2014) SMAD inhibition attenuates epithelial to mesenchymal transition by primary keratinocytes in vitro. Exp Dermatol 2014 May 21. doi: 10.1111/exd.12452

Yan C, Grimm WA, Garner WL, Qin L, Travis T, Tan N, Han YP. (2010) Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol. 2010 May;176(5):2247-58. doi: 10.2353/ajpath.2010.090048


By Johannes Neu and Günther Hofbauer, Department of Dermatology, University Hospital Zurich, Zurich, Switzerland