Weller, Richard

Brown, Simon

Tan, Siao Pei

Scottish Overseas Research Students Awards Scheme

2015-11-16T15:24:13Z

2015-11-16T15:24:13Z

2013-07-06

Atopic dermatitis, AD (synonym eczema) is a chronic inflammatory skin disease. It affects between 10 to 20% of children and 1 to 3% of adults worldwide. It is an important cause of morbidity and is estimated to cost £465 million per annum to the UK. AD is part of a family of Th-2 driven diseases and is often the first of these atopic diseases to manifest. The development of AD is often followed by asthma and allergic rhinitis later in life (a phenomenon known as the ‘atopic march’). Up to 50% of moderate to severe AD cases have been associated with genetic mutations affecting the epidermal barrier protein filaggrin. Filaggrin aggregates keratin filaments during terminal keratinocyte differentiation, allowing normal epidermal stratification. The role of filaggrin in maintaining a functional skin barrier is further supported by a clinical study conducted by ourselves. This is the first clinical study on a European cohort (58 participants) which showed that FLG mutations were associated with experimentally demonstrable defects of skin barrier function (increased baseline transepidermal water loss), more so following exposure to a chemical irritant. However, the majority of patients with AD, especially the milder cases, do not have FLG mutations. Some of the wild-type patients in our study were noticed to have accumulation of the large filaggrin proprotein and a lack of filaggrin monomers, indicating defective proteolysis of profilaggrin into the functional monomers. Our study also found disproportionately raised protease inhibitory activities amongst the AD participants. This inappropriately raised protease inhibition may interfere with profilaggrin proteolysis, leading to the development of AD in some wild-type patients. Having demonstrated that deficiency of filaggrin monomers is associated with a defective skin barrier, we focused on the function of filaggrin in the skin and attempted to improve the skin barrier function. In addition to keratin aggregation, filaggrin constitutes the natural moisturizing factors in the epidermis following its natural breakdown into amino acids. We note that filaggrin is disproportionately rich in amino acid histidine, implying that this amino acid may have a particular significance in maintaining a functional epidermal barrier. Using an in-house skin-equivalent model, we have shown that by increasing the histidine content in the cell culture media, we could increase the expression of filaggrin monomers and reduce the penetration of a fluorescent dye into the skin-equivalents. The latter indicates improved barrier function. Finally, we conducted a pilot human study which showed that histidine, when applied to mechanically damaged skin in AD and healthy participants, was associated with a faster recovery of the skin barrier function. These studies suggest that histidine is of therapeutic benefits in AD. A histidine-based treatment may be developed as an alternative to current anti-inflammatory and immunosuppressive agents used to treat AD.

http://hdl.handle.net/1842/11735

en

The University of Edinburgh

Tan, S.P., Brown, S.B., Weller, R. A pilot study on skin proteases and their inhibitors. Br. J. Dermatol. 160: 917-8 (2009)

Abdul Ghaffar, S., Tan, S.P., Campbell, L.E., Lee, L.H., Sergeant, A., McLean, W.I., Weller, R. The effects of filaggrin mutations on barrier function in eczema patients. J Invest Dermatol. 129: S17 (2009)

Tan, S.P., Abdul Ghaffar, S., Campbell, L.E., McLean, I., Weller, R., Brown, S.B. An imbalance of protease and antiprotease activities in the skin of eczema patients. J Invest Dermatol. 129: S19 (2009)

Tan, S.P., Weller, R., Brown, S.B. Protease–antiprotease imbalance: a potential confounder in the pathogenesis of eczema. Br. J. Dermatol . 162: 909–50 (2010)

Tan, S.P., Weller, R., Brown, S.B. Histidine increases the expression of filaggrin protein and improves barrier function. J Invest Dermatol. 131: S39 (2011)

Abdul-Ghaffar, S. et al. Filaggrin mutations are associated with altered epidermal barrier and antigen presenting cell immunophenotypes in atopic eczema patients. J Invest Dermatol. 131: S54 (2011)

Tan, S.P., Abdul-Ghaffar, S., Weller, R. B. & Brown, S. B. Protease-antiprotease imbalance may be linked to potential defects in profilaggrin proteolysis in atopic dermatitis. Br. J. Dermatol. 166, 1137–1140 (2012)

skin barrier function

atopic dermatitis

eczema

Improving the skin barrier function in atopic dermatitis

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy