Atopic eczema, asthma and allergy

Atopic (allergic) eczema (also known as atopic dermatitis) is the most common skin disorder in westernised nations, for example, affecting more than 20% of children in the UK and Ireland.  The disease is characterised by red, itchy inflamed skin, often associated with other allergic conditions that can include atopic asthma, allergies to house dust, animal dander and foodstuffs, including peanut allergy.  Atopic eczema is a common complex trait where a combination of multiple genetic predisposing factors act in concert with environmental stimuli to produce this inflammatory skin disease.  Filaggrin is a highly abundant protein expressed in the outer layers of the epidermis.  It has multiple functions including involving the biogenesis, hydration and pH regulation of the stratum corneum – the highly impermeable dead cell layers at the skin's surface. 

In 2006, we were the first group to identify loss-of-function mutations in the filaggrin gene as the cause of the very common dry, flaky skin condition ichthyosis vulgaris (IV).  To our surprise, these mutations are carried by more than 10% of the population, with more than 1% of the population carrying two mutations, with complete absence of filaggrin protein in the epidermis.  A combination of factors led us to consider that filaggrin mutations might also be a risk factor eczema and allergy.  Firstly, many IV patients have eczema (and vice versa).  Secondly, inherited eczema susceptibility had previously been mapped to a large cluster of genes on chromosome 1 that were known to be involved in skin barrier formation, including the filaggrin gene.  We subsequently showed that indeed, filaggrin mutations are the major genetic risk factor for eczema across several independent genetic transmission and case-control studies.  Filaggrin mutations are also strongly associated with other allergic diseases secondary to eczema, including atopic asthma and allergic rhinitis (hay fever). 

This work has won several major research awards, including Times Higher Education Research Project of the Year 2006, CERIES Dermatology Research Prize 2006, Gerson Unna Prize 2006/7 and the American Skin Association Achievement Award 2009, as well as the major prize lectures of the European, American and Japanese dermatology societies (Rene Tourraine, Montagna and Tanioku Kihei lectures, respectively).

Following on from our initial discoveries, we were able to experimentally prove that epidermal filaggrin deficiency leads to greatly enhanced antigen/allergen priming through the skin, providing compelling evidence for a skin barrier model of atopic disease. 

Early in 2011, we reported that filaggrin mutations are the first identified genetic risk factor for peanut allergy. 

More recently, we discovered that copy number variation within the filaggrin gene represents a further genetic risk for atopic eczema in addition to the loss-of-function mutations. This copy number variation leads to population differences in the amount of filaggrin made in the skin. Specifically, people with just 20% more filaggrin in their skin have a 40% reduction in their risk of getting eczema, showing that more filaggrin means less eczema.  This work validates the concept of finding new drugs to treat or prevent eczema by boosting filaggrin expression in the epidermis.

Currently, funded by The Wellcome Trust, we are working on identification of additional eczema susceptibility genes with an international network of collaborators. Importantly, in collaboration with the Drug Discovery Unit in the College of Life Sciences, we are trying to develop small molecules that can enhance filaggrin expression as a new therapeutic approach for this common group of diseases, however, this is a very challenging and long-term project. 

Our work in relation to eczema and allergy is carried out in close collaboration with Alan Irvine MD DSc (clinical dermatology and genetics), National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin and Trinity College Dublin, who is an Honorary Professor in the School of Life Sciences, University of Dundee. 

References:

  • Palmer CNA et al., (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature Genetics 38: 441-446 (PubMed ID: 16550169)
  • Fallon PG et al., (2008) A homozygous frameshift mutation in the murine filaggrin gene facilitates enhanced percutaneous allergen priming. Nature Genetics 41: 602-608 (PubMed ID: 19349982)
  • Brown SJ et al., (2011) Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J Allergy Clin Immunol 127: 661-7. (PubMed ID: 21377035)
  • McLean WHI (2011) The allergy gene: how a mutation in a skin protein revealed a link between eczema and asthma. F1000 Med Rep 3:2 (PubMed ID: 21399759)
  • Irvine AD, McLean WHI and Leung DYM (2011) Filaggrin mutations: associations with allergic, dermatologic and other epidermal diseases. New Eng J Med 365:1315-1327 (PubMed ID: 21991953).
  • Brown SJ, Kroboth K, Sandilands A, Campbell LE, Pohler E, Kezic S, Cordell HJ, McLean WHI and Irvine AD (2012) Intragenic Copy Number Variation within Filaggrin Contributes to the Risk of Atopic Dermatitis with a Dose-Dependent Effect. J Invest Dermatol 132:98-104 [Epub ahead of print 10th Nov 2011] (PubMed ID: 22071473)
  • Brown SJ, McLean WHI (2012) One Remarkable Molecule: Filaggrin. J Invest Dermatol 132:751-762 [Epub ahead of print 8th Dec 2011] (PubMed ID: 22158554)
  • McLean WHI and Irvine AD (2012) Heritable filaggrin disorders: the paradigm of atopic dermatitis. J Invest Dermatol [Epub ahead of print Nov 15, 2012] (PubMed ID: 23176819)
  • McLean WHI (2016) Filaggrin failure - from ichthyosis vulgaris to atopic eczema and beyond. Br J Dermatol. Suppl 2:4-7 (PMID: 27667308)