Defects of structural protein filaggrin as a risk factor for atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene encoding filaggrin in a subset of patients with AD.

The filaggrin gene (FLG) mutation leads an epithelial barrier defect. This epidermal defect leads to:

- compromised barrier against allergens and microbes
- polarized T(H)2 lymphocyte response
- chronic inflammation, including autoimmune mechanisms

Patients with atopic dermatitis have an acquired decrease in filaggrin expression that is further decreased by IL-4 and IL-13.

Compared with normal skin, filaggrin expression was reduced in acute AD skin.

AD skin is characterized by the overexpression of IL-4 and IL-13. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited reduced filaggrin gene expression.

Patients with AD have an acquired decrease in filaggrin expression that is further decreased by IL-4 and IL-13. Medications that block of IL-4 and IL-13 could improve skin barrier integrity.

Filaggrin mutations increase the risk for persistent dry skin and eczema independent of sensitization (JACI, 2012).

SNPs associated with atopic diseases

Filaggrin gene

Filaggrin is essential for epidermal barrier function. SNP associated with eczema and asthma. Gene defect can triple risk of peanut allergy - filaggrin has already been shown to be a factor in eczema and asthma. BBC, 2011.

17q12-21 gene

ORMDL3 protein defects associated with asthma.

5q22-32 gene

CD14 is a lipopolysaccharide (LPS) receptor. SNPs associated with asthma and atopy.

3p21-22 gene

CCR5 is a chemokine receptor. SNP can be protective against asthma.

Xp22 gene

TLR7 and TLR8 are recognition receptors for viral ssRNA. SNPs assciated with asthma, rhinitis, atopic dermatitis.

5q31 gene

IL-13 is a cytokine that induces IgE secretion, mucus production, and collagen synthesis (fibrosis). SNPs associated with asthma.

ADRB2 gene

ADRB2 gene encodes β2-adrenergic receptor. Argenteum (Arg) or Arg/Arg phenotype associated with decreased albuterol response compared to Gly/Gly phenotype at residue 16.

ADAM33 gene

Type 1 transmembrane protein involved in cell-to-cell interactions. SNPs associated with asthma.

References

Filaggrin in atopic dermatitis. O'Regan GM, Sandilands A, McLean WH, Irvine AD. J Allergy Clin Immunol. 2009 Sep;124(3S2):R2-R6.
Cytokine modulation of atopic dermatitis filaggrin skin expression. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY. J Allergy Clin Immunol. 2009 Sep;124(3S2):R7-R12.

Loss-of-function mutations in filaggrin gene are associated with atopic dermatitis, and now with peanut allergy too. JACI, 2011.

Gene defect can triple risk of peanut allergy - filaggrin has already been shown to be a factor in eczema and asthma. BBC, 2011.
Filaggrin gene mutations are associated with atopic asthma http://goo.gl/5mQlj

Early food sensitization and presence of FLG mutation in infants with eczema increase the risk for later asthma. JACI, 2011.
Image source: Atopic dermatitis. Wikipedia, GNU Free Documentation License.