Topical tacrolimus in atopic dermatitis: Effects of ... - Helda - Helsinki.fi

probably plays a protective role against allergens that are serine proteases (Kato et al.
2003). Also, some gene polymorphisms implicated in innate immunity, for example, a
polymorphism resulting in functional impairment of the intracellular receptor for
lipopolysaccharide involved in activation of a nuclear factor necessary for T cell
activation has been associated with risk for AD (Kabesch et al. 2003).
A genetic association with AD has appeared in mutations of the gene cluster
encoding the epidermal differentiation complex in chromosome 1q21 (Segre 2006). The
strongest evidence of genetic barrier dysfunction predisposing to AD has been found in
the FLG gene encoding the filaggrin protein—the same gene in which mutations are
linked in ichtyosis vulgaris. Null mutations leading to filaggrin deficiency occur in
about 6 to 10% of the European-origin population as a semidominant trait and with
incomplete penetrance (Smith et al. 2006, Weidinger et al. 2007). In studies looking at
AD and filaggrin mutations, 44% of subjects with one mutant allele and 76% with both
filaggrin alleles mutant had a diagnosis of AD (Palmer et al. 2006). FLG mutations have
been present in 25% of patients with IgE-associated but only 12% of patients with non-
IgE-associated AD. They have also been associated with asthma in the patients with AD
but not with asthma without AD (Marenholz et al. 2006, Weidinger et al. 2007).
Furthermore, these mutations associate with AD that starts early, is more severe, and
persists into adulthood (Barker et al. 2007, Stemmler et al. 2007, Weidinger et al. 2006).
Skin barrier function
One of the most crucial functions of the skin is to form a barrier against the microbes,
irritants, and allergens of the exterior world. This barrier function is impaired in AD.
Peptides with a molecular mass over 500 Da do not penetrate healthy normal skin,
whereas in AD, environmental allergens of up to 20 kDa may penetrate the skin (Bos
and Meinardi 2000). This makes the skin susceptible to environmental factors such as
detergents, irritants, allergens, microbial toxins, and physical or psychological stress.
The epidermis is formed of layers of keratinocytes which divide in the basal layer
next to the basement membrane, increasing their keratine content and flattening on their
way to the surface of the skin (Segre 2006). The skin barrier is formed in the outermost
part of the epidermis called the stratum corneum by compact flat layers of keratinocytes
called corneocytes and their surrounding hydrophobic lipid matrix (Segre 2006). Active
functional filaggrin is needed to condense the corneocytes (Palmer et al. 2006), whereas
the water-retaining properties of the hydrophobic lipid matrix are provided by structural
proteins such as the ceramides (Segre 2006).
Defects of epidermal differentiation such as filaggrin mutations weaken the
epidermal barrier and predispose patients with AD to epicutaneous allergic sensitization
as well as to physical, microbial, and irritant skin damage. This barrier-damage activates
keratinocytes to produce inflammatory cytokines and starts the inflammatory cycle
leading to T cell activation, IgE-production, and clinical AD (Vickery 2007, Segre
2006).
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