INTRODUCTION
Filaggrin is a filament-associated protein that is encoded by the
Filaggrin gene (FLG ),1 and is an important
contributor to the preservation of the skin
barrier.1,2 Approximately 10% of the European
population is heterozygote carrier of a disrupting mutation inFLG .3 Both complete loss-of-function and
reduced functional activity of filaggrin lead to destruction of the
stratum corneum (SC) and to skin barrier
dysfunction.2,4 This barrier dysfunction due toFLG mutations is presumed to be caused by lower numbers of tight
junctions, reduced density of the protein corneodesmosin and impaired
maturation and excretion of lamellar bodies in the epidermis which are
important in maintaining cell-to-cell integrity.1
Failure in barrier function through mutations in FLG results in
increased skin permeability for percutaneous transfer of exogenous
particles including allergens and pollutants including an increased
permeability of the skin for percutaneous protein
transfer.1,2,4 Accordingly, FLG mutations are
the strongest genetic risk factor for atopic dermatitis (AD),
predisposing to a form of AD that starts in early infancy and persists
into adulthood.2,3,5 Previous meta-analysis showed
that FLG haploinsuffiency results in an odds ratio (OR) of 3.12
for AD.6 In addition, FLG mutations in AD are
associated with a higher incidence of skin infections or superinfections
such as eczema herpeticum and a higher likelihood of having asthma,
inhalant or food allergies.1,7-9
The increased permeability of the skin as a result of FLGmutations is thought to affect immune responses and maturation of
adaptive immune cells. Filaggrin is also expressed in the thymus, the
primary lymphoid organ in which T cells are formed.10Hence, FLG mutations potentially affect the peripheral immune
cell compartment through effects in skin and thymus, and previous
studies observed higher γδT17, T helper (Th) 17 in mice bi-allelic forFLG disruption.10 A case study reported higher
numbers of circulating thymus-emigrated regulatory T (Treg) cells, Th2
in with 6 AD patients with a heterozygote FLGmutation.11 Another study with 2 heterozygous, 2
homozygous and 1 compound heterozygous AD patient showed increased Th17
cells in FLG -mutation group.12 On the other
hand, literature on the role of B cell dysregulation in AD is scarce and
conflicting.13-16. It can be hypothesized that
mutations in FLG can affect B-cell numbers due to skewing of the
Th-cell population.
Because of the function of filaggrin in skin barrier tissue and in
thymus, the presence of FLG mutations might be a contributor to
the shaping of T -and B cell maturation in children. However, no studies
on this association have been performed in the general pediatric
population and only case studies have been performed in AD
patients.11,12 Therefore, we here studied the
associations between common FLG mutations in the European
population and immune cell numbers, as determined using with 11-color
flow cytometry, within a population-based birth cohort study including a
subgroup of AD patients.