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.