Comparison with literature and interpretation
All previous studies on FLG mutations and immune cell numbers
have been performed within mice models or smaller numbers of AD
patients.10-12,23 This is the first study that
provides insight in the role of FLG mutations on immune cell
numbers in school-aged children of a general population. The setting of
this study within a population-based pediatric cohort study is unique to
study the association of FLG on immune cell numbers in a general
population.
In line with a previous study in mice, we observed higher Th22 cell
numbers in children with FLG mutations than in to children with
wild type FLG alleles. 23 Th22 cells are
characterized by the production of IL-22 and contributes to skin
integrity.24,25 Moreover, IL-22 is known for its role
in the defense of different pathogens in the skin by the production of
antimicrobial proteins.24,25 In AD, acute skin lesions
are associated with an upregulated Th22 immune
response.26,27 We speculate that the observed higher
number of Th22 cells is an immunological defense mechanism to the
damaged skin barrier. Nevertheless, future studies should confirm this
finding. When studying Th22 numbers only in AD children, no differences
were observed between both groups. This is could be explained by the
fact that children with AD have higher Th22 independent of theirFLG genotype. 26 In addition, the expression of
the protein filaggrin is decreased in AD which can cause Th22
alterations through skin barrier dysfunction independent of FLGmutation status.1,5 Unfortunately, literature on the
effect of FLG mutations on the numbers of Th22 in AD is lacking.
In contrast with small previous case studies in AD, we did not observe
differences in Th2, Th17 and Treg cell numbers between children with and
without FLG mutations both in the total study population and in
the subgroup of patients with AD. 10-12,23 The
associations of Th2, Th17 and Treg cell numbers with filaggrin in
previous studies were explained by increased TSLP activity due to
impaired skin barrier and impaired thymus functioning.11,28 In the thymus, an altered filaggrin expression
affects maturation of T cells and induces dendritic cells to stimulate
the differentiation of naive Treg cells into functionally different Treg
cells. 10,29 The discrepancies between previous
studies and our current study could be explained by differences in
investigated populations and species. The mice studies studiedFLG null mutations, in which no expression of filaggrin is
present.10 This is in contrast with our population,
encompassing mainly haploinsufficient children which leads to a 50%
reduction in filaggrin expression. 1 In addition,FLG knockdown skin equivalents in previous studies could
represent a different immunological setting than is present in human
skin. 23 Furthermore, it is likely that previous
results on immune cell numbers in AD populations are affected by disease
severity. Namely, immune cells in active AD skin can induce
downregulation of filaggrin protein expression in the skin independent
of FLG mutations, subsequently affecting immune cell composition.
Although we do not have information on disease severity in our AD
population, this study included a relatively healthy cohort in which we
expect relatively mild AD. A more severe AD phenotype has been linked to
homozygous and compound heterozygous FLG mutation phenotype.1 In addition, activated immune cells in more active
AD skin can in itself downregulate filaggrin protein expression in the
skin independent of FLG mutations and thereby affect skin barrier
function and subsequently immune cell alteration.1,5In accordance, a previous study in AD patients observed that circulating
Treg cell numbers were associated with AD activity and not withFLG genotype.11 In addition, we previously
showed that children with AD had higher Th17 and Treg memory cell
numbers.16 Therefore, alteration in immune cell
numbers is probably not only dependent on FLG mutation genotype,
but also on AD severity and epigenetic and environmental factors that
affect these two, as our data suggest.
In addition, we did not observe differences in memory B cell numbers
between children with and without FLG mutations, nor any
associations between memory B cell numbers and AD in our previous
study.16 No previous studies have investigated B cell
subsets in relation to FLG mutations. Possibly, T cells are more
affected by FLG mutations than B cells because of the effects of
filaggrin in the thymus.10