4.2 Immune system
The disturbed skin barrier in AE facilitates the entrance of allergens
which are presented by antigen presenting cells in the lymph nodes to
naïve T-cells, which in the presence of e.g. thymic stromal
lymphopoietin (TSLP) differentiate into allergen specific T-helper
cells. These cells release IL-4, IL-13 and IL-5 – a major hallmark in
AE - which lead to even stronger epithelial skin barrier disruption by
down regulation of filaggrin and claudins and recruitment of eosinophils
[73-75] [76]. Recently, vitamin D3 was found to induce
skin dendritic cells to differentiate Th2 cells [77]. Basophils were
identified as one of the main producer of IL-4 identified in mice and is
consequently a potential therapeutic target [78]. In turn, in-vitro
stimulation of eosinophils with IL-4 and IL-13 lead to an overexpression
of the histamine-receptor H4R whose antagonists are already in clinical
trials for AE [79, 80] [81]. Eosinophils, mast cells, dermal
dendritic cells, natural killer cells, and macrophages, were found in
significantly higher numbers in biopsies from lesional AE skin [82].
The innate immune system of the skin consisting of biochemical and
cellular components is the first line of defense and senses and
regulates the skin microbiome. [2, 83] Multiple mutations in the
innate immune system pathways (e.g. ADAM33, MIF, MMP9, ORM2, RETN, and
TLR2)[50], as well as a lack of antimicrobial peptides (AMPs) were
reported in the context of AE. The AMPs LL-37, hBD-2, and hBD-3 are
downregulated in AE skin lesions compared to psoriasis lesions [84,
85]. A deficiency of antimicrobial peptides in the sweat of AE
patients correlate with an impaired innate defense in AE [86].
Interestingly, AMPs are not only produced by the skin itself, but also
by microbes [87]. Not only AMPs but also pattern recognition
receptors like Toll-like receptors (TLRs) reveal polymorphisms and
aberrant expressions in AE, among them TLR2, which is capable of sensing
Gram-positive staphylococci as S. aureus and TLR-9. [88]
[89]. Interestingly, TLR2, which has been associated with severe
forms of AE, can both lead to amplification of cutaneous inflammation
and severe immunosuppression in combination with TLR6 [90]. S.
aureus strains of AE patients but not laboratory strains were reported
to accumulate in keratinocytes and induce IL-1alpha via TLR9 [91],
further exacerbating the inflammation.