The biodiversity hypothesis and immunotolerance in allergy.

Background: The human immune system is capable of detecting a multitude of substances and organisms in the environment and responding to these in a variety of ways. This includes immune responses to pathogens, on the one hand, and immunotolerance in the form of immunoregulatory responses, resulting in either the termination of immune responses or in tolerance to harmless and endogenous substances, on the other. The development of immunotolerance is an active process that is essentially characterized by interaction with microbiota and environmental components and is primarily mediated by regulatory T cells. Methods: This article provides an overview of selected scientific articles and is addressed also to non-specialists. It is based on a literature search in PubMed, specialist databases, and guidelines. Results: According to the diversity hypothesis, exposure in early childhood to broad biodiversity is now considered to reduce the risk of developing allergic diseases. Conclusion: Therefore, tolerance induction emerges in allergology not only as a potential concept for prevention, but also as a treatment approach in atopic diseases

Induction of IL-10-balanced immune profiles following exposure to LTA from <em>Staphylococcus&nbsp;epidermidis</em>.

Staphylococcus&nbsp;epidermidis colonises human skin without apparent inflammation, but a dominance of S.&nbsp;epidermidis and S.&nbsp;aureus is characteristic of cutaneous microbial dysbiosis in atopic dermatitis (AD). While S.&nbsp;aureus can trigger AD, the role of S.&nbsp;epidermidis is less understood. We characterised consequences of innate immune sensing of lipoteichoic acid (LTA) preparations derived from S.&nbsp;epidermidis (epi-LTA) or S.&nbsp;aureus (aureus-LTA). Therefore, dendritic cell (DC) activation and consecutive priming of antigen-specific T cells following exposure of DC to epi-LTA or aureus-LTA were investigated. Mimicking acute AD, exposure of DC to IL-4 and LTAs was analysed. Exposure to epi-LTA or aureus-LTA activated human immune cells and murine dendritic cells (DCs) via TLR2/MyD88, however, resulting in divergent immune profiles. Differences between LTAs were significant for IL-6, IL-12p40 and IL-12p70 but not for IL-10, which was best reflected by the IL-12p70-to-IL-10 ratio being IL-10-balanced for epi-LTA but pro-inflammatory for aureus-LTA. LTA-exposed DCs activated CD4+ T cells; however, while T-cell-derived IL-10 was equivalent between LTAs, IFN-γ and IL-17 were significantly higher for aureus-LTA. Mimicking acute AD by exposing DCs to IL-4 and LTAs revealed that IL-4 significantly and uniformly suppressed epi-LTA-induced cytokine production, keeping the IL-12p70-to-IL-10 ratio balanced. In contrast, exposure of DCs to aureus-LTA and IL-4 enhanced IL-12p70 but suppressed IL-10 levels, further unbalancing the IL-12p70-to-IL-10 ratio. These data demonstrate opposing immune consequences following exposure to staphylococcal LTAs. Epi-LTA induced IL-10-balanced, aureus-LTA pro-inflammatory immune profiles

Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10.

Atopic dermatitis (AD) is a T cell-mediated inflammatory skin disease, with TH2 cells initiating acute flares. This inflamed skin is immediately colonized with Staphylococcus aureus, which provides potent Toll-like receptor (TLR) 2 ligands. However, the effect of TLR2 ligands on the development of TH2-mediated AD inflammation remains unclear. We investigated the progression of TH2 cell-mediated dermatitis after TLR2 activation. Using models for acute AD with TH2 cells initiating cutaneous inflammation, we investigated the consequences of TLR2 activation. Dermatitis, as assessed by changes in ear skin thickness and histology, was analyzed in different BALB/c and C57BL/6 wild-type and knockout mouse strains, and immune profiling was carried out by using in vitro and ex vivo cytokine analyses. We show that TH2 cell-mediated dermatitis is self-limiting and depends on IL-4. Activation of TLR2 converted the limited TH2 dermatitis to chronic cutaneous inflammation. We demonstrate that the concerted activation of TLR2 and IL-4 receptor on dendritic cells is sufficient for this conversion. As an underlying mechanism, we found that the combinatorial sensing of the innate TLR2 ligands and the adaptive TH2 cytokine IL-4 suppressed anti-inflammatory IL-10 and consequently led to the exacerbation and persistence of dermatitis. Our data demonstrate that innate TLR2 signals convert transient TH2 cell-mediated dermatitis into persistent inflammation, as seen in chronic human AD, through IL-4-mediated suppression of IL-10. For the first time, these data show how initial AD lesions convert to chronic inflammation and provide another rationale for targeting IL-4 in patients with AD, a therapeutic approach that is currently under development