[Show abstract][Hide abstract] ABSTRACT: Atopic dermatitis (AD) is a chronic inflammatory skin disease predominantly mediated by T helper cells. While numerous adaptive immune mechanisms in AD pathophysiology have been elucidated in detail, deciphering the impact of innate immunity in AD pathogenesis has made substantial progress in recent years and is currently a fast evolving field. As innate and adaptive immunity are intimately linked, cross-talks between these two branches of the immune system are critically influencing the resulting immune response and disease. Innate immune recognition of the cutaneous microbiota was identified to substantially contribute to immune homeostasis and shaping of protective adaptive immunity in the absence of inflammation. Disturbances in the composition of the skin microbiome with reduced microbial diversity and overabundance of Staphylococcus spp. have been shown to be associated with AD inflammation. Distinct Staphylococcus aureus associated microbial associated molecular patterns (MAMPs) binding to TLR2 heterodimers could be identified to initiate long-lasting cutaneous inflammation driven by T helper cells and consecutively local immune suppression by induction of myeloid-derived suppressor cells further favoring secondary skin infections as often seen in AD patients. Moreover dissecting cellular and molecular mechanisms in cutaneous innate immune sensing in AD pathogenesis paved the way for exploiting regulatory and anti-inflammatory pathways to attenuate skin inflammation. Activation of the innate immune system by MAMPs of non-pathogenic bacteria on AD skin alleviated cutaneous inflammation. The induction of tolerogenic dendritic cells, interleukin-10 expression and regulatory Tr1 cells were shown to mediate this beneficial effect. Thus, activation of innate immunity by MAMPs of non-pathogenic bacteria for induction of regulatory T cell phenotypes seems to be a promising strategy for treatment of inflammatory skin disorders such as AD. These new findings demonstrate how detailed analyses identify partly opposing consequences of microbe sensing by the innate immune system and how these mechanisms translate into AD pathogenesis as well as new therapeutic strategies.
Frontiers in Immunology 07/2015; 6:353. DOI:10.3389/fimmu.2015.00353
[Show abstract][Hide abstract] ABSTRACT: Interleukin 4 (IL-4) can suppress delayed-type hypersensitivity reactions (DTHRs), including organ-specific autoimmune diseases in mice and humans. Despite the broadly documented antiinflammatory effect of IL-4, the underlying mode of action remains incompletely understood, as IL-4 also promotes IL-12 production by dendritic cells (DCs) and IFN-γ–producing TH1 cells in vivo. Studying the impact of IL-4 on the polarization of human and mouse DCs, we found that IL-4 exerts opposing effects on the production of either IL-12 or IL-23. While promoting IL-12–producing capacity of DCs, IL-4 completely abrogates IL-23. Bone marrow chimeras proved that IL-4–mediated suppression of DTHRs relies on the signal transducer and activator of transcription 6 (STAT6)-dependent abrogation of IL-23 in antigen-presenting cells. Moreover, IL-4 therapy attenuated DTHRs by STAT6- and activating transcription factor 3 (ATF3)-dependent suppression of the IL-23/TH17 responses despite simultaneous enhancement of IL-12/TH1 responses. As IL-4 therapy also improves psoriasis in humans and suppresses IL-23/TH17 responses without blocking IL-12/TH1, selective IL-4–mediated IL-23/TH17 silencing is promising as treatment against harmful inflammation, while sparing the IL-12–dependent TH1 responses.
Proceedings of the National Academy of Sciences 02/2015; DOI:10.1073/pnas.1416922112 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mechanisms how the innate immune system detects microbes and mounts a rapid immune response have been more and more elucidated in the past years. Subsequently it has been shown that innate immunity also shapes adaptive immune responses and determines their quality that can be either inflammatory or tolerogenic. As atopic dermatitis is characterized by disturbances of innate and adaptive immune responses, colonization with pathogens and defects in skin barrier function, insight into mechanisms of innate immunity has helped to understand the vicious circle of ongoing skin inflammation seen in atopic dermatitis patients. Elucidating general mechanisms of the innate immune system and its functions in atopic dermatitis paves the way for developing new therapies. Especially the novel insights into the human microbiome and potential functional consequences make the innate immune system a very fundamental and promising target. As a result atopic dermatitis manifestations can be attenuated or even resolved. These currently developed strategies will be introduced in the current review.
Der Hautarzt 01/2015; 66(2). DOI:10.1007/s00105-014-3563-z · 0.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Skin is constantly exposed to bacteria and antigens, and cutaneous innate immune sensing orchestrates adaptive immune responses. In its absence, skin pathogens can expand, entering deeper tissues and leading to life-threatening infectious diseases. To characterize skin-driven immunity better, we applied living bacteria, defined lipopeptides, and antigens cutaneously. We found suppression of immune responses due to cutaneous infection with Gram-positive S. aureus, which was based on bacterial lipopeptides. Skin exposure to Toll-like receptor (TLR)2-6-binding lipopeptides, but not TLR2-1-binding lipopeptides, potently suppressed immune responses through induction of Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs). Investigating human atopic dermatitis, in which Gram-positive bacteria accumulate, we detected high MDSC amounts in blood and skin. TLR2 activation in skin resident cells triggered interleukin-6 (IL-6), which induced suppressive MDSCs, which are then recruited to the skin suppressing T cell-mediated recall responses such as dermatitis. Thus, cutaneous bacteria can negatively regulate skin-driven immune responses by inducing MDSCs via TLR2-6 activation.
[Show abstract][Hide abstract] ABSTRACT: 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.
The Journal of allergy and clinical immunology 04/2014; 134(1). DOI:10.1016/j.jaci.2014.02.017 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In den letzten Jahren konnte eine Vielzahl von Mechanismen aufgedeckt werden, mit denen das angeborene Immunsystem in der Lage ist, Mikroorganismen zu erkennen und eine erste schnelle Immunantwort auszulösen. Dabei zeigte sich auch, dass das angeborene Immunsystem nicht nur frühzeitig reagiert, sondern vor allem auch die nachfolgend erworbene (adaptive) Immunität induziert und qualitativ beeinflusst. Diese Einblicke in grundlegende Mechanismen erlaubten auch, Pathogenese und Verlauf der atopischen Dermatitis besser zu verstehen. Patienten mit atopischer Dermatitis zeigen meist eine gestörte Hautbarriere, zusätzlich eine massive läsionale Besiedelung mit Bakterien sowie Störungen im Bereich der angeborenen und erworbenen Immunantwort. In ihrer Gesamtheit führen diese Veränderungen der Reaktionsbereitschaft des Oberflächenorgans Haut zu einer sich selbst verstärkenden und die Erkrankung charakterisierenden Entzündungsreaktion. Das Verständnis der zugrunde liegenden immunologischen Mechanismen bei atopischer Dermatitis ermöglicht es auch, für diese Erkrankung neue Therapieoptionen zu entwickeln, inklusive einer gezielten Regulation des Immunsystems. Basierend auf dem Verständnis der angeborenen Immunität wird dem Kliniker in dieser Übersichtsarbeit ein Einblick in sich entwickelnde neue Konzepte zu Krankheitsverständnis und Therapiestrategien bei atopischer Dermatitis gegeben.
During recent years our understanding how the innate immune system detects microbes and mounts a first and rapid immune response has grown tremendously. It has been shown that innate immunity not only represents the first line of defense but also initiates adaptive immune responses and orchestrates their different qualities that can be inflammatory or tolerogenic. Insights into these fundamental mechanisms of immune responses also helped to better understand the pathogenesis and disease course in atopic dermatitis. We know today that patients with atopic dermatitis most often present with defects in their skin barrier function, that lesions are heavily colonized with microbes, and that innate and adaptive immune responses are disturbed so that a vicious circle of self-amplifying skin inflammation develops. Detailed knowledge on the role of the innate immunity in general and its function in atopic dermatitis also helps to develop a new concept on disease mechanisms and therapeutic strategies some of which exploit immune pathways counter-balancing inflammation in atopic dermatitis. Based on the understanding of how the innate immune system functions, the current review provides insights to the clinician into the network of mechanisms as well as evolving therapeutic concepts in atopic dermatitis.
Allergo Journal: interdisziplinäre Zeitschrift für Allergologie und Umweltmedizin: Organ der Deutschen Gesellschaft für Allergie- und Immunitätsforschung 12/2013; 21(8):470-478. DOI:10.1007/s15007-012-0443-7
[Show abstract][Hide abstract] ABSTRACT: Beneficial effects of non-pathogenic bacteria are increasingly recognized. We reported in a placebo-controlled study with atopic dermatitis (AD) patients that cutaneous exposure to lysates of non-pathogenic bacteria alleviates skin inflammation. To now unravel underlying mechanisms, immune consequences of sensing non-pathogenic bacterium Vitreoscilla filiformis lysate (Vf) were characterized analyzing (i) differentiation of dendritic cells (DC) and, consecutively, (ii) effector functions of DC and Th cells in vitro and in a murine model of AD in NC/Nga mice in vivo. Topical treatment with Vf significantly reduced AD-like inflammation in NC/Nga mice. Importantly, cutaneous exposure to Vf in combination with the allergen FITC significantly reduced also subsequent allergen-induced dermatitis indicating active immune modulation. Indeed, innate sensing of Vf predominantly induced IL-10 producing DC, which was dependent on TLR2-activation. Vf-induced IL-10+ DC primed naïve CD4+ T helper cells to become regulatory IFN-γ(low) IL-10(high) Tr1 cells. These IL-10(high) Tr1 cells were also induced by Vf in vivo and strongly suppressed T effector cells and inflammation. In conclusion we show that innate sensing of non-pathogenic bacteria by TLR2 induces tolerogenic DC and regulatory Tr1 cells suppressing T effector cells and cutaneous inflammation. These findings indicate a promising therapeutic strategy for inflammatory skin diseases like AD.Journal of Investigative Dermatology accepted article preview online, 28 June 2013; doi:10.1038/jid.2013.291.
Journal of Investigative Dermatology 06/2013; DOI:10.1038/jid.2013.291 · 7.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The skin, hair and nail changes in four distinct ectodermal dysplasia syndromes are compared and reviewed. These syndromes comprise Christ-Siemens-Touraine syndrome; ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome; ankyloblepharon-ectodermal defects-cleft lip/palate syndrome and Rapp-Hodgkin syndrome. A comprehensive overview of the dermatological signs and symptoms in these syndromes was generated from the database of the Ectodermal Dysplasia Network Germany, the clinical findings in the patients seen in our department and an extensive review of the literature. The findings included abnormalities of skin, sweating, hair and nails. These clinical findings are discussed in relation to the underlying molecular defects known to play a role in these four ectodermal dysplasia syndromes.
[Show abstract][Hide abstract] ABSTRACT: T-cell activation and the subsequent transformation of activated T cells into T-cell blasts require profound changes in cell volume. However, the impact of cell volume regulation for T-cell immunology has not been characterized. Here we studied the role of the cell-volume regulating osmolyte transporter Taut for T-cell activation in Taut-deficient mice. T-cell mediated recall responses were severely impaired in taut(-/-) mice as shown with B16 melanoma rejection and hapten-induced contact hypersensitivity. CD4(+) and CD8(+) T cells were unequivocally located within peripheral lymph nodes of unprimed taut(-/-) mice but significantly decreased in taut(-/-) compared with taut(+/+) mice following in vivo activation. Further analysis revealed that Taut is critical for rescuing T cells from activation-induced cell death in vitro and in vivo as shown with TCR, superantigen, and antigen-specific activation. Consequently, reduction of CD4(+) and CD8(+) T cells in taut(-/-) mice upon antigen challenge resulted in impaired in vivo generation of T-cell memory. These findings disclose for the first time that volume regulation in T cells is an element in the regulation of adaptive immune responses and that the osmolyte transporter Taut is crucial for T-cell survival and T-cell mediated immune reactions.
European Journal of Immunology 04/2012; 42(4):831-41. DOI:10.1002/eji.201141690 · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The innate immune system is based on pathogen recognition receptors that bind conserved microbial molecular structures, so called pathogen-associated molecular patterns (PAMPs). The characterization of the innate immune system was long based on a linear step-wise concept of recognition, activation pathways and effector defense mechanisms. Only more recently it was recognized that the innate immune system needs regulatory elements, sideways and crosstalks that allows it to fine tune and adapt its response. Thus, it is an emerging field within innate immunity research to try to understand how the immune outcome of innate immune sensing is regulated and why immune responses can be substantially different, even though the same PAMPs may have been 'sensed' at the surface organs such as the skin. Only the expansion of the innate immune system from 'pure' linear activation pathways to fine tuned and regulated innate immune networks allows us to integrate the generation of gradually accentuated and qualitatively different effector and tolerogenic immune responses. This article provides a review of the basic concepts and players of the innate immune system and will present some of the newer data defining the innate immune networks effectively regulating the immune homoeostasis and immune effector mechanisms with special focus on the skin as one of the organs involved in regulating the immune interface between the environment and the organism.
[Show abstract][Hide abstract] ABSTRACT: Innate immune sensing of Staphylococcus aureus unravels basic mechanisms leading to either effective antibacterial immune responses or harmful inflammation. The nature and properties of S. aureus-derived pathogen-associated molecular pattern (PAMPs) are still not completely understood. We investigated the innate immune sensing of peptidoglycan (PGN) structures and subsequent immune consequences. Macromolecular PGN (PGN(polymer)) preparations activated NF-κB through human Toll-like receptors 2 (TLR2), as shown by luciferase reporter assays, and induced murine dendritic cell (DC) maturation and cytokine production. In contrast, PGN(polymer) from lgt-mutant S. aureus failed to stimulate human TLR2, demonstrating that lipoproteins within the macromolecular structures of PGN(polymer), but not PGN itself, activate TLR2. Thus, HPLC-purified monomeric PGN (PGN(monomer)) structures were investigated. Strikingly, PGN(monomer) completely lacked NF-κB activation, lacked TLR2 activity, and failed to functionally activate murine DCs. However, PGN(monomer) in concert with various TLR ligands most effectively stimulated DCs to up-regulate IL-12p70 and IL-23 by ≥3- to 5-fold. Consequently, DCs coactivated by PGN(monomer) markedly up-regulated Th1 and Th17 while suppressing Th2 cell priming. Notably, PGN(monomer) failed to coactivate NOD2(-/-) DCs. This demonstrates that PGN(monomer) is a natural ligand of NOD2, which was previously only demonstrated for synthetic compounds like muramyl dipeptide. Interestingly, murine DCs lacking TLR2 remained mute in response to the combinative immune sensing of S. aureus-derived PAMPs, including PGN(monomer), providing for the first time an explanation of why S. aureus can colonize the nasal mucosa in the absence of inflammation. This is very likely based on the lack of TLR2 expression in mucosal epithelial cells under normal conditions, which determines the unresponsiveness to S. aureus PAMPs.
The FASEB Journal 10/2010; 24(10):4089-102. DOI:10.1096/fj.09-151001 · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidemiologic studies suggest that elderly people are more prone to develop severe anaphylactic reactions. However, the exact cause for this phenomenon remains unclear.
To study the role of the serum tryptase as a diagnostic parameter for individual risk evaluation and its impact on the severity of allergic reactions in elderly people.
Two hundred and seventy-four consecutive patients visiting the Department of Dermatology, Tübingen, Germany, who were diagnosed with honeybee or wasp venom allergy, were included in the study.
Sting reaction severity increased with increased age and tryptase levels (P = 0.001 and P = 0.0003, respectively). Furthermore, we find not only a general increment in tryptase levels in elderly people (P = 0.0001) but also a continuous increase in tryptase concentrations even below the cut-off (11.4 microg/l) with increasing age (P = 0.0026).
Our data confirm serum tryptase as a risk factor for severe anaphylactic reaction to hymenoptera stings. Furthermore, we give first evidence that basal serum tryptase levels increase continuously with age and being an indicator for either increased mast cell load or reactivity this can at least partly be responsible for the observed aggravated allergic reactions in elderly people. As those patients are at increased risk for life-threatening anaphylactic reactions, it should be considered to adjust VIT especially in elderly patients with elevated tryptase levels as recommended for patients with mastocytosis by increasing venom doses during VIT and by considering its life-long continuation.
[Show abstract][Hide abstract] ABSTRACT: In dermatology probiotic microorganisms have primarily been used orally for the prophylaxis and treatment of atopic disorders. In contrast to the successes achieved for gastrointestinal disorders, positive effects for atopic dermatitis only have been found in a few studies. New insights could now fundamentally change the impact of probiotics on dermatology. Probiotics are - like microflora of the skin - non-pathogenic microbes, which do not induce inflammatory responses in the skin. Common pathways for probiotics, non-pathogenic microbes, and microflora are characterized, in order to facilitate their more effective therapeutic use. These microbes display a majority of their effects directly at the site of application and thereby induce natural defense mechanisms. However, promotion of immunological tolerance is just as important in producing positive effects. Tolerance of the resident flora on surface organs developed during evolution and the mechanisms of action are multifaceted. Therefore, the topical application of probiotics and non-pathogenic microbes for prophylaxis and therapy of overwhelming cutaneous pro-inflammatory immune reactions is very promising. Results of recent clinical trials already have demonstrated the efficacy of this new therapeutic concept.
Der Hautarzt 09/2009; 60(10):795-801. DOI:10.1007/s00105-009-1755-8 · 0.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IL-4 is expressed at high levels in allergic diseases and dominates the early phases of multiple acquired immune responses. However, the precise role of IL-4 during early inflammation and its impact on the differentiation of newly recruited DC precursors remains elusive. In order to characterize the impact of IL-4 on the differentiation of human DC, we investigated the role of IL-4 on the differentiation of monocytes into DC. Human DC were differentiated from peripheral blood precursors under either low or high concentrations of IL-4. We analyzed their cytokine profile and capacity to polarize T-cell differentiation. Concentrations of 5 (low) and 50 (high) ng/mL IL-4 induced two distinct types of DC. DC differentiated under low-dose IL-4 (5 ng/mL) produced almost no IL-12p70, and primed naïve CD4+ T cells allowing IL-4 secretion and Th2 induction. In contrast, DC generated under high concentrations of IL-4 (50 ng/mL) produced large amounts of IL-12p70, low IL-10 and primed naïve CD4+ T cells to become Th1 cells. Thus, we demonstrate that the Th2 cell cytokine IL-4 decisively determines the phenotype of ongoing immune responses by orchestrating the functional phenotype of newly immigrating DC precursors.
European Journal of Immunology 11/2008; 38(11):3138-49. DOI:10.1002/eji.200838463 · 4.03 Impact Factor