Summary
Allergic contact dermatitis affects a worrying proportion of the general population. The mechanisms underlying this chemical‐triggered delayed‐type hypersensitivity are still not fully ...understood. In recent years, basic research has shown that the immune system reacts to contact allergens by activation of signalling pathways that are usually used to fight infections. Ongoing work is aimed at the elucidation of the path that leads from the chemistry of contact allergens to the inflammatory skin disease. The cellular players and their complex interactions are being characterized. Proteins are being identified whose chemical modification by contact allergens results in the activation of signalling pathways involved in pathogenesis. Pathway identification is supported by genomic and proteomic techniques. All of these efforts will yield a cellular and molecular understanding of the orchestration of the innate and adaptive immune response to contact allergens. This knowledge will help in the identification of gene and protein signatures for improved diagnostics, the identification of novel drug targets for targeted treatments, as well the development of in vitro assays for contact allergen identification.
Allergic contact dermatitis is a skin disease resulting from an adverse reaction of the immune system to low-molecular-weight organic chemicals or metal ions. This review summarizes recent findings ...that highlight new details of the complex orchestration of the cellular and molecular immune response to contact allergens.
Progress has been made in the characterization of the roles of natural killer T cells, natural killer cells, mast cells and neutrophils, as well as in the elucidation of signaling pathways triggered by contact allergens. Global technologies begin to reveal gene signatures for contact allergen identification and improved diagnostics.
Recent progress in contact allergy research has deepened our understanding of the molecular and cellular pathomechanisms, and opens new avenues towards improved diagnostics and treatments, as well as prevention and risk assessment strategies.
: Contact allergens are small reactive chemicals. They cause allergic contact dermatitis (ACD) by activating the innate and adaptive immune system. Contact allergens are very peculiar because of ...their built‐in autoadjuvanticity that allows them to trigger sterile inflammation following skin penetration. The innate inflammatory response involves the triggering of pattern recognition receptors either by direct chemical interaction with such receptors or by induction of endogenous activators. I discuss here the recent findings regarding prevalence and predisposition, the identification of innate immune and stress response mechanisms relevant for sensitization and the orchestration of the innate and adaptive immune response to contact allergens. Despite still significant gaps of knowledge, recent advances in our understanding of the immunopathogenesis of ACD can now be used for the development of causative treatment strategies and of in vitro alternatives to animal testing for the identification of contact allergens in immunotoxicology.
The innate immune system recognizes deviation from homeostasis caused by infectious or non-infectious assaults. The threshold for its activation seems to be established by a calibration process that ...includes sensing of microbial molecular patterns from commensal bacteria and of endogenous signals. It is becoming increasingly clear that adaptive features, a hallmark of the adaptive immune system, can also be identified in the innate immune system. Such adaptations can result in the manifestation of a primed state of immune and tissue cells with a decreased activation threshold. This keeps the system poised to react quickly. Moreover, the fact that the innate immune system recognizes a wide variety of danger signals via pattern recognition receptors that often activate the same signaling pathways allows for heterologous innate immune stimulation. This implies that, for example, the innate immune response to an infection can be modified by co-infections or other innate stimuli. This “design feature” of the innate immune system has many implications for our understanding of individual susceptibility to diseases or responsiveness to therapies and vaccinations. In this article, adaptive features of the innate immune system as well as heterologous innate immunity and their implications are discussed.
Highlights ► Target proteins for contact allergen modification in the skin are being identified. ► Contact allergens activate pattern recognition receptors via DAMPs. ► Nickel is a direct activator ...for human TLR4. ► Mast cells are important in contact hypersensitivity.
Maintaining homeostasis is central to organismal health. Deviation is detected by a variety of sensors that react to alarm signals arising from injury, infection, and other inflammatory triggers. One ...important element of this alarm system is the innate immune system, which recognizes pathogen‐/microbe‐ or damage‐associated molecular patterns via pattern recognition receptors localized in the cytosol or in membranes of innate immune cells such as macrophages, dendritic cells, and mast cells but also of T cells, B cells, and epithelial cells. Activation of the innate immune system results in inflammation and is a pre‐requisite for activation of the adaptive immune system. Another important element is represented by the unfolded protein response (UPR), a stress response of the endoplasmic reticulum. The UPR regulates proteostasis and also contributes to the course of inflammatory diseases such as cancer, diabetes, obesity, and neurodegenerative diseases. In addition, the UPR is instrumental in allergic contact dermatitis. This inflammatory skin disease, affecting 5–10% of the population, is caused by T cells recognizing low‐molecular weight organic chemicals and metal ions.
In this mini‐review, we discuss the orchestration of inflammatory responses by the interplay of the innate immune system with cellular stress responses in allergic contact dermatitis, with a focus on the UPR.
Allergic contact dermatitis is a T‐cell‐mediated inflammatory skin disease. In this review, we discuss the mechanisms of skin inflammation in ACD focusing on the interplay of the innate immune system with cellular stress responses, especially highlighting ER stress and the unfolded protein response. The figure was created with BioRender.com.
Allergic contact dermatitis (ACD) represents a severe health problem with increasing worldwide prevalence. It is a T cell-mediated skin disease induced by protein-reactive organic and inorganic ...chemicals. A key feature of contact allergens is their ability to trigger an innate immune response that leads to skin inflammation. Previous evidence from the mouse contact hypersensitivity (CHS) model suggests a role for endogenous activators of innate immune signaling. Here, we analyzed the role of contact sensitizer induced ROS production and concomitant changes in hyaluronic acid metabolism on CHS responses.
We analyzed in vitro and in vivo ROS production using fluorescent ROS detection reagents. HA fragmentation was determined by gel electrophoresis. The influence of blocking ROS production and HA degradation by antioxidants, hyaluronidase-inhibitor or p38 MAPK inhibitor was analyzed in the murine CHS model. Here, we demonstrate that organic contact sensitizers induce production of reactive oxygen species (ROS) and a concomitant breakdown of the extracellular matrix (ECM) component hyaluronic acid (HA) to pro-inflammatory low molecular weight fragments in the skin. Importantly, inhibition of either ROS-mediated or enzymatic HA breakdown prevents sensitization as well as elicitation of CHS.
These data identify an indirect mechanism of contact sensitizer induced innate inflammatory signaling involving the breakdown of the ECM and generation of endogenous danger signals. Our findings suggest a beneficial role for anti-oxidants and hyaluronidase inhibitors in prevention and treatment of ACD.
The expression of E-cadherin on Langerhans cells (LC) is required for adequate dendrite intercalation between epidermal keratinocytes. Upon disruption of epidermal homeostasis by tape stripping, ...E-cadherin competent LC extend dendrites reaching up to the epidermal surface, while E-cad deficient LC lack this ability.
Exposure to certain chemicals disturbs skin homeostasis. In particular, protein-reactive chemical contact sensitizers trigger an inflammatory immune response resulting in eczema and allergic contact ...dermatitis. Chemical sensitizers activate innate immune cells which orchestrate the skin immune response. This involves oxidative and inflammatory pathways. In parallel, the Nrf2/Keap1 pathway, a major ubiquitous regulator of cellular oxidative and electrophilic stress is activated in the different skin innate immune cells including epidermal Langerhans cells and dermal dendritic cells, but also in keratinocytes. In this context, Nrf2 shows a strong protective capacity through the downregulation of both the oxidative stress and inflammatory pathways. In this review we highlight the important role of Nrf2 in the control of the innate immune response of the skin to chemical sensitizers.
Allergic contact dermatitis and its animal model, contact hypersensitivity (CHS), are T cell-mediated inflammatory skin diseases induced by contact allergens. Though numerous cellular and molecular ...players are known, the mechanism of chemical-induced sensitization remains poorly understood. Here, we identify neutrophils as crucial players in the sensitization phase of CHS. Genetic deficiency of neutrophils caused by myeloid-specific deletion of Mcl-1 or antibody-mediated depletion of neutrophils before sensitization abrogated the CHS response. Neutrophil deficiency reduced contact allergen-induced cytokine production, gelatinase release, and reactive oxygen species production in naive mice. Mast cell deficiency inhibited neutrophil accumulation at the site of sensitization. In turn, neutrophils were required for contact allergen-induced release of further neutrophil-attracting chemokines, migration of DCs to the draining lymph nodes, and priming of allergen-specific T cells. Lymph node cells from mice sensitized in the absence of neutrophils failed to transfer sensitization to naive recipients. Furthermore, no CHS response could be induced when neutrophils were depleted before elicitation or when normally sensitized lymph node cells were transferred to neutrophil-deficient recipients, indicating an additional role for neutrophils in the elicitation phase. Collectively, our data identify neutrophils to be critically involved in both the sensitization and elicitation phase of CHS.
PDF
