This review provides an overview of the inflammatory mechanisms and immunological aspects specific to atopic dermatitis. The review discusses publications on the roles of different T-cell subsets ...(that is, T helper 1 (Th1), Th2, T-regulatory, and Th17 cells), myeloid and plasmacytoid dendritic cells, and eosinophils. A further focus lies on keratinocyte–T-cell interactions, which may be of particular relevance in eczema. Mechanisms in innate and adaptive immunity that result in susceptibility to skin infections and in hyperreactivity to environmental stimuli, influencing the course and severity of atopic dermatitis, are summarized. Because the Journal of Investigative Dermatology has recently published reviews of specific features of barrier defects, defects in innate immunity, and, in this issue, genetics, these topics are only briefly discussed here in the context of immunology of atopic dermatitis.
Within the course of a single minute, millions of cells in the human body will undergo programmed cell death in response to physiological or pathological cues. The diminished energetic capacity of an ...apoptotic cell renders the cell incapable of sustaining plasma membrane integrity. Under these circumstances, intracellular contents that might leak into the surrounding tissue microenvironment, a process referred to as secondary necrosis, could induce inflammation and tissue damage. Remarkably, in most cases of physiologically rendered apoptotic cell death, inflammation is avoided because a mechanism to swiftly remove apoptotic cells from the tissue prior to their secondary necrosis becomes activated. This mechanism, referred to as efferocytosis, uses phagocytes to precisely identify and engulf neighboring apoptotic cells. In doing so, efferocytosis mantains tissue homeostasis that would otherwise be disrupted by normal cellular turnover and exacerbated further when the burden of apoptotic cells becomes elevated due to disease or insult. Efferocytosis also supports the resolution of inflammation, restoring tissue homesostasis. The importance of efferocytosis in health and disease underlies the increasing research efforts to understand the mechanisms by which efferocytosis occurs, and how a failure in the efferocytic machinery contributes to diseases, or conversely, how cancers effectively use the existing efferocytic machinery to generate a tumor-tolerant, immunosuppressive tumor microenvironment. We discuss herein the molecular mechanisms of efferocytosis, how the process of efferocytosis might support a tumor ‘wound healing’ phenotype, and efforts to target efferocytosis as an adjunct to existing tumor treatments.
Eczema herpeticum in atopic dermatitis Traidl, Stephan; Roesner, Lennart; Zeitvogel, Jana ...
Allergy (Copenhagen),
October 2021, Volume:
76, Issue:
10
Journal Article
Peer reviewed
Open access
Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases leading to pruritic skin lesions. A subset of AD patients exhibits a disseminated severe HSV infection called ...eczema herpeticum (EH) that can cause life‐threatening complications. This review gives an overview of the clinical picture, and characteristics of the patients as well as the diagnosis and therapy of EH. A special focus lies on the pathophysiological hallmarks identified so far that predispose for EH. This aspect covers genetic aberrations, immunological changes, and environmental influences displaying a complex multifactorial situation, which is not completely understood. Type 2 skewing of virus‐specific T cells in ADEH+ patients has been implicated in immune profile abnormalities, along with impaired functions of dendritic cells and natural killer cells. Furthermore, aberrations in interferon pathway‐related genes such as IFNG and IFNGR1 have been identified to increase the risk of EH. IL‐4, IL‐25, and thymic stromal lymphopoietin (TSLP) are overexpressed in EH, whereas antimicrobial peptides like human β‐defensins and LL‐37 are reduced. Concerning the epidermal barrier, single nucleotide polymorphisms (SNPs) in skin barrier proteins such as filaggrin were identified in ADEH+ patients. A dysbalance of the skin microbiome also contributes to EH due to an increase of Staphylococcus aureus, which provides a supporting role to the viral infection via secreted toxins such as α‐toxin. The risk of EH is reduced in AD patients treated with dupilumab. Further research is needed to identify and specifically target risk factors for EH in AD patients.
Clinical translation of therapies based on small interfering RNA (siRNA) is hampered by siRNA’s comprehensively poor pharmacokinetic properties, which necessitate molecule modifications and complex ...delivery strategies. We sought an alternative approach to commonly used nanoparticle carriers by leveraging the long-lived endogenous serum protein albumin as an siRNA carrier. We synthesized siRNA conjugated to a diacyl lipid moiety (siRNA-L₂), which rapidly binds albumin in situ. siRNA-L₂, in comparison with unmodified siRNA, exhibited a 5.7-fold increase in circulation half-life, an 8.6-fold increase in bioavailability, and reduced renal accumulation. Benchmarked against leading commercial siRNA nanocarrier in vivo jetPEI, siRNA-L₂ achieved 19-fold greater tumor accumulation and 46-fold increase in per-tumor-cell uptake in a mouse orthotopic model of human triple-negative breast cancer. siRNA-L₂ penetrated tumor tissue rapidly and homogeneously; 30 min after i.v. injection, siRNA-L₂ achieved uptake in 99% of tumor cells, compared with 60% for jetPEI. Remarkably, siRNA-L₂ achieved a tumor:liver accumulation ratio >40:1 vs. <3:1 for jetPEI. The improved pharmacokinetic properties of siRNA-L₂ facilitated significant tumor gene silencing for 7 d after two i.v. doses. Proof-of-concept was extended to a patient-derived xenograft model, in which jetPEI tumor accumulation was reduced fourfold relative to the same formulation in the orthotopic model. The siRNA-L₂ tumor accumulation diminished only twofold, suggesting that the superior tumor distribution of the conjugate over nanoparticles will be accentuated in clinical situations. These data reveal the immense promise of in situ albumin targeting for development of translational, carrier-free RNAi-based cancer therapies.
Background It has frequently been speculated that pruritus and skin lesions develop after topical exposure to aeroallergens in sensitized patients with atopic dermatitis (AD). Objective We sought to ...study cutaneous reactions to grass pollen in adult patients with AD with accompanying clear IgE sensitization to grass allergen in an environmental challenge chamber using a monocenter, double-blind, placebo-controlled study design. Methods Subjects were challenged on 2 consecutive days with either 4000 pollen grains/m3 of Dactylis glomerata pollen or clean air. The severity of AD was assessed at each study visit up to 5 days after challenge by (objective) scoring of AD (SCORAD). Additionally, air-exposed and non–air-exposed skin areas were each scored using local SCORAD scoring and investigator global assessments. Levels of a series of serum cytokines and chemokines were determined by using a Luminex-based immunoassay. The primary end point of the study was the change in objective SCORAD scores between prechallenge and postchallenge values. Results Exposure to grass pollen induced a significant worsening of AD. A pronounced eczema flare-up of air-exposed rather than covered skin areas occurred. In grass pollen–exposed subjects a significantly higher increase in CCL17, CCL22, and IL-4 serum levels was observed. Conclusions This study demonstrates that controlled exposure to airborne allergens of patients with a so-called extrinsic IgE-mediated form of AD induced a worsening of cutaneous symptoms.
In an article reviewing the status of gastrointestinal allergy in the New England Journal of Medicine in 1949, Ingelfinger et al1 decried the reliance on patients' "incrimination" of specific foods, ...outcome of trial diets, or association of abdominal complaints with symptoms believed to be allergic in making the diagnosis of food allergy. Recently, the National Institutes of Health-sponsored expert panel "Guidelines for the diagnosis and management of food allergy," reaffirmed the utility of the DBPCFC for diagnosing food allergy after an extensive review of the current literature.11 However, the expert panel noted that open or single-blind challenges could also be acceptable when the challenge outcome is negative or when objective symptoms are elicited that exactly recapitulate the history of the reaction.
A combination of anionic and RAFT polymerization was used to synthesize an ABC triblock polymer poly(propylenesulfide)-block-(N,N-dimethylacrylamide)-block-(N-isopropylacrylamide) ...(PPS-b-PDMA-b-PNIPAAM) that forms physically cross-linked hydrogels when transitioned from ambient to physiologic temperature and that incorporates mechanisms for reactive oxygen species (ROS) triggered degradation and drug release. At ambient temperature (25 °C), PPS-b-PDMA-b-PNIPAAM assembled into 66 ± 32 nm micelles comprising a hydrophobic PPS core and PNIPAAM on the outer corona. Upon heating to physiologic temperature (37 °C), which exceeds the lower critical solution temperature (LCST) of PNIPAAM, micelle solutions (at ≥2.5 wt %) sharply transitioned into stable, hydrated gels. Temperature-dependent rheology indicated that the equilibrium storage moduli (G') of hydrogels at 2.5, 5.0, and 7.5 wt % were 20, 380, and 850 Pa, respectively. The PPS-b-PDMA-b-PNIPAAM micelles were preloaded with the model drug Nile red, and the resulting hydrogels demonstrated ROS-dependent drug release. Likewise, exposure to the peroxynitrite generator SIN-1 degraded the mechanical properties of the hydrogels. The hydrogels were cytocompatible in vitro and were demonstrated to have utility for cell encapsulation and delivery. These hydrogels also possessed inherent cell-protective properties and reduced ROS-mediated cellular death in vitro. Subcutaneously injected PPS-b-PDMA-b-PNIPAAM polymer solutions formed stable hydrogels that sustained local release of the model drug Nile red for 14 days in vivo. These collective data demonstrate the potential use of PPS-b-PDMA-b-PNIPAAM as an injectable, cyto-protective hydrogel that overcomes conventional PNIPAAM hydrogel limitations such as syneresis, lack of degradability, and lack of inherent drug loading and environmentally responsive release mechanisms.
Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other ...comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti–IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment.
Although siRNA-based nanomedicines hold promise for cancer treatment, conventional siRNA-polymer complex (polyplex) nanocarrier systems have poor pharmacokinetics following intravenous delivery, ...hindering tumor accumulation. Here, we determined the impact of surface chemistry on the in vivo pharmacokinetics and tumor delivery of siRNA polyplexes. A library of diblock polymers was synthesized, all containing the same pH-responsive, endosomolytic polyplex core-forming block but different corona blocks: 5 kDa (benchmark) and 20 kDa linear polyethylene glycol (PEG), 10 kDa and 20 kDa brush-like poly(oligo ethylene glycol), and 10 kDa and 20 kDa zwitterionic phosphorylcholine-based polymers (PMPC). In vitro, it was found that 20 kDa PEG and 20 kDa PMPC had the highest stability in the presence of salt or heparin and were the most effective at blocking protein adsorption. Following intravenous delivery, 20 kDa PEG and PMPC coronas both extended circulation half-lives 5-fold compared to 5 kDa PEG. However, in mouse orthotopic xenograft tumors, zwitterionic PMPC-based polyplexes showed highest in vivo luciferase silencing (>75% knockdown for 10 days with single IV 1 mg/kg dose) and 3-fold higher average tumor cell uptake than 5 kDa PEG polyplexes (20 kDa PEG polyplexes were only 2-fold higher than 5 kDa PEG). These results show that high molecular weight zwitterionic polyplex coronas significantly enhance siRNA polyplex pharmacokinetics without sacrificing polyplex uptake and bioactivity within tumors when compared to traditional PEG architectures.
To the Editor: IL-33 is a member of the IL-1 family of cytokines that is constitutively expressed in healthy skin and was found to be increased in the skin of patients with atopic dermatitis (AD). ...Because it can be released after tissue damage or physical stress including scratching of the skin,1 it has been classified as an alarmin concerned with alerting the immune system.2 It enhances TH2 responses by inducing IL-5 and IL-13 as well as TH1 responses via upregulation of IFN-γ. Because existing FLG within the stratum corneum is not expected to be affected by 24-hour stimulation, evaluation was restricted to keratinocytes with detectable nuclear counterstaining.
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