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Immunity
Modulation of Inflammatory Proteins in Serum May Reflect Cutaneous Immune Responses in Cancer Immunotherapy
Diphencyprone (DPCP), a topical contact sensitizer, has shown efficacy in treating cutaneous melanoma metastases, including at times beyond the directly treated sites, but biomarkers indicative of treatment response have not been characterized. Thus, we performed a proteomic analysis of the skin and serum of five patients with cutaneous melanoma metastases treated with DPCP on days 0, 63, and 112 of the treatment course. In the serum, we found a significant upregulation (P < 0.05) in 13 of 96 assessed immuno-oncology proteins after DPCP treatment.Endogenous Derivatives of Linoleic Acid and their Stable Analogs Are Potential Pain Mediators
Psoriasis is characterized by intense pruritus, with a subset of individuals with psoriasis experiencing thermal hypersensitivity. However, the pathophysiology of thermal hypersensitivity in psoriasis and other skin conditions remains enigmatic. Linoleic acid is an omega-6 fatty acid that is concentrated in the skin, and oxidation of linoleic acid into metabolites with multiple hydroxyl and epoxide functional groups has been shown to play a role in skin barrier function. Previously, we identified several linoleic acid‒derived mediators that were more concentrated in psoriatic lesions, but the role of these lipids in psoriasis remains unknown.Dermatologic Manifestations of Noninflammasome-Mediated Autoinflammatory Diseases
Autoinflammatory diseases (AIDs) arise from disturbances that alter interactions of immune cells and tissues. They give rise to prominent (auto)inflammation in the absence of aberrant autoantibodies and/or autoreactive T cells. AIDs that are predominantly caused by changes in the inflammasome pathways, such as the NLRP3- or pyrin-associated inflammasome, have gained substantial attention over the last years. However, AIDs resulting primarily from other changes in the defense system of the innate immune system are less well-studied.CARD14 Missense Variant Underlying CARD14-Associated Papulosquamous Eruption with Beneficial Response to Secukinumab
CARD14-associated papulosquamous eruption is an autosomal dominant genodermatosis characterized by early-onset, generalized erythematous patches and plaques with prominent scales, mostly with facial involvement. Heterozygous gain-of-function variants in the CARD14 gene have been reported to be causative for this entity. The pathogenesis mainly involves the IL-23‒IL-17 inflammatory circuit, yet the efficacy of anti‒IL-17 treatment remained less examined. In this study, we report one previously unidentified variant underlying the CARD14-associated papulosquamous eruption and showed its gain-of-function property.Current Utilization of Qualitative Methodologies in Dermatology: A Scoping Review
The focus of this review was to determine how qualitative methods are used in dermatology research and whether published manuscripts meet current standards for qualitative research. A scoping review of manuscripts published in English between January 1, 2016 and September 22, 2021 was conducted. A coding document was developed to collect information on authors, methodology, participants, research theme, and the presence of quality criteria as outlined by the Standards for Reporting Qualitative Research.Contact Sensitization and Phototoxic and Photoallergic Potential of Tirbanibulin 1% Ointment in Healthy Volunteers
Tirbanibulin 1% ointment is approved for the topical treatment of actinic keratosis, applied once daily for 5 days. Three phase 1 randomized, single-center, controlled, within-subject comparison studies were conducted to evaluate the sensitization (KX01-AK-006), phototoxic (KX01-AK-008), and photoallergic (KX01-AK-009) potential of tirbanibulin 1% ointment in healthy adults. In KX01-AK-006 and KX01-AK-009, subjects received repeated applications of tirbanibulin or vehicle for induction (followed by irradiation in KX01-AK-009) and an additional application for the challenge on naïve sites.Impact of Season and Other Factors on Initiation, Discontinuation, and Switching of Systemic Drug Therapy in Patients with Psoriasis: A Retrospective Study
This study investigated whether systemic drug prescribing for psoriasis varies by season and other exacerbating factors. Eligible patients with psoriasis were assessed for each season for initiation, discontinuation, and switching of systemic drugs. A total of 360,787 patients were at risk of initiating any systemic drugs in 2016‒2019; 39,572 patients and 35,388 patients were at risk of drug discontinuation or switching to a biologic and a nonbiologic systemic drug, respectively. The initiation of biologic therapy in 2016‒2019 peaked in spring (1.28%), followed by summer (1.11%), fall (1.08%), and winter (1.01%).Peripheral Blood Gene Expression Profile of Infants with Atopic Dermatitis
To enhance the understanding of molecular mechanisms and mine previously unidentified biomarkers of pediatric atopic dermatitis, PBMC gene expression profiles were generated by RNA sequencing in infants with atopic dermatitis and age-matched controls. A total of 178 significantly differentially expressed genes (DEGs) (115 upregulations and 63 downregulations) were seen, compared with those in healthy controls. The DEGs identified included IL1β, TNF, TREM1, IL18R1, and IL18RAP. DEGs were validated by real-time RT- qPCR in a larger number of samples from PBMCs of infants with atopic dermatitis aged <12 months.Compromised T Cell Immunity Links Increased Cutaneous Papillomavirus Activity to Squamous Cell Carcinoma Risk
Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer, with increased incidence in immunosuppressed patients. β-Human papillomavirus has been proposed as a contributor to cSCC risk partly on the basis of increased β-human papillomavirus viral load and seropositivity observed among patients with cSCC. Experimental data in mice colonized with mouse papillomavirus type 1 suggest that T cell immunity against β-human papillomavirus suppresses skin cancer in immunocompetent hosts, and the loss of this immunity leads to the increased risk of cSCC.Type 2 Inflammation Contributes to Skin Barrier Dysfunction in Atopic Dermatitis
Skin barrier dysfunction, a defining feature of atopic dermatitis (AD), arises from multiple interacting systems. In AD, skin inflammation is caused by host–environment interactions involving keratinocytes as well as tissue-resident immune cells such as type 2 innate lymphoid cells, basophils, mast cells, and T helper type 2 cells, which produce type 2 cytokines, including IL-4, IL-5, IL-13, and IL-31. Type 2 inflammation broadly impacts the expression of genes relevant for barrier function, such as intracellular structural proteins, extracellular lipids, and junctional proteins, and enhances Staphylococcus aureus skin colonization.A Human Skin Model for Assessing Arboviral Infections
Arboviruses such as flaviviruses and alphaviruses cause a significant human healthcare burden on a global scale. Transmission of these viruses occurs during human blood feeding at the mosquito-skin interface. Not only do pathogen immune evasion strategies influence the initial infection and replication of pathogens delivered, but arthropod salivary factors also influence transmission foci. In vitro cell cultures do not provide an adequate environment to study complex interactions between viral, mosquito, and host factors.Cutaneous Type 2 Innate Lymphoid Cells Come in Distinct Flavors
In a new article published in JID Innovations, Nakatani-Kusakabe et al. (2021) show that type 2 innate lymphoid cells (ILC2s) in the skin of mice with IL-33 overexpression in keratinocytes are heterogeneous and consist of two distinct populations: skin-resident ILC2s and circulating ILC2s. They show that the circulating subset of skin ILC2s migrates to draining lymph nodes during hapten-induced cutaneous inflammation to potentially enhance the adaptive immune response.Hyperactivated Mast Cells Pathogenesis Hypothesis for COVID-19 Cutaneous Manifestations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes mucocutaneous manifestations, including maculopapular eruptions, urticaria, and unusual acral vasculopathic rashes (pseudochilblains, pernio-like lesions) referred to as COVID toe. Cutaneous manifestations can occur in asymptomatic individuals, sometimes preceding COVID-19 symptoms, concurrent with COVID-19, or commonly after other COVID-19 symptoms (Freeman et al., 2020a; Seirafianpour et al., 2020). In a case series of 505 patients, 55% of the patients' only symptoms were pernio-like lesions lasting a median of 14 days (Freeman et al., 2020b).Monitoring Cellular Movement with Photoconvertible Fluorescent Protein and Single-Cell RNA Sequencing Reveals Cutaneous Group 2 Innate Lymphoid Cell Subtypes, Circulating ILC2 and Skin-Resident ILC2
We previously generated a transgenic mouse line expressing skin-specific IL-33 (IL33tg mice) and showed that IL-33 elicits group 2 innate lymphoid cell (ILC2)–dependent atopic dermatitis–like skin inflammation. ILC2s are believed to be tissue-resident cells under steady-state conditions, but the dynamics of ILC2 migration are not fully understood. We sorted ILC2s from the skin and draining lymph nodes of IL33tg mice and analyzed their transcriptomes using the single-cell RNA sequencing technique, which revealed that the skin ILC2s had split into two clusters: circulating ILC2 and skin-resident ILC2.TNF-α and IL-1β Do Not Induce Langerhans Cell Migration by Inhibiting TGFβ Activation
In the skin, Langerhans cells (LCs) require autocrine latent TGFβ that is transactivated by the integrins ανβ6 and ανβ8 expressed by keratinocytes (KCs) for long-term epidermal retention. Selective expression of a ligand-independent, constitutively active form of TGFβR1 inhibits LC migration during homeostasis and in response to UVB exposure. In this study, we found that LC migration in response to inflammatory stimuli was also inhibited by ligand-independent TGFβR1 signaling. Contrary to UVB stimulation, which reduced KC expression of ανβ6, in vitro and in vivo exposure to TNF-α or IL-1β increased ανβ6 transcript and protein expression by KCs.Cytokine RNA In Situ Hybridization Permits Individualized Molecular Phenotyping in Biopsies of Psoriasis and Atopic Dermatitis
Detection of individual cytokines in routine biopsies from patients with inflammatory skin diseases has the potential to personalize diagnosis and treatment selection, but this approach has been limited by technical feasibility. We evaluate whether a chromogen-based RNA in situ hybridization approach can be used to detect druggable cytokines in psoriasis and atopic dermatitis. A series of psoriasis (n = 20) and atopic dermatitis (n = 26) biopsies were stained using RNA in situ hybridization for IL4, IL12B (IL-12/23 p40), IL13, IL17A, IL17F, IL22, IL23A (IL-23 p19), IL31, and TNF (TNF-α).T-Cell Adhesion in Healthy and Inflamed Skin
The diverse populations of tissue-resident and transitory T cells present in the skin share a common functional need to enter, traverse, and interact with their environment. These processes are largely dependent on the regulated expression of adhesion molecules, such as selectins and integrins, which mediate bidirectional interactions between immune cells and skin stroma. Dysregulation and engagement of adhesion pathways contribute to ectopic T-cell activity in tissues, leading to the initiation and/or exacerbation of chronic inflammation.Dupilumab Effects on Innate Lymphoid Cell and Helper T Cell Populations in Patients with Atopic Dermatitis
Group 2 innate lymphoid cells (ILCs) are thought to contribute to the pathogenesis of atopic dermatitis (AD). IL-4 stimulates T helper type 2 (Th2) cells and ILC2s to proliferate and produce cytokines. Dupilumab, an antibody against the IL-4 receptor, is used in AD therapy. We speculated that its efficacy might involve blocking the activation of Th2 cells and ILC2s via IL-4. Here, we examined circulating Th2 cells and ILC2s in 27 Japanese patients with AD before and after the administration of dupilumab.Hidradenitis Suppurativa: Host-Microbe and Immune Pathogenesis Underlie Important Future Directions
Hidradenitis suppurativa (HS) is an inflammatory disease of the skin with a chronic, relapsing-remitting course. The pathogenesis of the disease is poorly understood and involves multiple factors, including genetics, environment, host-microbe interactions, and immune dysregulation. In particular, the composition of the cutaneous microbiome shifts as the disease progresses, although it is unclear whether this is a primary or secondary process. Trials with immunomodulatory therapy elucidate the role of specific immune pathways and cytokine signaling in disease mechanism, such as TNF-α, IL-1β, IL-12, IL-17, IL-23, and complement.
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