Congenital Deficiency of Conventional Dendritic Cells Promotes the Development of Atopic Dermatitis-Like Inflammation.

Atopic dermatitis (AD) is a common pruritic inflammatory skin disease characterized by impaired epidermal barrier function and dysregulation of Thelper-2 (TH2)-biased immune responses. While the lineage of conventional dendritic cells (cDCs) are implicated to play decisive roles in T-cell immune responses, their requirement for the development of AD remains elusive. Here, we describe the impact of the constitutive loss of cDCs on the progression of AD-like inflammation by using binary transgenic (Tg) mice that constitutively lacked CD11chi cDCs. Unexpectedly, the congenital deficiency of cDCs not only exacerbates the pathogenesis of AD-like inflammation but also elicits immune abnormalities with the increased composition and function of granulocytes and group 2 innate lymphoid cells (ILC2) as well as B cells possibly mediated through the breakdown of the Fms-related tyrosine kinase 3 ligand (Flt3L)-mediated homeostatic feedback loop. Furthermore, the constitutive loss of cDCs accelerates skin colonization of Staphylococcus aureus (S. aureus), that associated with disease flare. Thus, cDCs maintains immune homeostasis to prevent the occurrence of immune abnormalities to maintain the functional skin barrier for mitigating AD flare.

Síndrome de hiperinmunoglobulinemia E: dermatitis atópica como manifestación inicial. A propósito de un caso / Hyper IgE syndrome: atopic dermatitis as first manifestation. Case report

La dermatitis atópica es la forma más frecuente de eccema durante el primer año de vida; sin embargo, cuando la presentación es atípica o se asocia a infecciones, constituye un desafío diagnóstico para el pediatra. Es importante mantener un índice alto de sospecha para detectar inmunodeficiencias primarias asociadas a eccemas graves desde el período neonatal. Un ejemplo de estas es el síndrome de hiperinmunoglobulinemia E (hiper-IgE) autosómico dominante. Este cuadro se caracteriza por la presencia de infecciones cutáneas y respiratorias recurrentes, dermatitis atópica, eosinofilia y aumento de IgE. Se reporta el caso clínico de una niña de 1 mes y 29 días con diagnóstico de hiper-IgE con afección cutánea desde el nacimiento.

Atopic dermatitis is the most common form of eczema often developed before the first year of life. Nevertheless, when the presentation is atypical or related to infections the diagnostic represents a challenge for the pediatricians. It is important to maintain a high index of suspicion for the detection of primary immunodeficiency associated to severe eczema. One of them is the autosomal dominant hyper-IgE syndrome characterized by recurrent skin and respiratory infections, atopic dermatitis, eosinophilia, and high serum IgE concentrations. In this paper, we report a 1 months and 29 days old baby girl diagnosed with hyper-IgE and a skin involvement since birth.

Primary care provider-reported prevalence of vaccine and polyethylene glycol allergy in Canada.

BACKGROUND: The coronavirus disease 2019 pandemic has highlighted the importance of accurate capture of vaccine, and vaccine component, allergy. There remains a gap in the prevalence literature from the perspective of direct primary care provider (PCP) reporting at a population level. OBJECTIVE: To determine the prevalence of PCP-documented vaccine and polyethylene glycol (PEG) allergy using electronic medical record data from the Canadian Primary Care Sentinel Surveillance Network. METHODS: Retrospective cohort study using the Canadian Primary Care Sentinel Surveillance Network repository. Machine learning algorithms were applied to evaluate for vaccine allergy documentation, and Anatomic Therapeutic Chemical codes were used for PEG allergy or allergy to common injectable medications containing PEG (CIMCP). RESULTS: The prevalence of PCP-documented vaccine allergy in Canada was 0.037% (395/1,055,677) and of PEG allergy was 0.0009% (10/1,055,677). In total, 0.01% of patients had a documented allergy to either PEG or CIMCP (135/1,055,677). None of the patients with PEG allergy had a documented allergy to a CIMCP. Patients with vaccine allergy and PEG allergy were significantly more likely to have other atopic comorbidities, including asthma (P < .001 for both), eczema (P < .001 and P = .001, respectively), rhinitis (P = .002 and P < .001, respectively), and food allergy (P < .001 for both). Significantly higher rates of depression (P < .001 and P < .001, respectively) and anxiety (P = .003 and P < .001, respectively) were found in those with vaccine allergy, or PEG allergy, than those without vaccine allergy or PEG allergy. CONCLUSION: This is the first study to estimate the prevalence of vaccine and PEG allergy in a national cohort that uses PCP documentation, revealing a low reported rate of vaccine allergy and PEG allergy.

Insights into allergic risk factors from birth cohort studies.

OBJECTIVE: To present an update of birth cohort study designs and their contributions to allergic risk. DATA SOURCES: The PubMed database was used to search for relevant articles. STUDY SELECTIONS: Peer-reviewed prospective and retrospective studies involving the assessment of allergy using human birth cohorts between 2014 and 2021 were evaluated. RESULTS: Parental history of allergic diseases, especially in cases involving both parents, is associated with increased risk of allergy. Exposure to prenatal and postnatal smoking and limited diet diversity were associated with increased allergic burden. The impact of early-life infections and antibiotics on disease development may be associated with the onset of asthma, though this remains debated. Cohort studies also revealed that the mode of delivery and breastfeeding duration affect the odds ratio of asthma and eczema development. Household exposures, including pets, house dust mites, and scented aeroallergens may confer protective effects, whereas high air pollution exposure and low socioeconomic status may be risk enhancing. Exposure to antibiotics during early life may be associated with increased asthma risk, whereas viral infections may lead to disease protection, though the impact of the coronavirus disease 2019 pandemic on allergic risk is yet to be understood. CONCLUSION: Although evaluating the risk of allergic disease development is complex, clinicians can apply these insights on the multifactorial nature of atopy to better understand and potentially mitigate disease development.

A population-based study on associations of stool microbiota with atopic diseases in school-age children.

BACKGROUND: Infants with less diverse gut microbiota seem to have higher risks of atopic diseases in early life, but any associations at school age are unclear. OBJECTIVES: This study sought to examine the associations of diversity, relative abundance, and functional pathways of stool microbiota with atopic diseases in school-age children. METHODS: We performed a cross-sectional study within an existing population-based prospective cohort among 1440 children 10 years of age. On stool samples, 16S ribosomal RNA gene sequencing was performed, and taxonomic and functional tables were produced. Physician-diagnosed eczema, allergy, and asthma were measured by questionnaires, allergic sensitization by skin prick tests, and lung function by spirometry. RESULTS: The α-diversity of stool microbiota was associated with a decreased risk of eczema (odds ratio [OR], 0.98; 95% CI, 0.97, 1.00), and ß-diversity was associated with physician-diagnosed inhalant allergy (R2 = 0.001; P = .047). Lachnospiraceae, Ruminococcaceae_UCG-005, and Christensenellaceae_R-7_group species were associated with decreased risks of eczema, inhalant allergic sensitization, and physician-diagnosed inhalant allergy (OR range, 0.88-0.94; 95% CI range, 0.79-0.96 to 0.88-0.98), while Agathobacter species were associated with an increased risk of physician-diagnosed inhalant allergy (OR, 1.23; 95% CI, 1.08-1.42). Functional pathways related to heme and terpenoid biosynthesis were associated with decreased risks of physician-diagnosed inhalant allergy and asthma (OR range, 0.89-0.86; 95% CI range, 0.80-0.99 to 0.73-1.02). No associations of stool microbiota with lung function were observed. CONCLUSIONS: The diversity, relative abundance and functional pathways of stool microbiota were most consistently associated with physician-diagnosed inhalant allergy in school-age children and less consistently with other atopic diseases.

Heterogeneous associations of polyomaviruses and herpesviruses with allergy-related phenotypes in childhood.

BACKGROUND: Evidence suggests a complex interplay between infections and allergic diseases. OBJECTIVE: To explore the association of 14 common viruses with eczema, asthma, and rhinoconjunctivitis in childhood. METHODS: We used cross-sectional (n = 686) and prospective (n = 440) data from children participating in the Rhea birth cohort. Immunoglobulin G to polyomaviruses (BK polyomavirus, JC polyomavirus, KI polyomavirus [KIPyV], WU polyomavirus [WUPyV], human polyomavirus 6, human polyomavirus 7, Trichodysplasia spinulosa polyomavirus, Merkel cell polyomavirus, human polyomavirus 9, and human polyomavirus 10) and herpesviruses (Epstein-Barr virus, Cytomegalovirus, Herpes simplex virus-1, Herpes simplex virus-2) were measured at age 4 years by fluorescent bead-based multiplex serology. Definitions of eczema, asthma, and rhinoconjunctivitis at ages 4 and 6 years were based on questionnaires. Mediation of the associations by immune biomarkers was tested. RESULTS: Less likely to have eczema at age 4 years were KIPyV-seropositive (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.27-0.82) and human polyomavirus 6 (OR, 0.44; 95% CI, 0.26-0.73) compared with their seronegative counterparts. Seropositivity to Epstein-Barr virus was negatively associated with eczema at age 4 years (OR, 0.39; 95% CI, 0.22-0.67) and 6 years (OR, 0.50; 95% CI, 0.25-0.99). Children with a higher burden of herpesviruses or of skin polyomaviruses had the lowest odds of eczema at age 4 years. Higher odds for asthma at age 4 years were found for WUPyV-seropositive children (OR, 3.98; 95% CI, 1.38-11.51), and for children seropositive to both respiratory polyomaviruses (KIPyV and WUPyV) (OR, 7.35; 95% CI, 1.66-32.59) compared with children seronegative to both. No associations were observed for rhinoconjunctivitis. There was no evidence of mediation by immune biomarkers. CONCLUSION: A heterogeneous pattern of infections and allergic diseases was observed with common infections associated with a decreased eczema risk and an increased asthma risk in children.

The potential pathways underlying the association of propyl-paraben exposure with aeroallergen sensitization and EASI score using metabolomics analysis.

Propyl-paraben exposure is associated with aeroallergen sensitization, but its association with atopic dermatitis (AD) is inconclusive. No studies have been conducted on the metabolomic pathways underlying these associations. We investigated the associations between propyl-paraben exposure and aeroallergen sensitization, AD, and Eczema Area and Severity Index (EASI) score and identified the underlying pathways using untargeted metabolomics analysis. We enrolled 455 children in a general population study. Skin prick tests were performed with the assessment of EASI score. Urinary propyl-, butyl-, ethyl-, and methyl-paraben levels were measured. Untargeted metabolomics analysis was performed on the first and fifth urine propyl-paraben quintile groups. The highest urine propyl-paraben quintile group was associated with aeroallergen sensitization, but not with AD. Glycine, threonine, serine, ornithine, isoleucine, arabinofuranose, D-lyxofuranose, citrate, and picolinic acid levels were higher, whereas palmitic acid and 2-palmitoylglycerol levels were lower in the highest quintile propyl-paraben group, than in the lowest quintile group. The propyl-paraben-induced metabolic perturbations were associated with serine and glycine metabolisms, branched-chain amino acid metabolism, and ammonia recycling. Propyl-paraben exposure was associated with aeroallergen sensitization and EASI score, partially via metabolomic changes related with oxidative stress, mTOR, peroxisome proliferator-activated receptors pathway, aryl hydrocarbon receptor signaling pathways, and tricarboxylic acid cycle.

The molecular features of normal and atopic dermatitis skin in infants, children, adolescents, and adults.

BACKGROUND: Although atopic dermatitis (AD) often presents in infancy and persists into adulthood, comparative characterization of AD skin among different pediatric age groups is lacking. OBJECTIVE: We sought to define skin biopsy profiles of lesional and nonlesional AD across different age groups (0-5-year-old infants with disease duration <6 months, 6-11-year-old children, 12-17-year-old adolescents, ≥18-year-old adults) versus age-appropriate controls. METHODS: We performed gene expression analyses by RNA-sequencing and real-time PCR (RT-PCR) and protein expression analysis using immunohistochemistry. RESULTS: TH2/TH22 skewing, including IL-13, CCL17/thymus and activation-regulated chemokine, IL-22, and S100As, characterized the common AD signature, with a global pathway-level enrichment across all ages. Nevertheless, specific cytokines varied widely. For example, IL-33, IL-1RL1/IL-33R, and IL-9, often associated with early atopic sensitization, showed greatest upregulations in infants. TH17 inflammation presented a 2-peak curve, with highest increases in infants (including IL-17A and IL-17F), followed by adults. TH1 polarization was uniquely detected in adults, even when compared with adolescents, with significant upregulation in adults of IFN-γ and CXCL9/CXCL10/CXCL11. Although all AD age groups had barrier abnormalities, only adults had significant decreases in filaggrin expression. Despite the short duration of the disease, infant AD presented robust downregulations of multiple barrier-related genes in both lesional and nonlesional skin. Clinical severity scores significantly correlated with TH2/TH22-related markers in all pediatric age groups. CONCLUSIONS: The shared signature of AD across ages is TH2/TH22-skewed, yet differential expression of specific TH2/TH22-related genes, other TH pathways, and barrier-related genes portray heterogenetic, age-specific molecular fingerprints.

Urbanized microbiota in infants, immune constitution, and later risk of atopic diseases.

BACKGROUND: Urbanization is linked with an increased burden of asthma and atopic traits. A putative mechanism is insufficient exposure to beneficial microbes early in life, leading to immune dysregulation, as was previously shown for indoor microbial exposures. OBJECTIVE: Our aim was to investigate whether urbanization is associated with the microbiota composition in the infants' body and early immune function, and whether these contribute to the later risk of asthma and atopic traits. METHODS: We studied the prospective Copenhagen Prospective Studies on Asthma in Childhood 20102010 mother-child cohort of 700 children growing up in areas with different degrees of urbanization. During their first year of life, airway and gut microbiotas, as well as immune marker concentrations, were defined. When the children were 6 years of age, asthma and atopic traits were diagnosed by pediatricians. RESULTS: In adjusted analyses, the risk of asthma and aeroallergen sensitization were increased in urban infants. The composition of especially airway but also gut microbiotas differed between urban and rural infants. The living environment-related structure of the airway microbiota was already associated with immune mediator concentrations at 1 month of age. An urbanized structure of the airway and gut microbiotas was associated with an increased risk of asthma coherently during multiple time points and also with the risks of eczema and sensitization. CONCLUSION: Our findings suggest that urbanization-related changes in the infant microbiota may elevate the risk of asthma and atopic traits, probably via cross talk with the developing immune system. The airways may facilitate this effect, as they are open for colonization by environmental airborne microbes and serve as an immune interface.

Atopic phenotypes and their implication in the atopic march.

INTRODUCTION: Eczema, allergic rhinitis, and asthma are traditionally considered atopic (or allergic) diseases. They are complex, multifactorial, and are caused by a variety of different mechanisms, which result in multiple heterogeneous clinical phenotypes. Atopic march is usually interpreted as the sequential development of symptoms from eczema in infancy, to asthma, and then allergic rhinitis. Areas covered: The authors reviewed the evidence on the multimorbidity of eczema, asthma, and rhinitis, and the implication of results of data-driven analyses on the concept framework of atopic march. A literature search was conducted in the PubMed and Web of Science for peer-reviewed articles published until July 2020. Application of Bayesian machine learning framework to rich phenotypic data from birth cohorts demonstrated that the postulated linear progression of symptoms (atopic march) does not capture the heterogeneity of allergic phenotypes. Expert opinion: Eczema, wheeze, and rhinitis co-exist more often than would be expected by chance, but their relationship can be best understood in a multimorbidity framework, rather than through atopic march sequence. The observation of their co-occurrence does not imply any specific relationship between them, and certainly not a progressive or causal one. It is unlikely that a sngle mechanism such as allergic sensitization underpins different multimorbidity manifestations.

Can moderate-intensity aerobic exercise ameliorate atopic dermatitis?

It has been shown that aerobic exercise improves atopic dermatitis (AD), although the mechanism is not clear. Here, we propose a hypothesis that moderate-intensity aerobic exercise improves AD in a mouse model through modulating allergic inflammation. The DNCB-treated mouse model for eczema was divided into 3 groups: (a) not subjected to aerobic exercise, (b) subjected to continuous aerobic exercise and (c) subjected to accumulated aerobic exercise. After given exercise using a treadmill device either 30 min/d or 10 min × 3/day at a speed of 16 m/min, for 9 days, respectively, dermatitis symptom score, thickness of epidermis/dermis and eosinophil infiltration were decreased in the 2 exercise groups compared to the sedentary living group. The serum levels of IgE, MCP-1 and MDC showed a significant decrease both in the continuous or accumulated exercise groups. Moderate-intensity aerobic exercise ameliorates dermatitis symptoms through immune modulation in the DNCB-treated mouse model for eczema.

Tissue-resident memory T cells in the skin.

PURPOSE: Tissue-resident memory T (TRM) cells are a newly described subset of memory T cells. The best characterized TRM cells are CD8+ and express CD103 and CD69. These cells are non-recirculating and persist long term in tissues, providing immediate protection against invading pathogens. However, their inappropriate activation might contribute to the pathogenesis of autoimmune and inflammatory disorders. In the skin, these cells have been described in psoriasis, vitiligo, and melanoma among other diseases. METHODS: Literature review was done to highlight what is currently known on the phenotype and function of TRM cells and summarizes the available data describing their role in various cutaneous conditions. RESULTS: Resolved psoriatic skin and disease-naïve non-lesional skin contain a population of IL-17-producing TRM cells with shared receptor sequences that recognize common antigens and likely contribute to disease recurrence after cessation of therapy. In vitiligo, TRM cells produce perforin, granzyme B, and interferon-γ following stimulation by interleukin-15 and collaborate with recirculating memory T cells to maintain disease. In melanoma, increased accumulation of TRM cells was recently shown to correlate with improved survival in patients undergoing therapy with immune checkpoint inhibitors.