Allergy and Clinical Immunology

Defining B cell defects and correlation with complications in Common Variable Immune Deficiency patients Publication date: Available online 29 June 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Helen Chapel, Smita Patel

Evaluation of Long-term Course in Children with Eosinophilic Esophagitis Reveals Distinct Histologic Patterns and Clinical Characteristics Publication date: Available online 28 June 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Cathleen Collins, Jacob Palmquist, James A. Proudfoot, Alex Qian, Hannah Wangberg, Emad Khosh-Hemmat, Ranjan Dohil, Seema S. Aceves Abstract Background Eosinophilic esophagitis (EoE) is a chronic, increasingly prevalent antigen driven disease. There is a paucity of information on long-term course in children. Objective To understand the longitudinal trajectory of pediatric EoE during routine clinical care. Methods We prospectively enrolled children into an EoE database and reviewed their medical and pathology records over 13 years. Results From 2011 to 2015, 146 EoE children seen for their first visit at our center had ≥2 years of follow up and ≥3 endoscopies over an average follow up time of 5.13 years (range 2-13). Longitudinal eosinophilic inflammation during treatment demonstrated 3 patterns over time. Children with <15 eosinophils per high power field (hpf) for >75% of their follow up time were termed “continuous responders” (CR). Children with waxing and waning inflammation of <15 eosinophils per hpf for <75% but ≥25% of follow up time were termed “intermittent responders” (IR). “Non- responders” (NR) were defined as <15 eosinophils per hpf for <25% of their follow up. 59 of 146 (40%) patients were CR; 65 of 146 (45%) were IR; 22 of 146 (15%) were NR. CR patients differed from IR and NR patients on the parameters of male to female ratio (1:1 in CR, 4:1 in IR, 6:1 in NR) (p<.001) and in their initial response to any therapy, including PPI (p<.001). Endoscopic severity correlated with esophageal eosinophilia (r=0.73, p<.001). On multivariate analysis, female sex and initial therapeutic response to medications or elimination diet associated with long-term control of esophageal eosinophilia. Conclusions Long-term pediatric EoE followed 3 different longitudinal trajectories of inflammation. The long-term histologic groups differed significantly in biological sex and initial therapeutic response. Graphical abstract

Clinical onset of atopic eczema: Results from two nationally representative British birth cohorts followed through mid-life Publication date: Available online 28 June 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Katrina Abuabara, Morgan Ye, Charles E. McCulloch, Alice Sullivan, David J. Margolis, David P. Strachan, Lavinia Paternoster, Yik Weng Yew, Hywel C. Williams, Sinéad M. Langan Abstract Background Atopic eczema onset is described primarily in early childhood; the frequency and characteristics of adult-onset disease remain controversial. Objective To determine the proportion of individuals who report atopic eczema symptoms between birth and mid adulthood, and to examine demographic, immunologic, and genetic factors associated with period of symptom onset. Methods We conducted a longitudinal study using data from two nationally representative community-based birth cohorts from the United Kingdom: the British Cohort Studies 1958 and 1970. Individuals were followed from birth through age 42-50. The primary outcome was the age period of self-reported atopic eczema symptom onset based on repeated measures of self-reported atopic eczema at each survey wave. Results The annual period prevalence of atopic eczema ranged from 5-15% in two cohorts of over 17,000 participants each followed from birth through mid-age. There was no clear trend in prevalence by age, and among adults reporting active atopic eczema during a given year, only 38% had symptom onset reported in childhood. When compared with individuals whose eczema started in childhood, those with adult-onset disease were more likely to be women, from Scotland or Northern England, of lower childhood socio-economic group, smokers in adulthood, and less likely to have a history of asthma. In a sub-analysis using data from the 1958 cohort only, genetic mutations previously associated with atopic eczema, including filaggrin null mutations, and allergen-specific IgE were more common among those with childhood-onset disease. Conclusion Rates of self-reported atopic eczema remain high after childhood, and adult-onset atopic eczema has different risk factor associations than childhood-onset eczema.

Exposure: S. aureus skin colonization predisposes to food allergy in the LEAP and LEAP-On studies Publication date: Available online 27 June 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Joan M. Cook-Mills, Mark H. Kaplan, Matthew J. Turner, Kirsten M. Kloepfer, Rajesh Kumar

Staphylococcus aureus internalisation in mast cells in nasal polyps - Characterisation of interactions and potential mechanisms Publication date: Available online 27 June 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Stephen H. Hayes, Timothy C. Biggs, Simon P. Goldie, Philip G. Harries, Andrew F. Walls, Raymond N. Allan, Sylvia L.F. Pender, Rami J. Salib Abstract Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common chronic condition. The exact cause of nasal polyps remains unknown. Recently, we made the novel observation of intracellular localisation of Staphylococcus aureus (S aureus) within mast cells in nasal polyps. Objective This follow-up study aimed to further characterise interactions between S aureus and mast cells in this setting, and elucidate potential internalisation mechanisms with particular emphasis on the role of S aureus enterotoxin B (SEB). Methods A prospective study was performed using an explant tissue model with ex vivo inferior turbinate mucosa obtained from CRSwNP patients (n=7) and non-CRS (n=5) patients. Immunohistochemistry was used to characterise S aureus uptake into mast cells and investigate the effects of SEB on this process. An in vitro cell culture model was used to investigate mast cell-S aureus interactions using a combination of fluorescent in situhybridisation, confocal laser scanning microscopy, scanning electron microscopy, transmission electron microscopy, and proliferation assays. Results S aureus were entrapped by extracellular traps and entered mast cells through phagocytosis. Proliferating intracellular S aureus led to the expansion and eventual rupture of mast cells, resulting in release of viable S aureusinto the extracellular space. The presence of SEB appeared to promote internalisation of S aureus into mast cells. Conclusion This study provides new insights into the interactions between S aureus and mast cells, including the internalisation process, and demonstrates a prominent role for SEB in promoting uptake of the bacteria into these cells. Graphical abstract

RAGE-induced asthma: a role for the receptor for advanced glycation end products in promoting allergic airway disease. Publication date: Available online 25 June 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Eric B. Brandt, Ian P. Lewkowich

TSLP epigenetically upregulates FcRγ-related receptors on APCs and induces TH2/TH17 polarization via dectin-2 Publication date: Available online 25 June 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Yunsheng Liang, Bihui Yu, Junchen Chen, Haijin Wu, Yingping Xu, Bin Yang, Qianjin Lu Abstract Background Fc receptor gamma subunit (FcRγ)-related receptors expressed on antigen-presenting cells (APCs) enhance allergen sensitization and allergic inflammation. DNA demethylation of the Fc fragment of IgE receptor Ig (FCER1G) leads to FcRγ and FcεR1 overexpression on monocytes from patients with atopic dermatitis (AD). Objective We investigated epigenetic mechanisms underlying FCER1G demethylation and upregulation of FcRγ-related receptors on APCs and the consequent impact on allergic responses. Methods Effects of thymic stromal lymphopoietin (TSLP) on the expression of FcRγ and its related receptors, and methylation or hydroxymethylation of FCER1G in human monocytes were assessed. Recruitment of ten-eleven translocation protein 2 (TET2) to FCER1G by TSLP-activated phospho-signal transducer and activator of transcription 5 (pSTAT5) was evaluated. Effects of TSLP on the expression of FcRγ-related receptors and costimulatory receptors on monocyte-derived dendritic cells (MoDCs) and ability of DCs to take-up ovalbumin were analyzed. TSLP-induced TH polarization and related cytokine production were also analyzed. Results pSTAT5 activation by TSLP resulted in TET2 recruitment to FCER1G, leading to FCER1G demethylation and subsequent upregulation of FcRγ-related receptors on monocytes. TSLP not only stimulated MoDC maturation but also maintained their allergen uptake ability likely through maintenance and upregulation of FcRγ-related receptors. Allergen sensitization and upregulation of TH2/TH17-related cytokines contributed to TSLP-DC-induced TH2/TH17 polarization. The latter was attenuated upon neutralization with a dectin-2 antibody. Conclusions TSLP mediated upregulation of FcRγ-related receptors on APCs through activation of pSTAT5, which recruited TET2 to induce FCER1G demethylation. TSLP-induced allergic TH2/TH17 polarization likely depends on dectin-2-mediated allergen sensitization and upregulation of TH2/TH17-related cytokines.

Ambient Air Pollution, Asthma Drug Response and Telomere Length in African American Youth Publication date: Available online 24 June 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Eunice Y. Lee, Sam S. Oh, Marquitta J. White, Celeste S. Eng, Jennifer R. Elhawary, Luisa N. Borrell, Thomas J. Nuckton, Andrew M. Zeiger, Kevin L. Keys, Angel C.Y. Mak, Donglei Hu, Scott Huntsman, Maria G. Contreras, Lesly-Anne Samedy, Pagé C. Goddard, Sandra L. Salazar, Emerita N. Brigino-Buenaventura, Adam Davis, Kelley E. Meade, Michael A. LeNoir Abstract Background Telomere length can serve as a potential biomarker for conditions associated with chronic oxidative stress and inflammation such as asthma. Air pollution can induce oxidative stress. Understanding the relationship between telomere length, asthma, and air pollution is important for identifying risk factors contributing to unhealthy aging in children. Objectives To investigate the associations between exposures to ambient air pollutants and telomere length (TL) in African American children and adolescents, and to examine whether African ancestry, asthma status and steroid medication use alter the association. Methods Linear regression was used to examine associations between absolute TL and the estimated annual average residential ozone (O3) and fine particulate matter (PM2.5) exposures in a cross-sectional analysis of 1,072 children in an existing asthma case-control study. African ancestry, asthma status and the use of steroid medications were examined as effect modifiers. Results Participants’ absolute TL was measured by quantitative polymerase chain reaction. A 1-ppb and a 1-μg/m3 increase in annual average exposure to O3 and PM2.5 were associated with a decrease in absolute TL of 37.1 kb (95% CI: -66.7 kb to -7.4 kb) and 57.1 kb (95% CI: -118.1 kb to 3.9 kb), respectively. African ancestry and asthma were not effect modifiers; however, exposure to steroid medications modified the relationships between TL and the pollutants. Past year exposure to O3 and PM2.5 were associated with shorter TL in patients without steroid use. Conclusion Exposure to air pollution was associated with shorter telomere length in non-asthmatic children and adolescents. This was not the case for asthmatic children as a group, but those on steroid medication had less shortening than those not using steroids. Reduced exposure to air pollution in childhood may help to preserve telomere length.

Dendritic cell recognition by ILC3 via DNAM-1 triggers pro-inflammatory reciprocal cell activations Publication date: Available online 24 June 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Stefania Campana, Emma Di Carlo, Claudia De Pasquale, Chiara Barberi, Daniela Oliveri, Giacomo Sidoti Migliore, Serafinella Patrizia Cannavò, Bruno Galletti, Daniela Pende, Paolo Carrega, Guido Ferlazzo

Advances in Drug Allergy, Urticaria, Angioedema and Anaphylaxis in 2018 Publication date: Available online 24 June 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Rachel L. Miller, Maria Shtessel, Lacey B. Robinson, Aleena Banerji Synopsis Many notable advances in drug allergy, urticaria, angioedema and anaphylaxis were reported in 2018. Broad spectrum antibiotic use and consequently antibiotic resistance is widespread, and algorithms to clarify β-lactam allergy and optimize antibiotic use were described. Meaningful data emerged on the pathogenesis of delayed drug hypersensitivity reactions. Progress not only in defining biomarkers, but also in understanding the impact on quality of life and developing better treatments have been made for individuals with chronic idiopathic urticaria. Patients with hereditary angioedema have gained additional access to highly efficacious therapies with associated improvements in quality of life, and some progress was made in our understanding of recurrent angioedema in patients with normal labs. Guidelines have defined clear goals to help providers optimize therapies in patients with hereditary angioedema. The epidemiology and triggers of anaphylaxis, and the mechanisms underlying anaphylaxis, were elucidated further. In summary, these disorders (and labels) cause substantial burdens for individuals and even society. Fortunately, publications in 2018 have informed on advancements in diagnosis and management and have provided better understanding of mechanisms that potentially could yield new therapies. This progress should lead to better health outcomes and paths forward in drug allergy, urticaria, hereditary angioedema and anaphylaxis.