An exhausted phenotype of TH2 cells is primed by allergen exposure, but not reinforced by allergen-specific immunotherapy
Wang S-H, Zissler UM, Buettner M, et al.
Background: Studies show that proallergic TH2 cells decrease after successful allergen-specific immunotherapy (AIT). It is likely that iatrogenic administration of allergens drives these cells to exhaustion due to chronic T-cell receptor stimulation. This study aimed to investigate the exhaustion of T cells in connection with allergen exposure during AIT in mice and two independent patient cohorts.
Methods: OVA-sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion in local and systemic TH2 cells was analyzed. In patients, the expression of exhaustion-associated surface markers on TH2 cells was evaluated using flow cytometry in a cross-sectional grass pollen allergy cohort with and without AIT. The treatment effect was further studied in PBMC collected from a prospective long-term AIT cohort.
Results: The exhaustion-associated surface markers CTLA-4 and PD-1 were significantly upregulated on TH2 cells upon OVA aerosol exposure in OVA-allergic compared to non-allergic mice. CTLA-4 and PD-1 decreased after AIT, in particular on the surface of local lung TH2 cells. Similarly, CTLA-4 and PD-1 expression was enhanced on TH2 cells from patients with allergic rhinitis with an even stronger effect in those with concomitant asthma. Using an unbiased Louvain clustering analysis, we discovered a late-differentiated TH2 population expressing both markers that decreased during up-dosing but persisted long term during the maintenance phase.
Conclusions: This study demonstrates in a mouse model of AIT and in two independent patient cohorts that chronic allergen exposure results in higher expression of CTLA-4 and PD-1 on TH2 cells and that the proallergic TH2 cells with an exhausted phenotype persist long term during AIT, albeit with a reduction during up-dosing. The persistence of exhausted TH2 cells may explain the long duration of AIT treatment required to effectively reduce symptom burden and improve the quality of life for allergic patients.
Biological treatment in allergic disease
Shamji, Mohamed H; Palmer, Elizabeth, et al.
Emerging targeted therapeutics underscore immunologic heterogeneity of asthma
Masato Tamari, MD, PhD; Anna M. Trier, BA; and Brian S. Kim, MD, MTR
IgE autoantibodies: An innate connection to adaptive immunity
Xin Huang, MD, PhD and Mikael C. I. Karlsson, PhD
Impact of early life geohelminths on wheeze, asthma and atopy in Ecuadorian children at 8 years
Cooper PJ, Chis Ster I, Chico ME, et al.
Background: Early-life exposures to geohelminths may protect against development of wheeze/asthma and atopy.
Methods: Birth cohort of 2404 neonates followed to 8 years in rural Ecuador. Data on wheeze/asthma were collected by questionnaire and atopy by skin prick test (SPT) reactivity to 9 allergens. We measured airways reactivity to bronchodilator, fractional exhaled nitric oxide (FeNO) and nasal eosinophilia. Stool samples were examined for geohelminths by microscopy.
Results: 1933 (80.4%) children were evaluated at 8 years. Geohelminths were detected in 45.8% of mothers and 45.5% of children to 5 years. Frequencies of outcomes at 8 years were as follows: wheeze (6.6%), asthma between 5 and 8 years (7.9%), SPT (14.7%), airways reactivity (10%) and elevated FeNO (10.3%) and nasal eosinophilia (9.2%). Any maternal geohelminth was associated with reduced SPT prevalence (OR 0.72). Childhood Trichuris trichiura infections during the first 5 years were associated with reduced wheeze (OR 0.57) but greater parasite burdens with Ascaris lumbricoides at 5 years were associated with increased wheeze (OR 2.83) and asthma (OR 2.60). Associations between maternal geohelminths and wheeze/asthma were modified by atopy. Parasite-specific effects on wheeze/asthma and airways reactivity and inflammation were observed in non-atopic children.
Conclusions: Our data provide novel evidence for persistent effects of in utero geohelminth exposures on childhood atopy but highlight the complex nature of the relationship between geohelminths and the airways
Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C)
Chou, Janet, MD; Platt, Craig D, MD, PhD; et al.
Background: Multisystem inflammatory syndrome in children (MIS-C) is a pediatric complication of severe acute respiratory syndrome coronavirus 2 infection that is characterized by multiorgan inflammation and frequently by cardiovascular dysfunction. It occurs predominantly in otherwise healthy children. We previously reported haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of type I and II interferons, as a genetic risk factor for MIS-C.
Methods: In a single-center, prospective cohort study, whole exome sequencing was performed on patients with MIS-C. The impact of candidate variants was tested by using patients’ PBMCs obtained at least 7 months after recovery.
Results: We enrolled 18 patients with MIS-C (median age 5 8 years; interquartile range 5 5-12.25 years), of whom 89% had no conditions other than obesity. In 2 boys with no significant infection history, we identified and validated hemizygous deleterious defects in XIAP, encoding X-linked inhibitor of apoptosis, and CYBB, encoding cytochrome b-245, beta subunit. Including the previously reported SOCS1 haploinsufficiency, a genetic diagnosis was identified in 3 of 18 patients (17%). In contrast to patients with mild COVID-19, patients with defects in SOCS1, XIAP, or CYBB exhibit an inflammatory immune cell transcriptome with enrichment of differentially expressed genes in pathways downstream of IL-18, oncostatin M, and nuclear factor kB, even after recovery.
Conclusions: Although inflammatory disorders are rare in the general population, our cohort of patients with MIS-C was enriched for monogenic susceptibility to inflammation. Our results support the use of next-generation sequencing in previously healthy children who develop MIS-C.
Prevalence and early-life risk factors of school-age allergic multimorbidity: The EuroPrevall-iFAAM birth cohort
Sigurdardottir ST, Jonasson K, Clausen M, et al.
Background: Coexistence of childhood asthma, eczema and allergic rhinitis is higher than can be expected by chance, suggesting a common mechanism. Data on allergic multimorbidity from a pan-European, population-based birth cohort study have been lacking. This study compares the prevalence and early-life risk factors of these diseases in European primary school children.
Methods: In the prospective multicentre observational EuroPrevall-iFAAM birth cohort study, we used standardized questionnaires on sociodemographics, medical history, parental allergies and lifestyle, and environmental exposures at birth, 12 and 24 months. At primary school age, parents answered ISAAC-based questions on current asthma, rhinitis and eczema. Allergic multimorbidity was defined as the coexistence
of at least two of these.
Results: From 10,563 children recruited at birth in 8 study centres, we included data from 5,572 children (mean age 8.2 years; 51.8% boys). Prevalence estimates were as follows: asthma, 8.1%; allergic rhinitis, 13.3%; and eczema, 12.0%. Allergic multimorbidity was seen in 7.0% of the whole cohort, ranging from 1.2% (Athens, Greece) to 10.9% (Madrid, Spain). Risk factors for allergic multimorbidity, identified with AICc, included family-allergy-score, odds ratio (OR) 1.50 (95% CI 1.32–1.70) per standard deviation; early-life allergy symptoms, OR 2.72 (2.34 3.16) for each symptom; and caesarean birth, OR 1.35 (1.04–1.76). Female gender, OR 0.72 (0.58–0.90); older siblings, OR 0.79 (0.63–0.99); and day care, OR 0.81 (0.63–1.06) were protective factors.
Conclusion: Allergic multimorbidity should be regarded as an important chronic childhood disease in Europe. Some of the associated early-life factors are modifiable and may be considered for prevention strategies.
Real-life impact of COVID-19 pandemic lockdown on the management of pediatric and adult asthma: A survey by the EAACI Asthma Section
Eguiluz-Gracia I, van den Berge M, Boccabella C, et al.
Background: The restrictions imposed by the COVID-19 pandemic impact heavily the management of chronic diseases like asthma. This study aimed to evaluate the management of adults and children with asthma during COVID-19-related lockdown.
Methods: A survey was launched by the European Academy of Allergy and Clinical Immunology (EAACI) via e-mail, website, and social media to EAACI members and members of peer societies.
Results: The survey was completed by 339 healthcare professionals from 52 countries.79% of follow-up consultations were replaced by phone calls, whereas 49% of newly referred patients attended the clinic. 62%, 76%, 66%, 76%, and 87% of responders did not conduct spirometry, impulse oscillometry, bronchodilator test, FeNO, or methacholine provocation, respectively, for asthma diagnosis in adults. The numberswere similar for children. 73% of responders based the initial asthma diagnosis and the prescription of inhaled therapy on clinical parameters only. Lung function tests were used in 29% of cases to monitor asthma worsening, and only 56% of participants were recommended to their patients ambulatory peak expiratory flow (PEF) measurements. Using a 1 (not at all) to 5 (very much) scale, the responders considered that the quality of healthcare provided and the patients’ asthma status had deteriorated during the lockdown with 3.2 points and 2.8 points, respectively.
Conclusion: Collectively, these results suggest that all necessary resources should be allocated to ensure the performance of lung function tests for initial diagnosis, whereas digital remote monitoring should be reinforced for the follow-up of children and adults with asthma
Regulatory B cells, A to Z
Jansen K, Cevhertas L, Ma S, Satitsuksanoa P, Akdis M, van de Veen W.
Abstract: B cells play a central role in the immune system through the production of antibodies. During the past two decades, it has become increasingly clear that B cells also have the capacity to regulate immune responses through mechanisms that extend beyond antibody production. Several types of human and murine regulatory B cells have been reported that suppress inflammatory responses in autoimmune disease, allergy, infection, transplantation, and cancer. Key suppressive molecules associated with regulatory B-cell function include the cytokines IL-10, IL-35, and TGF-β as well as cell membrane-bound molecules such as programmed death-ligand 1, CD39, CD73, and aryl hydrocarbon receptor. Regulatory B cells can be induced by a range of different stimuli, including microbial products such as TLR4 or TLR9 ligands, inflammatory cytokines such as IL-6, IL-1β, and IFN-α, as well as CD40 ligation. This review provides an overview of our current knowledge on regulatory B cells. We discuss different types of regulatory B cells, the mechanisms through which they exert their regulatory functions, factors that lead to induction of regulatory B cells and their role in the alteration of inflammatory responses in different diseases.