Background: Southeast Asian populations are increasingly affected by allergic airway diseases. Etiology and specific causes, however, are still unknown. The aim of this study is therefore to identify allergens and risk factors for the high prevalence of allergic airway disease in the tropical urban environment.Methods: Symptoms of allergic rhinitis (AR), asthma, and allergic dermatitis were recorded in two independent cohorts of 576 and 7373 ethnic Chinese individuals living in Singapore. Reactivity against common allergens was determined by skin prick tests (SPT); specific immunoglobulin E (sIgE) titers against 12 common allergens, as well as total serum IgE (tIgE), were measured in the smaller cohort.Results: Immunoglobulin E sensitization was almost exclusively directed against house dust mite (HDM) allergens. More than 80% of individuals were HDM‐sIgE positive. Of these, less than 30% also had sIgE for other allergens, and similarly, few of the HDM‐sIgE‐negative individuals reacted to other allergens. Titers for HDM‐sIgE were 8–30 times higher than other non‐HDM allergen titers and correlated directly with total serum tIgE levels. Migrants from nontropical countries typically arrived with low or undetectable HDM‐sIgE but developed substantial titers in a time‐dependent fashion. Importantly, prolonged stay in Singapore also resulted in the manifestation of AR and asthma symptoms, contributing to some of the highest national prevalence rates worldwide.Conclusion: In a tropical urban environment, the allergic response is dominated by a single allergen class. The mono‐specific IgE sensitization against HDM translates into increased prevalence of allergic airway diseases, which now impact a large proportion of the population in Singapore.

The immune responses and mechanisms limiting symptom progression in asymptomatic cases of SARS‐CoV‐2 infection remain unclear. We comprehensively characterized transcriptomic profiles, cytokine responses, neutralization capacity of antibodies, and cellular immune phenotypes of asymptomatic patients with acute SARS‐CoV‐2 infection to identify potential protective mechanisms. Compared to symptomatic patients, asymptomatic patients had higher counts of mature neutrophils and lower proportion of CD169 ⁺ expressing monocytes in the peripheral blood. Systemic levels of pro‐inflammatory cytokines were also lower in asymptomatic patients, accompanied by milder pro‐inflammatory gene signatures. Mechanistically, a more robust systemic Th2 cell signature with a higher level of virus‐specific Th17 cells and a weaker yet sufficient neutralizing antibody profile against SARS‐CoV‐2 was observed in asymptomatic patients. In addition, asymptomatic COVID‐19 patients had higher systemic levels of growth factors that are associated with cellular repair. Together, the data suggest that asymptomatic patients mount less pro‐inflammatory and more protective immune responses against SARS‐CoV‐2 indicative of disease tolerance. Insights from this study highlight key immune pathways that could serve as therapeutic targets to prevent disease progression in COVID‐19.

Phenotype and function of regulatory T cells (Treg) largely depend on the presence of the transcription factor FOXP3. In contrast to mice, human Treg cells express isoforms of this protein. Besides the full length version (FOXP3fl), an isoform lacking the exon 2 (FOXP3Δ2) is co-expressed in comparable amounts. Recently, a third splice variant has been described that in addition to exon 2 also misses exon 7 (FOXP3Δ2Δ7). Exon 7 encodes for a leucine zipper motif commonly used as structural dimerization element. Mutations in exon 7 have been linked to IPEX, a severe autoimmune disease suggested to be caused by impaired dimerization of the FOXP3 protein. This study shows that the lack of exon 7 does not affect (homo-) dimerization. Moreover, the interaction of FOXP3Δ2Δ7 to RUNX1, NFAT and NF-kB appeared to be unchanged in co-immunoprecipitation experiments and reporter gene assays, when compared to FOXP3fl and FOXP3Δ2. Nevertheless, retroviral transduction with FOXP3Δ2Δ7 failed to induce the typical Treg-associated phenotype. The expression of FOXP3-induced surface molecules such as CD25 and CTLA-4 were not enhanced in FOXP3Δ2Δ7 transduced CD4+ T cells, which also failed to exhibit any suppressive capacity. Notably, however, co-expression of FOXP3fl with FOXP3Δ2Δ7 resulted in a reduction of CD25 expression by a dominant negative effect. The leucine zipper of FOXP3 does not mediate dimerization or interaction with NFAT, NF-kB and RUNX1, but is indispensable for the characteristic phenotype and function in Treg cells. FOXP3Δ2Δ7 could play a role in regulating the function of the other FOXP3 isoforms and may be involved in cancer pathogenesis, as it is overexpressed by certain malignant cells.

Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1β inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.