Integrated genomics point to immune vulnerabilities in pleural mesothelioma.

Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

Early-life domestic aeroallergen exposure and IgE sensitization at age 4 years.

BACKGROUND: Although it is widely assumed that childhood sensitization to common aeroallergens is directly related to allergen exposure in early life, few longitudinal studies have investigated this issue, and available data are scarce and mainly limited to high-risk groups. OBJECTIVE: We sought to assess the role of early exposure to 2 major household aeroallergens (Der p 1 and Fel d 1) in sensitization at the age of 4 years. METHODS: Pregnant women and their children were recruited for the Asthma Multicenter Infant Cohort Study. Three cohorts (Ashford in the United Kingdom and Menorca and Barcelona in Spain) followed the same research protocol. A total of 1611 newborn children were initially included in the cohort, from whose homes we collected dust samples at 3 months of age for 1474; Der p 1 and Fel d 1 levels were measured. Of these children, we obtained blood for specific IgE determination in 1019. RESULTS: The risk of Fel d 1 sensitization increased with exposure in a nonlinear manner. No association was found between specific IgE to Der p 1 and aeroallergen levels of exposure at early life in 2 centers, but a positive association was observed in the third. CONCLUSIONS: The dose-response relationships between allergen exposure and sensitization differ between allergens and might vary between different locales. The hypothesis that sensitization to house dust mite is directly related to levels of allergen exposure might not apply to the general population or to different ranges of exposure. CLINICAL IMPLICATIONS: Aeroallergen avoidance might not have any important effect on the incidence of sensitization.

Modified Th2 responses at high-dose exposures to allergen: using an occupational model.

RATIONALE: The relationships between allergen exposures and allergy and asthma are complex. High exposure levels to cat allergen are associated with IgG- and IgG(4)-specific antibody responses without sensitization or risk of asthma, a process described as a "modified Th2 response." Attenuation of risk of allergy and asthma at high exposure levels has been reported in longitudinal studies of both childhood and occupational asthma. OBJECTIVES: To investigate, using an occupational model, the relationships among estimated exposure to aeroallergens, the production of specific IgE, IgG and IgG(4) antibodies, and the prevalence of associated symptoms. METHODS: Cross-sectional survey of employees exposed to rats at work on six pharmaceutical sites across the United Kingdom. A total of 689 (89%) provided a blood sample and completed a questionnaire. MEASUREMENTS AND MAIN RESULTS: At highest exposure to rats, there was an attenuation of the exposure response for sensitization and symptoms. In contrast, the frequency of individuals producing high quantities of specific IgG and IgG(4) increased with exposure intensity. Ratios of IgG(4)/IgE were highest in those handling the greatest number of rats. Risk of developing work-related chest symptoms was lower for those who produced both specific IgE and IgG(4) compared to those with specific IgE only. CONCLUSIONS: High exposure to rats is associated with lower rates of specific IgE and symptoms but an increased frequency of high specific IgG and IgG(4) production. Specific IgG(4) produced together with specific IgE may reduce the risk of developing work-related chest symptoms compared with when specific IgE is produced alone.

Is occupational asthma to diisocyanates a non-IgE-mediated disease?

BACKGROUND: Exposure to diisocyanates in the workplace is an important cause of occupational asthma. The majority of patients with diisocyanate-induced asthma have no detectable diisocyanate-specific IgE antibodies in serum. There has been much debate as to whether this is due to diisocyanate-induced asthma being mediated by non-IgE mechanisms or whether it is the result of using inappropriate conjugates. OBJECTIVE: We sought to determine whether RNA message for Cepsilon, IL-4, and other associated inflammatory markers could be detected locally within the bronchial mucosa after diisocyanate challenge. METHODS: Fiberoptic bronchoscopic bronchial biopsy specimens were obtained at 24 hours after both a control and an active challenge in 5 patients with positive and 7 patients with negative inhalation test responses to diisocyanates. Using both immunohistochemistry and in situ hybridization, we determined mRNA for Cepsilon, IL-4, IL-5, and other associated inflammatory markers. RESULTS: There was a striking absence of Cepsilon and IL-4 mRNA-positive cells in bronchial biopsy specimens from patients challenged with diisocyanate (Cepsilon median of 0 and interquartile range of 0-1.85; IL-4 median of 0 and interquartile range of 0-0.85). In contrast, there were increased numbers of IL-5-, CD25-, and CD4-positive cells and a trend toward an increase in eosinophils after active challenge with diisocyanate. CONCLUSION: We found a striking absence of both bronchial Cepsilon and IL-4 RNA message after inhalation challenge with diisocyanates, irrespective of whether the challenge test response was positive or negative. We propose that diisocyanate-induced asthma is a non-IgE-mediated disease, at least in patients in whom specific IgE antibodies to diisocyanates are undetectable.

HLA associations with occupational sensitization to rat lipocalin allergens: a model for other animal allergies?

BACKGROUND: Laboratory animal allergy is a common occupational health problem affecting between 11% and 44% of exposed researchers. Allergy to rats and mice is most common, probably because these are the animals most frequently used. OBJECTIVE: We hypothesized that HLA class II molecules, involved in the presentation of allergen to the T cell and likely candidates for controlling the immune response, might be associated with sensitization to rat urinary proteins among laboratory animal handlers. METHODS: We undertook a cross-sectional study of 741 employees at 6 pharmaceutical sites across the United Kingdom who had contact at work with laboratory rats. In all, 109 cases with specific sensitization to rat proteins and 397 referents were HLA-typed for DRB1 and DQB1 loci. Amino acid analyses of significantly associated HLA molecules were carried out. RESULTS: HLA-DR7 was associated with sensitization (odds ratio [OR], 1.82; CI, 1.12-2.97), respiratory symptoms at work (OR, 2.96; CI, 1.64-5.37) and, most strongly, sensitization with symptoms (OR, 3.81; CI, 1.90-7.65). HLA-DR3 was protective against sensitization (OR, 0.55; CI, 0.31-0.97). Amino acid analyses of these 2 molecules indicated a biologically plausible explanation for the associations. CONCLUSION: HLA phenotype is an important determinant of individual susceptibility to sensitization and asthma among laboratory animal workers. Similar mechanisms might apply in other animal allergies.