In October 2021, researchers from the German Society of Allergy and Clinical Immunology (DGAKI) and from the Japanese Society of Allergology (JSA) focused their attention on the pathological ...conditions and modifiers of various allergic diseases. Topics included 1) the pathophysiology of IgE/mast cell-mediated allergic diseases; 2) the diagnosis and prevention of IgE/mast cell-mediated diseases; 3) the pathophysiology, diagnosis, and treatment of eosinophilic airway diseases; and 4) host–pathogen interaction and allergic diseases. This report summarizes the panel discussions, which highlighted the importance of recognizing the diversity of genetics, immunological mechanisms, and modifying factors underlying allergic diseases.
Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheat allergy ...in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP).
The aim of the present study was to investigate genetic variation that can contribute to susceptibility to HWP allergy.
We conducted a genome-wide association study of HWP allergy in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Replication was assessed by genotyping single nucleotide polymorphisms in independent samples comprising 45 patients with HWP allergy and 326 control subjects.
Through the genome-wide association study, we identified significant associations with the class II HLA region on 6p21 (P = 2.16 × 10−24 for rs9271588 and P = 2.96 × 10−24 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10−9). The associations were also confirmed in the replication data set. Both amino acid polymorphisms (HLA-DQβ1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA-DQ molecule achieved the genome-wide significance level (P < 5.0 × 10−8).
Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants.
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TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that ...multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations.
We performed a candidate gene case–control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations.
A meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene–gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively.
Our study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese.
Background To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations. Objective We ...hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs. Methods We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults). Results The lowest P value for GWAS analysis in the CAMP trial was 8.94 × 10−8 (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 × 10−5 ), rs2388639 (combined P = 8.56 × 10−9 ), and rs10044254 (combined P = 9.16 × 10−8 ) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants. Conclusions We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.
Long-term macrolide therapy used in the treatment of DPB has been shown to have beneficial effects on neutrophilic asthma and exacerbation of COPD by modulating mucin gene expression and mucin ...protein production and also by inhibiting neutrophil chemotaxis and survival.9 When we investigated the genetic effect of rs2523870 on the development of DPB (n = 108)7 or COPD (n = 307) using 4044 healthy adults as control subjects (the combined healthy subjects of the 2 discovery and replication samples), the C allele at rs2523870, the risk allele for late-onset asthma, was associated with DPB (P = 3.06 x 10-4; OR, 1.65) and COPD (P = 6.14 x 10-3; OR, 1.28; see Table E3 in this article's Online Repository at www.jacionline.org).
Hyperprogression has recently been recognized as a new pattern of progression in patients undergoing immune checkpoint inhibitor treatment. Here, we report two cases that showed hyperprogression ...during the initial phase of pembrolizumab treatment for metastatic urothelial carcinoma. The first patient, who received pembrolizumab as a second-line treatment, developed severe respiratory failure due to the rapid progression of lung metastases on the ninth day after the third pembrolizumab treatment. The second patient developed jaundice and hepatic dysfunction due to the progression of a metastatic lymph node of the liver hilum after the first administration of pembrolizumab. She developed multiple brain metastases with intraventricular bleeding on the 10th day after the second administration of pembrolizumab. It is important to be aware that hyperprogression sometimes occurs quite a while after starting treatment, and that both pseudoprogression and hyperprogression may occur in the early stage of treatment.
Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine that triggers dendritic cell-mediated T helper (Th)2 inflammatory responses, and is implicated in the pathogenesis of allergic diseases in ...humans. Two TSLP splice variants have been reported. To find functional genetic variants that might contribute to disease, we conducted analyses of single nucleotide polymorphisms (SNPs) of the TSLP gene in human bronchial epithelial cells. We surveyed SNPs on the TSLP gene by sequencing genomic DNA from 36 subjects, and characterized the linkage disequilibrium of the gene. We examined whether the SNPs have functional effects on mRNA expression or protein production using real-time PCR, reporter gene analysis, and enzyme-linked immunosorbent assay. We identified a total of 23 polymorphisms in the TSLP gene. The long form of TSLP, which is associated with allergic inflammation, was highly induced by poly(I:C) (double-stranded RNA) stimulation in normal human bronchial epithelial cells (NHBE) (P = 0.0060). The SNP rs3806933 (-847C > T) in the promoter region of long-form TSLP was found to create a binding site for the transcription factor activating protein (AP)-1, and in vitro functional analyses demonstrated that the SNP enhanced AP-1 binding to the regulatory element. The functional variant increased promoter-reporter activity of long-form TSLP in response to poly(I:C) stimulation in NHBE. Functional genetic polymorphism of the TSLP gene appears to contribute to Th2-polarized immunity through higher TSLP production by bronchial epithelial cells in response to viral respiratory infections.
Background NLR family, pyrin domain containing 3 (NLRP3), controls the activity of inflammatory caspase-1 by forming inflammasomes, which leads to cleavage of the procytokines IL-1β and IL-18. Recent ...studies have shown associations of human NLRP3 polymorphisms with susceptibility to various inflammatory diseases; however, the association with allergic diseases remains unclear. Objective We sought to examine whether NLRP3 polymorphisms are associated with susceptibility to food allergy, food-induced anaphylaxis, and aspirin-induced asthma (AIA). Methods We selected 15 tag single nucleotide polymorphisms (SNPs) of NLRP3 and conducted association analyses of NLRP3 using 574 and 1279 samples for food allergy and AIA, respectively. We further performed functional analyses of the susceptible SNPs. Results Two NLRP3 SNPs (rs4612666 and rs10754558) were significantly associated with susceptibility to food-induced anaphylaxis ( P = .00086 and P = .00068, respectively). The NLRP3 haplotype of the 2 SNPs also showed a significant association ( P = .000098). We could confirm the association with susceptibility to another hypersensitivity phenotype, AIA (rs4612666, P = .0096). Functional analysis revealed that the risk alleles of rs4612666 and rs10754558 increased the enhancer activity of NLRP3 expression and NLRP3 mRNA stability, respectively. Conclusion Our results indicate that the NLRP3 SNPs might play an important role in the development of food-induced anaphylaxis and AIA in a gain-of-function manner. Further research on the NLRP3 inflammasome will contribute to the development of novel diagnostic and therapeutic methods for food-induced anaphylaxis and AIA.
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