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Food allergy affects an estimated 8% of children in the United States. Oral immunotherapy (OIT) is a recently approved treatment, with outcomes ranging from sustained tolerance to food allergens to no apparent benefit. The immunological underpinnings that influence clinical outcomes of OIT remain largely unresolved. Using single-cell RNA-Seq and paired T cell receptor α/β (TCRα/β) sequencing, we assessed the transcriptomes of CD154+ and CD137+ peanut-reactive T helper (Th) cells from 12 patients with peanut allergy longitudinally throughout OIT. We observed expanded populations of cells expressing Th1, Th2, and Th17 signatures that further separated into 6 clonally distinct subsets. Four of these subsets demonstrated a convergence of TCR sequences, suggesting antigen-driven T cell fates. Over the course of OIT, we observed suppression of Th2 and Th1 gene signatures in effector clonotypes but not T follicular helper-like (Tfh-like) clonotypes. Positive outcomes were associated with stronger suppression of Th2 signatures in Th2A-like cells, while treatment failure was associated with the expression of baseline inflammatory gene signatures that were present in Th1 and Th17 cell populations and unmodulated by OIT. These results demonstrate that differential clinical responses to OIT are associated with both preexisting characteristics of peanut-reactive CD4+ T cells and suppression of a subset of Th2 cells.

Current laboratory tests are less than 50% accurate in distinguishing between people who have food allergies (FA) and those who are merely sensitized to foods, resulting in the use of expensive and potentially dangerous Oral Food Challenges. This study presents a purely-computational machine learning approach, conducted using DNA Methylation (DNAm) data, to accurately diagnose food allergies and potentially find epigenetic targets for the disease. An unbiased feature-selection pipeline was created that narrowed down 405,000+ potential CpG biomarkers to 18. Machine-learning models that utilized subsets of this 18-feature aggregate achieved perfect classification accuracy on completely hidden test cohorts (on an 8-fold hidden dataset). Ensemble classification was also shown to be effective for this High Dimension Low Sample Size (HDLSS) DNA methylation dataset. The efficacy of these machine learning classifiers and the 18 CpGs was further validated by their high accuracy on a large number of hidden data permutations, where the samples in the training, cross-validation, and hidden sets were repeatedly randomly allocated. The 18-CpG signature mapped to 13 genes, on which biological insights were collected. Notably, many of the FA-discriminating genes found in this study were strongly associated with the immune system, and seven of the 13 genes were previously associated with FA. Previous studies have also created highly-accurate classifiers for this dataset, using both data-driven and a priori biological insights to construct a 96-CpG signature. This research builds on previous work because it uses a completely computational approach to obtain a perfect classification accuracy while using only 18 highly discriminating CpGs (0.005% of the total available features). In machine learning, simpler models, as used in this study, are generally preferred over more complex ones (other things being equal). Lastly, the completely data-driven methodology presented in this research eliminates the need for a priori biological information and allows for generalizability to other DNAm classification problems.

Mechanisms driving acute food allergic reactions have not been fully characterized. We profile the dynamic transcriptome of acute peanut allergic reactions using serial peripheral blood samples obtained from 19 children before, during, and after randomized, double-blind, placebo-controlled oral challenges to peanut. We identify genes with changes in expression triggered by peanut, but not placebo, during acute peanut allergic reactions. Network analysis reveals that these genes comprise coexpression networks for acute-phase response and pro-inflammatory processes. Key driver analysis identifies six genes ( LTB4R , PADI4 , IL1R2 , PPP1R3D , KLHL2 , and ECHDC3 ) predicted to causally modulate the state of coregulated networks in response to peanut. Leukocyte deconvolution analysis identifies changes in neutrophil, naive CD4 + T cell, and macrophage populations during peanut challenge. Analyses in 21 additional peanut allergic subjects replicate major findings. These results highlight key genes, biological processes, and cell types that can be targeted for mechanistic study and therapeutic targeting of peanut allergy. Rising rates of peanut allergy pose a public health problem. Here, the authors profile blood transcriptomes during double-blind, placebo-controlled oral challenge in peanut-allergic children to identify gene and cell composition changes, and construct causal networks to detect key allergic reaction drivers.

Mutations in the filaggrin gene are associated with a broad range of skin and allergic diseases. The biology of this molecule and the role of mutations in its altered function offer new insights into a range of conditions not previously thought to be related to one another. Mutations in the filaggrin gene ( FLG ) are among the most common and profound single-gene defects identified to date in the causation and modification of disease. FLG encodes an important epidermal protein abundantly expressed in the outer layers of the epidermis. 1 Approximately 10% of persons of European ancestry are heterozygous carriers of a loss-of-function mutation in FLG, resulting in a 50% reduction in expressed protein. 2 The critical role of filaggrin in epidermal function underlies the pathogenic importance of this gene in common dermatologic and allergic diseases. The spectrum of such diseases encompasses monogenic disorders of keratinization through complex abnormalities . . .

Hypersensitivity reactions to abacavir are tightly associated with HLA-B*5701. In this global, multicenter, prospective, randomized study, 1956 patients with HIV-1 infection who had not previously received abacavir were randomly assigned to undergo HLA-B*5701 screening or to receive the standard of care. Screening eliminated immunologically confirmed hypersensitivity reaction to abacavir in this predominantly white population. In this case, a pharmacogenetic test can prevent the toxic effects of this drug. Hypersensitivity reactions to abacavir are tightly associated with HLA-B*5701. In this study of patients with HIV-1 infection, HLA-B*5701 screening eliminated immunologically confirmed hypersensitivity reaction to abacavir. Pharmacogenetic testing is not widely used in routine clinical practice to optimize drug choice or clinical management. 1 This gap between scientific knowledge and clinical application may be explained by the fact that the successful incorporation of a pharmacogenetic test into routine practice requires a combination of high-level evidence that can be generalized to diverse clinical settings, widespread availability of cost-effective and reliable laboratory tests, and effective strategies to incorporate testing into routine clinical practice. Abacavir is a nucleoside reverse-transcriptase inhibitor with activity against the human immunodeficiency virus (HIV), available for once-daily use in combination with other antiretroviral agents, that has . . .

We investigated the interplay between genetics and oral peanut protein exposure in the determination of the immunological response to peanut using the targeted intervention in the LEAP clinical trial. We identified an association between peanut-specific IgG4 and HLA-DQA1*01:02 that was only observed in the presence of sustained oral peanut protein exposure. The association between IgG4 and HLA-DQA1*01:02 was driven by IgG4 specific for the Ara h 2 component. Once peanut consumption ceased, the association between IgG4-specific Ara h 2 and HLA-DQA1*01:02 was attenuated. The association was validated by observing expanded IgG4-specific epitopes in people who carried HLA-DQA1*01:02. Notably, we confirmed the previously reported associations with HLA-DQA1*01:02 and peanut allergy risk in the absence of oral peanut protein exposure. Interaction between HLA and presence or absence of exposure to peanut in an allergen- and epitope-specific manner implicates a mechanism of antigen recognition that is fundamental to driving immune responses related to allergy risk or protection.

RationaleTraffic-related air pollution has been shown to augment allergy and airway disease. However, the enhancement of allergenic effects by diesel exhaust in particular is unproven in vivo in the human lung, and underlying details of this apparent synergy are poorly understood.ObjectiveTo test the hypothesis that a 2 h inhalation of diesel exhaust augments lower airway inflammation and immune cell activation following segmental allergen challenge in atopic subjects.Methods18 blinded atopic volunteers were exposed to filtered air or 300 µg PM2.5/m3 of diesel exhaust in random fashion. 1 h post-exposure, diluent-controlled segmental allergen challenge was performed; 2 days later, samples from the challenged segments were obtained by bronchoscopic lavage. Samples were analysed for markers and modifiers of allergic inflammation (eosinophils, Th2 cytokines) and adaptive immune cell activation. Mixed effects models with ordinal contrasts compared effects of single and combined exposures on these end points.ResultsDiesel exhaust augmented the allergen-induced increase in airway eosinophils, interleukin 5 (IL-5) and eosinophil cationic protein (ECP) and the GSTT1 null genotype was significantly associated with the augmented IL-5 response. Diesel exhaust alone also augmented markers of non-allergic inflammation and monocyte chemotactic protein (MCP)-1 and suppressed activity of macrophages and myeloid dendritic cells.ConclusionInhalation of diesel exhaust at environmentally relevant concentrations augments allergen-induced allergic inflammation in the lower airways of atopic individuals and the GSTT1 genotype enhances this response. Allergic individuals are a susceptible population to the deleterious airway effects of diesel exhaust.Trial registration numberNCT01792232.

The immune system defends the body against certain tumor cells and against foreign agents such as fungi, parasites, bacteria, and viruses. One of its main roles is to distinguish endogenous components from non-self-components. An unproperly functioning immune system is prone to primary immune deficiencies caused by either primary immune deficiencies such as genetic defects or secondary immune deficiencies such as physical, chemical, and in some instances, psychological stressors. In the manuscript, we will provide a brief overview of the immune system and immunotoxicology. We will also describe the biochemical mechanisms of immunotoxicants and how to evaluate immunotoxicity.

Tick-bite hypersensitivity encompasses a range of clinical manifestations, from localized allergic reactions to systemic conditions like alpha-gal syndrome (AGS), an IgE-mediated allergy to galactose-α-1,3-galactose (α-Gal). This study investigated the clinical, molecular, immunological, and genetic features of two hypersensitivity cases. Two cases were analyzed: a 30-year-old woman with fixed drug reaction (FDR)-like hypersensitivity and a 10-year-old girl with AGS exhibiting borderline α-Gal-specific IgE. Diagnostic methods included allergen-specific IgE quantification, HLA genotyping, histopathological examination, and the molecular detection of tick-borne pathogens using microfluidic PCR. Case I demonstrated histopathological features of chronic lymphocytic inflammation and eosinophilic infiltrates, with HLA-B13 and DRB113 alleles indicating genetic susceptibility to hypersensitivity, while histological findings suggested a localized FDR-like reaction. Case II exhibited borderline α-Gal-specific IgE, resolving completely with a mammalian-free diet. The presence of HLA-DRB101 and DQB1*05 in the second patient indicated a genetic predisposition to AGS and other atopic conditions. No infectious etiology was identified in either case. These findings emphasize the heterogeneity of tick-related hypersensitivity and the importance of HLA genotypes in susceptibility. Comprehensive molecular, immunological, and genetic profiling offers valuable insights into the mechanisms of hypersensitivity, supporting personalized approaches for the diagnosis and management of tick-induced allergic conditions.

Key Points Allopurinol is a highly effective, cheap and simple therapy for gout if dosing is adequate and patients adhere to the therapy Serious allopurinol-related adverse events (for example, allopurinol hypersensitivity syndrome [AHS]) are rare, but are associated with high morbidity and mortality Risk factors for allopurinol-related serious adverse events include recent introduction of allopurinol, the presence of the HLA-B * 58:01 allele, a higher starting dose, renal impairment and the concomitant use of diuretics Allopurinol hypersensitivity is primarily mediated by an oxypurinol-specific T-cell response Although a generally safe and effective drug that is widely used in the treatment of gout, allopurinol can in rare instances be associated with severe adverse events. The presentation, risk factors and mechanisms of allopurinol-induced hypersensitivity are the focus of this Review, as well as strategies to avoid or minimize such reactions. Allopurinol is the most commonly prescribed urate-lowering therapy for the management of gout. Serious adverse reactions associated with allopurinol, while rare, are feared owing to the high mortality. Such reactions can manifest as a rash combined with eosinophilia, leukocytosis, fever, hepatitis and progressive kidney failure. Risk factors for allopurinol-related severe adverse reactions include the recent introduction of allopurinol, the presence of the HLA-B * 58:01 allele, and factors that influence the drug concentration. The interactions between allopurinol, its metabolite, oxypurinol, and T cells have been studied, and evidence exists that the presence of the HLA-B * 58:01 allele and a high concentration of oxypurinol function synergistically to increase the number of potentially immunogenic-peptide–oxypurinol– HLA-B * 58:01 complexes on the cell surface, thereby increasing the risk of T-cell sensitization and a subsequent adverse reaction. This Review will discuss the above issues and place this in the clinical context of reducing the risk of serious adverse reactions.