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Allergic diseases (atopic dermatitis, food allergy, eosinophilic esophagitis, asthma and allergic rhinitis), perhaps more than many other traditionally grouped disorders, share several overlapping inflammatory pathways and risk factors, though we are still beginning to understand how the relevant patient and environmental factors uniquely shape each disease. Precision medicine is the concept of applying multiple levels of patient-specific data to tailor diagnoses and available treatments to the individual; ideally, a patient receives the right intervention at the right time, in order to maximize effectiveness but minimize morbidity, mortality and cost. While precision medicine in allergy is in its infancy, the recent success of biologics, development of tools focused on large data set integration and improved sampling methods are encouraging and demonstrates the utility of refining our understanding of allergic endotypes to improve therapies. Some of the biggest challenges to achieving precision medicine in allergy are characterizing allergic endotypes, understanding allergic multimorbidity relationships, contextualizing the impact of environmental exposures (the “exposome”) and ancestry/genetic risks, achieving actionable multi-omics integration, and using this information to develop adequately powered patient cohorts and refined clinical trials. In this paper, we highlight several recently developed tools and methods showing promise to realize the aspirational potential of precision medicine in allergic disease. We also outline current challenges, including exposome sampling and building the “knowledge network” with multi-omics integration.

Hard metal lung disease (HMLD) is an occupational lung disease specific to inhalation of cobalt-containing particles whose mechanism is largely unknown. Cobalt is a known hypoxia mimic and stabilizer of the alpha subunits of hypoxia-inducible factors (HIFs). Previous work revealed that though HIF1α contrib utes to cobalt toxicity in vitro, loss of HIF1α in the alveolar epithelial cells does not provide in vivo protection from cobalt-induced lung inflammation. HIF1α and HIF2α show unique tissue expression profiles, and HIF2α is known to be the predominant HIF mRNA isoform in the adult lung. Thus, if HIF2α activation by cobalt contributes to pathophysiology of HMLD, we hypothesized that loss of HIF2α in lung epithelium would provide protection from cobalt-induced inflammation. Mice with HIF2α-deficiency in Club and alveolar type II epithelial cells (ATIIs) (HIF2α(Δ/Δ)) were exposed to cobalt (60 µg/day) or saline using a subacute occupational exposure model. Bronchoalveolar lavage cellularity, cytokines, qRT-PCR, and histopathology were analyzed. Results show that loss of HIF2α leads to enhanced eosinophilic inflammation and increased goblet cell metaplasia. Additionally, control mice demonstrated a mild recovery from cobalt-induced lung injury compared with HIF2α(Δ/Δ) mice, suggesting a role for epithelial HIF2α in repair mechanisms. The expression of important cytokines, such as interleukin (IL)-5 and IL-10, displayed significant differences following cobalt exposure when HIF2α(Δ/Δ) and control mice were compared. In summary, our data suggest that although loss of HIF2α does not afford protection from cobalt-induced lung inflammation, epithelial HIF2α signaling does play an important role in modulating the inflammatory and repair response in the lung.

Hereditary angioedema (HAE) is defined as a rare genetic disease with recurrent episodes of localized bradykinin-mediated swelling of the deep tissues of the skin, respiratory, and gastrointestinal tracts that can be life threatening. Classification of HAE has evolved over time with our further understanding of clinical phenotypes, underlying causes, and available testing. In most cases, HAE is caused by a deficiency of C1-esterase inhibitor (C1-INH) on the Serpin Family G Member 1 (SERPING1) gene, either through decreased amounts of C1-INH protein (C1-INH‐HAE, type 1) or decreased function of C1-INH (C1-INH‐HAE, type 2). HAE with normal C1-INH levels and function are divided into unknown cause or into non‐C1-INH‐HAE forms, which include known mutational defects in factor XII (called FXII-HAE in the Hereditary Angioedema International Working Group consensus), angiopoietin-1, plasminogen, and kininogen 1 genes. It is possible that, after an initial workup, a patient without a family history of HAE could be classified with an acquired form of angioedema (nonhereditary) that may later prove to be HAE due to a de-novo SERPING1 mutation. Because there are forms of nonhistaminergic (H1-antihistamine unresponsive) angioedema that appear clinically very similar to HAE, it is essential that the patient undergoes a thorough clinical history and diagnostic evaluation to ensure that he or she is properly diagnosed and classified.

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Hypoxia is a state of decreased oxygen reaching the tissues of the body. During prenatal development, the fetus experiences localized occurrences of hypoxia that are essential for proper organogenesis and survival. The response to decreased oxygen availability is primarily regulated by hypoxia-inducible factors (HIFs), a family of transcription factors that modulate the expression of key genes involved in glycolysis, angiogenesis, and erythropoiesis. HIF-1α and HIF-2α, two key isoforms, are important in embryonic development, and likely are involved in lung morphogenesis. We have recently shown that the inducible loss of Hif-1α in lung epithelium starting at E4.5 leads to death within an hour of parturition, with symptoms similar to neonatal respiratory distress syndrome (RDS). In addition to Hif-1α, Hif-2α is also expressed in the developing lung, although the overlapping roles of Hif-1α and Hif-2α in this context are not fully understood. To further investigate the independent role of Hif-2α in lung epithelium and its ability to alter Hif-1α-mediated lung maturation, we generated two additional lung-specific inducible Hif-α knockout models (Hif-2α and Hif-1α+Hif-2α). The intrauterine loss of Hif-2α in the lungs does not lead to decreased viability or observable phenotypic changes in the lung. More interestingly, survivability observed after the loss of both Hif-1α and Hif-2α suggests that the loss of Hif-2α is capable of rescuing the neonatal RDS phenotype seen in Hif-1α-deficient pups. Microarray analyses of lung tissue from these three genotypes identified several factors, such as Scd1, Retlnγ, and Il-1r2, which are differentially regulated by the two HIF-α isoforms. Moreover, network analysis suggests that modulation of hormone-mediated, NF-κB, C/EBPα, and c-MYC signaling are central to HIF-mediated changes in lung development.

Allergic airway disease is characterized by a T helper type 2 cell-mediated airway inflammation and airway hyperresponsiveness. Little is known about the role of hypoxia-mediated signaling in the progression of the disease. To address this knowledge gap, a mouse model was created in which doxycycline exposure induces the functional deletion of hypoxia inducible factor-1α from alveolar type II and Clara cells of the lung. When hypoxia inducible factor-1α deletion was induced during the early postnatal development period of the lung, the mice displayed an enhanced response to the ovalbumin model of allergic airway disease. These hypoxia inducible factor-1α-deficient mice exhibit increased cellular infiltrates, eosinophilia in the lavage fluid and parenchyma, and T helper type 2 cytokines, as compared with ovalbumin-treated control mice. Moreover, these hypoxia inducible factor-1α-deficient mice display increased airway resistance when compared with their control counterparts. Interestingly, if the loss of hypoxia inducible factor-1α was induced in early adulthood, the exacerbated phenotype was not observed. Taken together, these results suggest that epithelial hypoxia inducible factor-1α plays an important role in establishing the innate immunity of the lung and epithelial-specific deficiency in the transcription factor, during early postnatal development, increases the severity of inflammation and functional airway resistance, following ovalbumin challenge. Finally, these results might explain some of the chronic respiratory pathology observed in premature infants, especially those that receive supplemental oxygen. This early hyperoxic exposure, from normal ambient and supplemental oxygen, would presumably inhibit normal hypoxia inducible factor-1α signaling, mimicking the functional deletion described.