This review aims to summarize the established and potential targets of glucocorticoids (GCs) on mast cells, which are implicated in the pathophysiology of various allergic and inflammatory diseases including asthma, allergic rhinitis, and atopic dermatitis. We sought to answer the following questions: (1) How do glucocorticoids inhibit the release of mediators from mast cells? (2) What are the effects of glucocorticoids on mast cell signaling molecules? (3) By what mechanisms do glucocorticoids induce mast cell apoptosis? and (4) What are the genomic and non-genomic mechanisms underlying these effects? Evidence published since 2020 reinforces that glucocorticoid effects on mast cells are context dependent rather than uniform. Dexamethasone can directly suppress selected functions of human and murine mast cells, including in combination with inhibitory CD300a signaling [22]. Conversely, activated human lung mast cells can reduce corticosteroid responsiveness in neighboring airway smooth muscle cells by altering glucocorticoid-regulated transcription [23]. In patients with asthma, six weeks of inhaled budesonide reduced airway mast cell infiltration and improved airway hyperresponsiveness; importantly, associations differed according to mast cell phenotype, airway location, and inflammatory phenotype [25]. Single-cell studies now reveal multiple human mast cell transcriptional states across tissues [7, 8], while integrated RNA-seq and H3K27ac profiling in primary human mast cells demonstrates selective regulation of mast-cell identity genes and super-enhancer networks [92]. These findings place glucocorticoid responsiveness within a framework of mast cell state, tissue niche, species, glucocorticoid compound, and experimental context. Glucocorticoid-associated mast cell depletion may involve reduced stromal/fibroblast-derived SCF and, in IL-3-dependent murine models, reduced IL-3 receptor expression; these are mechanistically distinct effects. Glucocorticoids can target mast cells at several levels, including mediator synthesis and release, intracellular signaling, survival, and transcriptional regulation, but the magnitude and nature of these effects vary substantially among species, tissue compartments, mast cell phenotypes/states, glucocorticoid compounds, activation pathways, and experimental conditions. Classical GR-dependent transcription involves GRE-dependent regulation and interactions with transcription factors such as NF-κB and AP-1, yet mast-cell-specific GR-regulated gene and chromatin programs remain incompletely defined. Rapid effects on degranulation are also unresolved, with evidence for membrane-associated classical GR signaling as well as other rapid mechanisms. Contemporary human and single-cell data therefore argue against treating mast cells as a single uniformly corticosteroid-responsive population. Future studies should define the molecular basis of rapid glucocorticoid signaling and map GR-responsive transcriptional and chromatin programs across primary human mast cell states and tissue niches.
The prevalence of cannabis and nicotine vaporizer use appears to be increasing, but their effects on the respiratory system are incompletely elucidated. This review brings together clinical, pathologic, and molecular knowledge describing airway disease, acute lung injury syndromes, and structural lung injury resulting from nicotine and cannabis vaporizer use. We describe consistent epidemiologic associations of nicotine vaporizer use with obstructive lung disease, bronchitis, emphysema, and constrictive bronchiolitis; cannabis vaporizer use is more frequently associated with acute lung injury and airway disease symptoms. At a molecular level, nicotinic receptor activation drives collagen deposition, epithelial barrier dysfunction, and impaired mucociliary clearance; cannabinoid receptor activation has effects on airway inflammation, epithelial integrity, and immune cell function. Oxidative stress and mitochondrial dysfunction likely mediate effects of nicotine and cannabis vaporizer exposure through receptor-independent mechanisms. Use of nicotine and cannabis vaporizers affects clinical pulmonary disease through a variety of converging molecular and cellular mechanisms in the respiratory epithelium. Significant knowledge gaps remain, particularly with regard to molecular investigations of cannabis vaporizer use and dual nicotine-cannabis vaporizer use. Future investigations integrating molecular mechanisms of disease with clinical and histopathologic outcomes are necessary to better characterize the effects of these increasingly impactful public health risks.
Asthma and obesity are affecting children and teenagers at higher rates than previous generations. Epidemiological data link obesity during childhood with the subsequent development of asthma. In this review we describe developmental and inflammatory factors that contribute to asthma severity in children with obesity. Asthma driven by obesity is likely due to both structural and inflammatory changes. Excess weight places mechanical stress on the airway thereby reducing lung volumes. In addition, obesity is linked to chronic inflammation. Adipose tissue releases pro-inflammatory cytokines (IL-6 and TNF-α) which drives the airway towards hyperresponsiveness. This “obesity-related asthma” phenotype does not respond well to corticosteroids making these patients difficult to treat. In children and teenagers, treatment options are limited to currently approved asthma medications; however, improvement in asthma control has been observed in adults utilizing metformin and GLP-1 agonists. Children with obesity are more likely to develop asthma. Their asthma symptoms tend to be more frequent and harder to control. With the rate of obesity on the rise, it is paramount to identify the mechanisms underlying systemic inflammation in those with elevated BMIs. This will allow us to find better treatment options for “obesity-related asthma.”
Delayed drug hypersensitivity reactions span mild cutaneous eruptions, severe cutaneous adverse reactions (SCARs), and internal-organ injury. We review how pharmacogenomic, single-cell, and spatial methods have shown that these syndromes are driven by shared effector mechanisms, and how identifying which one predominates opens the way to targeted treatment. HLA associations are necessary but not sufficient to explain who reacts. Susceptibility is increasingly attributed to a pre-existing, often virus-shaped T-cell repertoire and to where tissue-resident memory T cells reside. Multiomic profiling of SJS/TEN identifies a cytotoxic CD8⁺ resident-memory population shared across HLA alleles and culprit drugs and implicates interferon and JAK-STAT signaling in keratinocyte death. AGEP and generalized pustular psoriasis show concordant transcriptomic signatures, placing AGEP within a targetable IL-36-driven spectrum. The IL-5 axis and herpesvirus reactivation are reframing DRESS, generalized bullous fixed drug eruption is increasingly recognized as a SCAR, and the same effector signature recurs in checkpoint inhibitor toxicity. Diagnostic testing remains unstandardized, and no biomarker reliably identifies the dominant mechanism. Because the dominant mechanism determines the phenotype more than the culprit drug does, therapy can be directed at the effector, with TNF-α, IL-36, IL-5, and JAK inhibitors. Rarity makes randomized trials difficult, so registry-based and adaptive designs are more realistic.
Allergic disease is common in the United States, and a growing number of otherwise qualified applicants and service members present with histories of food allergy, venom allergy, medication reactions, physical urticarias, or prior anaphylaxis. The challenge for clinicians is to translate a nuanced allergy-immunology evaluation into strict military accession and retention standards designed for readiness, austere care, and deployability, rather than for diagnosis alone. The current accession standard disqualifies a history of anaphylaxis other than to a single medication or medication class; systemic allergic reactions to biting or stinging insects unless limited to a large local reaction or accompanied by documentation of 3 years of maintenance venom immunotherapy; acute allergic reactions to fish, crustaceans, shellfish, peanuts, or tree nuts when food-specific IgE is accompanied by a correlating clinical history; and cold- or exercise-induced urticaria [1]. Retention standards are more functional and focus on recurrent anaphylaxis that persists despite treatment, requires long-term duty limitations, or prevents return to duty [2]. Newer therapeutic options, including oral immunotherapy (OIT) and omalizumab, raise reaction thresholds for selected patients but do not establish unrestricted tolerance.[3, 4] This latter point precludes serving in operational settings. A clinically useful waiver evaluation should differentiate sensitization from clinical allergy. Resolved allergy versus desensitization or sustained unresponsiveness should also be determined. The identification of cofactors that lower reaction thresholds, and specifying whether the individual can safely train, deploy, subsist on field rations, and function without refrigeration-dependent or injectable therapy is imperative. Major gaps remain. These include few military-specific outcome data on allergy waivers, limited validated biomarkers that predict future anaphylaxis severity, and no standardized pathway for cold- or exercise-induced urticaria comparable with the venom immunotherapy exception. Military allergy standards are risk standards, not allergy practice parameters. The operative question is whether the condition predicts unacceptable operational risk or duty limitation. IgE sensitization without a convincing clinical history should not be equated with food (or venom) allergy; conversely, a remote history of anaphylaxis requires objective documentation of resolution or durable risk reduction. A successful oral food challenge is the most useful way to document tolerance, but it must specify food form, dose schedule, cumulative amount, observation findings, and pass/fail outcome. Venom allergy is unique because DoDI explicitly recognizes a waiver-supporting pathway after 3 years of maintenance venom immunotherapy. Oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and omalizumab may reduce risk, but ongoing dependence on daily dosing, injections, or refrigeration may conflict with accession standards and deployment requirements.
