R. Stokes Peebles

Background: Most peanut allergic patients have antibodies to Ara h 1. Many studies have focused on the C‐terminal vicilin region, with less attention concentrated on the N‐terminal α‐hairpinin domain. This study evaluated human monoclonal antibodies targeted to both regions. Methods: Microarrays of Ara h 1 peptides were probed for serum IgE binding. Human monoclonal antibodies to Ara h 1 were discovered from single‐cell sequencing and hybridoma technologies. Western blots evaluated the cleavage pattern of Ara h 1 in peanuts. A mouse model of passive systemic anaphylaxis (PSA) evaluated the functional coupling of antibodies. ELISAs established antibody specificities. Results: In 75 allergic patients, the most frequently recognized peptides from Ara h 1 were in the unstructured region (91%), the α‐hairpinin (86%), and the vicilin region (79%). Monoclonal antibodies were divided by specificity for the α‐hairpinin and vicilin regions with no significant cross‐reactivity observed. The anti‐α‐hairpinin mAb 40C7 blocked 55%–92% of patient IgE to the domain in seven patients; ELISA results showed the epitope of 40C7 was associated with a frequently recognized peptide found via microarray. Pairing of anti‐α‐hairpinin mAbs failed to induce anaphylaxis via PSA; however, a single mAb against the vicilin region induced anaphylaxis when challenged with nAra h 1. Conclusions: The α‐hairpinin of Ara h 1 contains a dominant epitope that is both frequently recognized and blocks a majority of the IgE against this domain. Including this region in tests may improve diagnosis of peanut allergy. The trimeric structure of the vicilin region explains the ability of Ara h 1 to induce anaphylaxis with a single antibody.

Prostaglandin I2 (PGI2) signaling is vasoprotective. Further, PGI2 signaling exhibits immunomodulatory properties that largely promote an anti-inflammatory state. Inflammation and immune activity are associated with the development of hypertension. However, it remains unknown whether exogeneous PGI2 can restrain the immune and inflammatory responses in the context of hypertension. A phenome-wide association study evaluated single-nucleotide polymorphisms (SNPs) in the receptor for PGI2, IP (gene name PTGIR), and the associated odds of developing cardiovascular pathologies. C57Bl/6J mice underwent one of two models to evaluate the effect of an exogenous PGI2 analog on aortic inflammation and hypertension. Mice were either administered the PGI2 analog, treprostinil (TPL), at the initiation of angiotensin II (Ang II) infusion to determine the effect of TPL on the development of inflammation and hypertension, or mice were administered TPL after 2 weeks of Ang II to determine the ability of TPL to reduce blood pressure and inflammation in established hypertension. Humans who were heterozygous for an SNP in IP had a significantly greater odds ratio for several vascular pathologies compared to controls. Mice that received TPL at the onset of Ang II infusion were protected from developing hypertension and exhibited reduced aortic inflammation. Mice that received TPL two weeks after initiation of Ang II infusion exhibited a significant reduction in their blood pressure, decreased aortic inflammation, diminished aortic fibrosis, and fewer splenic Th1 cells compared to vehicle treatment. Exogeneous PGI2 signaling protects against the development and/or maintenance of Ang II-induced hypertension, possibly through inhibition of Th1 cell function.

Estrogen receptor-alpha (ER-α) signaling increased obesity and allergen-induced airway inflammation in mice. In addition, women with obesity and asthma had increased circulating Th17 cells compared with men with obesity and asthma. These findings provide mechanistic insights into the intersection of obesity, sex hormones, and airway inflammation—underscoring the importance of personalized approaches to managing individuals with obesity and asthma.

Pulmonary group 2 innate lymphoid cells (ILC2s) are key drivers of Type 2 inflammation in diseases like asthma, yet the molecular mechanisms regulating their function are incompletely understood. Using the genetically diverse Collaborative Cross (CC) mouse panel, we mapped a quantitative trait locus (QTL) that governs ILC2 prevalence in the lung after aeroallergen exposure. This QTL induces a large population of ILC2s in the lung that are resistant to activation and have diminished Type 2 effector function. We identified free-fatty acid receptor 3 ( Ffar3 ) as a gene responsible for this effect and demonstrated that FFAR3 signaling reprograms ILC2s to an anti-inflammatory state by promoting their survival, reducing Type 2 cytokine production, and enhancing IL-10 expression. This anti-inflammatory state is dependent on IL-2 signaling, is characterized by decreased ST2 expression, and is distinct from previously described IL-10-producing ILC2 phenotypes. FFAR3-dependent reprogramming is mediated by epidermal growth factor receptor (EGFR) upregulation, and FFAR3’s anti-inflammatory effect is partially conserved in human ILC2s.

Pulmonary type 2 innate lymphoid cells (ILC2s) exhibit immune memory, termed “trained immunity,” which enhances their activation following exposure to an independent protease-containing allergen. The role of prostaglandin I2 (PGI2), a cyclooxygenase (COX) pathway metabolite, in modulating these trained ILC2 responses remains unclear. PGI2 acts through its G protein–coupled receptor IP. We hypothesized that IP signaling inhibits ILC2 training. To test this hypothesis, we used a mouse ILC2 training model in which we challenged wild-type (WT) and IP knockout (KO) mice with Alternaria alternata extract (Alt) to induce ILC2 activation and training. After a 33-d resting period, ILC2 responses subsided to a homeostatic level. Mice were then intranasally challenged with papain to evaluate responses to an unrelated allergen. IP KO mice displayed significantly heightened ILC2 interleukin (IL)-13 expression and with concomitant increased eosinophilia in the lungs post–papain challenge compared with WT control mice. Notably, neither WT nor IP KO mice challenged with papain only, devoid of ILC2 training, exhibited lung type 2 responses. The augmented type 2 inflammation observed in IP KO mice following both Alt and papain challenges correlated with increased numbers and percentages of IL-13-producing ILC2s and greater mean fluorescence intensity of IL-13 compared with WT mice. Furthermore, RNA sequencing of sorted ILC2s from WT and IP KO mice following Alt-papain challenges revealed heightened activation of immune response pathways and mitochondrial respiratory pathways in IP-deficient ILC2s. These findings reveal an inhibitory role of PGI2 signaling in trained ILC2 responses, emphasizing its pivotal contribution to innate immune responses and allergic inflammation.

Cystic fibrosis (CF) is a common autosomal recessive disease resulting from mutations of the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR). Although severe pulmonary neutrophilic inflammation is a primary pathologic feature of CF, more recent studies reveal a role for type 2 inflammation that is characterized by eosinophilia directed by both the innate and adaptive immune systems through ILC2 and CD4⁺ Th2 cells, respectively. We have published that a clear type endotype exists within CF subjects stratified by Th2 inflammation, defined by increased obstructive pulmonary disease and a distinct phenotypic signature of increased allergic disease, infections, and burden of CF complications. Further, we showed an increased risk of death among CF subjects with type 2 inflammatory signatures compared to CF subjects lacking significant type 2 inflammation. The mechanisms of this heightened type 2 inflammatory signature in CF are still being defined, but it is clear that airway epithelial cells from CFTR‐deficient mice have increased expression and release of IL‐33, a key activator of ILC2 and Th2 cells, compared to persons with normal CFTR function. Further, there is strong evidence that CF regulates CD4⁺ Th2 function in a cell‐intrinsic fashion. These concepts are explored in this review article.

Glucagon-like peptide-1 (GLP-1) is a hormone that regulates blood glucose levels and is produced by the enteroendocrine glands in the large and small intestines in response to the consumption of foods that contain carbohydrates, fats, and proteins. When GLP-1 is secreted, it acts on the pancreas to increase insulin production and secretion, while decreasing pancreatic glucagon secretion in order to lower serum glucose. However, GLP-1 also regulates metabolism through the gut-brain axis. While GLP-1 is primarily produced in the gut and released into the bloodstream, small quantities of it can also be synthesized in distinct areas of neurons located in the hindbrain. Recent studies have proposed that GLP-1 receptor (GLP-1R) agonists (GLP-1RAs) may protect against neuroinflammatory diseases. GLP-1RAs may also be a therapeutic target for asthma as animal models show that these drugs reduce allergen-induced airway inflammation, as the GLP-1R is expressed on lung epithelial and endothelial cells. There is a notable association between insulin resistance and the onset of asthma, particularly among obese people, with this association suggesting that metabolic dysfunction may play a role in asthma development. There is also evidence that there may be a link between asthma pathobiology and neuroinflammation, suggesting that GLP-1 and its analogs may regulate neuroinflammatory pathways that contribute to asthma pathogenesis. Interest is growing, though research remains limited, in how inflammation in the nervous system and lung might be linked. This review will explore how GLP-1R signaling could inhibit interdependent inflammation in both the lung and nervous system. This review will first focus on the inflammation that is known to exist in asthma, then pivot to the current state of neural regulation of asthma, and finally speculate on how GLP-1RA signaling could inhibit both neural and lung inflammation in asthma treatment.

Background: Consultations to pediatric allergy/immunology are of benefit to many hospitalized inpatients, but there is limited current information about how T-cell receptor excision circles (TREC) screening may have changed these patterns for pediatric populations. We aimed to determine the types of consults being requested and their relative frequencies for primary pediatric allergy/immunology consults under an academic fellowship program since the start of TREC screening in 2016. Information gained could help identify focal concepts for pediatric allergy inpatient training curricula for fellowship and graduate medical education programs. Methods: Under an IRB approved study of an academic allergy fellowship consultation log, we retrospectively reviewed electronic medical records of pediatric allergy and immunology consults and categorized consultations by their primary indication. Results: Three-hundred and eighty-three pediatric allergy/immunology consultations were seen between September 4, 2016 to November 24, 2022. In terms of frequency, the most common consultation was for immunodeficiency evaluation or treatment, n=205 (53.5%), followed by drug allergy n=55 (14.4%), general allergy concerns n=43 (11.2%), skin allergy n=35 (9.1%), and less commonly inflammatory syndromes, n=26 (6.8%) and food allergy, n=19 (5.0%). Questions related to TREC screening comprised 21% of all immunodeficiency consults, at n=43. Conclusion: At an academic allergy center where all allergy/immunology service lines are currently provided, the most common reason for pediatric consultations were for help with immunodeficiency evaluation/treatment and drug allergy. TREC screening is a new key indication for consultation. Fellowship programs may benefit from focusing on these content areas for the pediatric inpatient setting.

Female individuals have an increased prevalence of many Th17 cell–mediated diseases, including asthma. Androgen signaling decreases Th17 cell–mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell–mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared with female individuals, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined that females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and that AR signaling attenuated glutamine uptake in CD4 ⁺ T cells by reducing expression of glutamine transporters. In patients with asthma, circulating Th17 cells from men had minimal reliance upon glutamine uptake compared to Th17 cells from women. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.