A Distinct Esophageal mRNA Pattern Identifies Eosinophilic Esophagitis Patients With Food Impactions

Eosinophilic esophagitis (EoE), a Th2-type allergic immune disorder characterized by an eosinophil-rich esophageal immune infiltrate, is often associated with food impaction (FI) in pediatric patients but the molecular mechanisms underlying the development of this complication are not well understood. We aim to identify molecular pathways involved in the development of FI. Due to large variations in disease presentation, our analysis was further geared to find markers capable of distinguishing EoE patients that are prone to develop food impactions and thus expand an established medical algorithm for EoE by developing a secondary analysis that allows for the identification of patients with food impactions as a distinct patient population. To this end, mRNA patterns from esophageal biopsies of pediatric EoE patients presenting with and without food impactions were compared and machine learning techniques were employed to establish a diagnostic probability score to identify patients with food impactions (EoE+FI). Our analysis showed that EoE patients with food impaction were indistinguishable from other EoE patients based on their tissue eosinophil count, serum IgE levels, or the mRNA transcriptome-based p(EoE). Irrespectively, an additional analysis loop of the medical algorithm was able to separate EoE+FI patients and a composite FI-score was established that identified such patients with a sensitivity of 93% and a specificity of 100%. The esophageal mRNA pattern of EoE+FI patients was typified by lower expression levels of mast cell markers and Th2 associated transcripts, such as FCERIB, CPA3, CCL2, IL4, and IL5. Furthermore, lower expression levels of regulators of esophageal motility (NOS2 and HIF1A) were detected in EoE+FI. The EoE+FI -specific mRNA pattern indicates that impaired motility may be one underlying factor for the development of food impactions in pediatric patients. The availability of improved diagnostic tools such as a medical algorithm for EoE subpopulations will have a direct impact on clinical practice because such strategies can identify molecular inflammatory characteristics of individual EoE patients, which, in turn, will facilitate the development of individualized therapeutic approaches that target the relevant pathways affected in each patient

A Distinct Esophageal mRNA Pattern Stamp Identifies a Subpopulation of EoE Patients With Food Impactions

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory disorder of esophagus characterized by eosinophil-rich infiltrates. A significant portion of EoE patients suffer from esophageal food impactions. The underlying mechanism of food impactions is not well understood. Food impactions can happen in the absence of an anatomical problem in the esophagus. Previous literature shows evidence for abnormal esophageal motility in EoE patients. This implies that impaired motility of the esophagus is likely the cause of food impactions in EoE patients. Motility in the gastrointestinal tract is under the control of the nervous system. Nitric oxide (NO) is the main inhibitory neurotransmitter that causes relaxation of the smooth muscle in the gastrointestinal tract. NO is synthesized by nitric oxide synthases (NOS). Inducible NOS (iNOS) is an isoform of NOS that is induced in immune cells upon stimulation by proinflammatory cytokines. We hypothesized that low levels of NO due to low expression of iNOS might cause the impaired motility in EoE and result in food impactions. Using a digital mRNA profiling method, we identify a distinct subpopulation of EoE that is characterized by low transcript levels of iNOS and suffers from food impactions. In addition, we show that the esophageal mRNA pattern stamp of this low-iNOS patient subpopulation shows lower expression levels of Th2-type inflammatory markers IL-4, IL-5, eotaxin-1, carboxypeptidase A3, Fc receptors for IgE and OX40L; along with lower expression levels of other inflammatory markers such as IFN-γ, CD14, IL-2, IL-12β, IFN-β1, IL-10, Fc receptors for IgG, CCL2 and CCR3. The ability to prospectively define the subpopulation of EoE patients that is prone to food impactions has important direct implications for clinical practice. Identification of these patients can help clinicians to inform them about the likely course of their EoE phenotype, which can improve their quality of lives. Furthermore, therapeutic strategies for food impactions targeting NO can be developed for future use in this subpopulation

Biallelic PI4KA variants cause neurological, intestinal and immunological disease.

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex