Notch Signaling During T Helper 2 Cell-Mediated Inflammation in Allergic Asthma

Enhanced activation of T helper-2 (Th2) cells producing Th2-cytokines (IL-4/IL-5/IL-13) explains many hallmarks of allergic asthma, including eosinophilic airway inflammation and bronchial hyperreactivity. Th2 cell differentiation is thought to be instructed by interaction of Notch on the T cell surface with its ligand Jagged on dendritic cells (DCs). Therefore, we studied the role of Notch signaling in allergic airway inflammation in vivo. In acute and chronic mouse models of house dust mite (HDM)-mediated allergic asthma, we found that expression of Notch and its nuclear effector RBPJκ in T cells is essential for disease development. Our findings suggest that Notch signaling is involved in migration of Th2 cells into the lung. Transgenic overexpression of the key Th2 transcription factor Gata3 in the absence of Notch was not sufficient to induce allergic inflammation, indicating that Notch signaling has additional downstream targets next to Gata3. Mice lacking Jagged1/2 on DCs, T cells or lymph node stromal cells still developed HDM-driven airway inflammation. Importantly, hallmarks of asthma could be suppressed by the Notch inhibitory peptide SAHM1 – which interferes with RBPJκ function - but not by a control peptide. Finally, we obs

Notch signaling in T cells is essential for allergic airway inflammation, but expression of the Notch ligands Jagged 1 and Jagged 2 on dendritic cells is dispensable

__Background:__ Allergic asthma is characterized by a TH2 response induced by dendritic cells (DCs) that present inhaled allergen. Although the mechanisms by which they instruct TH2 differentiation are still poorly understood, expression of the Notch ligand Jagged on DCs has been implicated in this process. __Objective:__ We sought to establish whether Notch signaling induced by DCs is critical for house dust mite (HDM)-driven allergic airway inflammation (AAI) in vivo. __Methods:__ The induction of Notch ligand expression on DC subsets by HDM was quantified by using quantitative real-time PCR. We used an HDM-driven asthma mouse model to compare the capacity of Jagged 1 and Jagged 2 single- and double-deficient DCs to induce AAI. In addition, we studied AAI in mice with a T cell-specific deletion of recombination signal-binding protein for immunoglobulin Jκ region (RBPJκ), a downstream effector of Notch signaling. __Results:__ HDM exposure promoted expression of Jagged 1, but not Jagged 2, on DCs. In agreement with published findings, in vitro-differentiated and HDM-pulsed Jagged 1 and Jagged 2 double-deficient DCs lacked the capacity to induce AAI. However, after in vivo intranasal sensitization and challenge with HDM, DC-specific Jagged 1 or Jagged 2 single- or double-deficient mice had eosinophilic airway inflammation and a TH2 cell activation phenotype that was not different from that in control littermates. In contrast, RBPJκ-def

International prospective observational study investigating the disease course and heterogeneity of paediatric-onset inflammatory bowel disease: the protocol of the PIBD-SETQuality inception cohort study

INTRODUCTION: Patients with paediatric-onset inflammatory bowel disease (PIBD) may develop a complicated disease course, including growth failure, bowel resection at young age and treatment-related adverse events, all of which can have significant and lasting effects on the patient's development and quality of life. Unfortunately, we are still not able to fully explain the heterogeneity between patients and their disease course and predict which patients will respond to certain therapies or are most at risk of developing a more complicated disease course. To investigate this, large prospective studies with long-term follow-up are needed. Currently, no such European or Asian international cohorts exist. In this international cohort, we aim to evaluate disease course and which patients are most at risk of therapy non-response or development of complicated disease based on patient and disease characteristics, immune pathology and environmental and socioeconomic factors. METHODS AND ANALYSIS: In this international prospective observational study, which is part of the PIBD Network for Safety, Efficacy, Treatment and Quality improvement of care (PIBD-SETQuality), children diagnosed with inflammatory bowel disease <18 years are included at diagnosis. The follow-up schedule is in line with standard PIBD care and is intended to continue up to 20 years. Patient and disease characteristics, as well as results of investigations, are collected at baseline and during follow-up. In addition, environmental factors are being assessed (eg, parent's smoking behaviour, dietary factors and antibiotic use). In specific centres with the ability to perform extensive immunological analyses, blood samples and intestinal biopsies are being collected and analysed (flow cytometry, plasma proteomics, mRNA expression and immunohistochemistry) in therapy-naïve patients and during follow-up. ETHICS AND DISSEMINATION: Medical ethical approval has been obtained prior to patient recruitment for all sites. The results will be disseminated through peer-reviewed scientific publications. TRIAL REGISTRATION NUMBER: NCT03571373