On the Origin of Type 2 Inflammation in the Intestinal Tract

Aberrant type 2 inflammation in the intestinal tract, the topic of this thesis, affects the largest and arguably most complex mucosal surface of our body. It underlies several immune-mediated disorders (such as food allergy and eosinophilic gastrointestinal diseases) that are characterized by rapidly increasing incidence and prevalence in children (and adults) in Westernized societies. The overarching goal of this thesis is to improve our understanding of the pathophysiology of type 2 intestinal inflammation. To this end, two complimentary approaches have been applied, and they are described in detail in the two parts that make up this work.

In Part 1, we have aimed to obtain novel insights into the pathogenesis of allergic intestinal inflammation from a cohort of pediatric patients with established eosinophilic esophagitis, a type 2 inflammatory disorder of the upper GI tract. Using clinical data in combination with mRNA expression analysis in tissue biopsies of these children, we demonstrate considerable immunological heterogeneity, which suggests that distinct mechanisms may underlie a final common pathway of disease. These observations are indicative of the existence of disease subtypes, which may inform therapeutic and preventative strategies in the future.

In Part 2, we have approached the problem of aberrant type 2 intestinal inflammation by characterizing a novel experimental model of food allergy that allows for the interrogation of the critical pathways involved in its pathogenesis. We show that patients with Wiskott-Aldrich syndrome develop IgE responses against common food allergens and that spontaneous food allergies also occur in the corresponding mouse model (Was-/- mice). We go on to demonstrate that both induction and effector phases of food allergic responses are faithfully mimicked in Wiskott-Aldrich Syndrome protein (WASP)-deficient mice and conclude that Was-/- animals compare favorably to commonly used, adjuvant-based mouse models in terms of homology to human disease. By using a Cre-lox recombination system that allows for cell-specific knock-out of WASP, we describe that deletion of WASP confined to FOXP3+ Tregs is not only sufficient for the allergic sensitization and intestinal mast cell expansion, but that this allergic phenotype is aggravated when compared to complete Was-/- mice. The contributory effect of WASP deficiency in non-Treg cellular components (e.g. effector T cells, B cells, antigen presenting cells, mast cells and basophils) on spontaneously occurring food allergy is comprehensively explored further, leading us to conclude that absence of WASP from all hematopoietic lineages is associated with both pro- as well as anti-allergic effects.