Early-onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

Abstract

Rare, monogenetic diseases present unique models to dissect gene functions and biological pathways, concomitantly enhancing our understanding of the etiology of complex (and often more common) traits. Although inflammatory bowel disease (IBD) is a generally prototypic complex disease, it can also manifest in an early-onset, monogenic fashion, often following Mendelian modes of inheritance. Recent advances in genomic technologies have spurred the identification of genetic defects underlying rare, very early-onset IBD (VEO-IBD) as a disease subgroup driven by strong genetic influence, pinpointing key players in the delicate homeostasis of the immune system in the gut and illustrating the intimate relationships between bowel inflammation, systemic immune dysregulation, and primary immunodeficiency with increased susceptibility to infections. As for other human diseases, it is likely that adult-onset diseases may represent complex diseases integrating the effects of host genetic susceptibility and environmental triggers. Comparison of adult-onset IBD and VEO-IBD thus provides beautiful models to investigate the relationship between monogenic and multifactorial/polygenic diseases. This review discusses the present and novel findings regarding monogenic IBD as well as key questions and future directions of IBD research.

Keywords: genetics; inborn errors of immunity; inflammatory bowel disease; pathomechanisms.

Figure 1

Advances in identification of genetic etiologies underlying inflammatory bowel disease and inborn errors of immunity. (A) The percentage of inborn errors of immunity with IBD. Classification according to the 2017 International Union of Immunological Societies (IUIS) phenotypic classification of inborn errors of immunity.35 (B) Discoveries of inborn errors of immunity with IBD and VEO‐IBD genes through the years. Gene defects that were described between 2015 to 2018 are highlighted in bold

Figure 2

Cell types and molecular mechanisms involved in the pathogenesis of inflammatory bowel disease. The inner circle represents cell types and cell components involved in IBD pathogenesis, as detailed in the text. The middle circle depicts the molecular mechanisms affected by mutations in genes presenting with an IBD phenotype. The outer circle represents the molecular pathomechanisms leading to IBD. Treg IL10: T‐cell immunodeficiencies with bowel inflammation and Defects in Tregs or IL10 signaling. Phagocytes: Congenital defects of phagocyte number or function. Complement: Complement deficiencies. Bacterial recognition: Defects in host‐microbiota interactions, bacterial sensing. Epithelial barrier: Epithelial barrier defects. B cells and antibodies: Predominantly antibody deficiencies with IBD. Innate immune cells: Systemic autoinflammatory diseases and IBD. PRR: pattern‐recognition receptor