Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease

Abstract

Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract, including Crohn’s disease, ulcerative colitis and inflammatory bowel disease-undefined (IBD-U). IBD are understood to be multifactorial, involving genetic, immune, microbial and environmental factors. Advances in next generation sequencing facilitated the growing identification of over 80 monogenic causes of IBD, many of which overlap with Inborn errors of immunity (IEI); Approximately a third of currently identified IEI result in gastrointestinal manifestations, many of which are inflammatory in nature, such as IBD. Indeed, the gastrointestinal tract represents an opportune system to study IEI as it consists of the largest mass of lymphoid tissue in the body and employs a thin layer of intestinal epithelial cells as the critical barrier between the intestinal lumen and the host. In this mini-review, a selection of pertinent IEI resulting in monogenic IBD is described involving disorders in the intestinal epithelial barrier, phagocytosis, T and B cell defects, as well as those impairing central and peripheral tolerance. The contribution of disrupted gut-microbiota-host interactions in disturbing intestinal homeostasis among patients with intestinal disease is also discussed. The molecular mechanisms driving pathogenesis are reviewed along with the personalized therapeutic interventions and investigational avenues this growing knowledge has enabled.

Eosinophilic Gastrointestinal Diseases in Inborn Errors of Immunity

“…Eosinophils are also implicated in IBD pathogenesis, probably playing a significant role in the chronic inflammatory process. In recent years, a growing number of IEI manifesting with IBD have been described [ 7 ]. XIAP deficiency is considered one of the mendelian causes of inherited IBD in infancy [ 34 ].…”

“…According to the IUIS classification, IEI are categorized into ten groups based on the specific clinical and immunological phenotype: combined immunodeficiencies (I); combined immunodeficiencies with syndromic features (II); predominantly antibody deficiencies (III); diseases of immune dysregulation (IV); congenital defects of phagocytes (V); defects in intrinsic and innate immunity (VI); autoinflammatory diseases (VII); complement deficiencies (VIII); bone marrow failure (IX); and phenocopies of inborn errors of immunity (X) [ 5 ]. Although IEI present with a broad spectrum of clinical features, in about one-third of them, various degrees of gastrointestinal (GI) involvement have been described, and for some IEI, the GI manifestations represent the characteristic clinical feature [ 6 , 7 ]. In addition, there has been an increasing understanding of which IEI carry an increased risk for specific atopic manifestations, with most studies focusing on atopic dermatitis, allergic rhinitis, asthma, and immunoglobulin E (IgE)-mediated food allergy [ 8 ].…”

Recent Advances in the Management of Gastrointestinal Disease

“…1 The pathophysiology of IBD is believed to be multifactorial, involving genetics, the gut microbiome, and environmental factors. 2 The available treatments for IBD have grown over the past decade, but it is important to personalise disease management through prognostication of the patient's disease course and therapeutic response. Medium-term (16-24 weeks) Long-term (4852 weeks)…”