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

Abstract

Summary 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.

Network Analysis of Inflammatory Bowel Disease Reveals PTPN2 As New Monogenic Cause of Intestinal Inflammation

“…Monogenic defects underlying IBD were defined as recently described 9 . We have opted to use a widely-utilized and cited resource to obtain our list of GWAS genes, therefore the GWAScatalog 16 was used to query significant SNPs associated with IBD by queries for “inflammatory bowel disease”, “Crohn’s disease” and “ulcerative colitis” respectively (https://www.ebi.ac.uk/gwas/).…”

“…Accordingly, much of the heritability of IBD remains unexplained 8 and one of the major challenges of today is linking significantly associated genes through GWAS studies to the pathobiology of IBD. Interestingly, IBD can also manifest as an early-onset monogenic disease 9 . While to date only few gene defects have been found to cause monogenic IBD affecting exclusively or predominantly bowel immune homeostasis, IBD-like features can be the first signs of an underlying, systemic inborn errors of immunity as illustrated in over 50 Mendelian disorders that can present with an IBD-like phenotype 9 .…”

“…Interestingly, IBD can also manifest as an early-onset monogenic disease 9 . While to date only few gene defects have been found to cause monogenic IBD affecting exclusively or predominantly bowel immune homeostasis, IBD-like features can be the first signs of an underlying, systemic inborn errors of immunity as illustrated in over 50 Mendelian disorders that can present with an IBD-like phenotype 9 . These monogenic forms of IBD point out to crucial non redundant molecular mechanisms maintaining intestinal homeostasis, both involving innate and adaptive immunity, while GWAS typically yield many genes with moderate effect size and often unclear pathobiological impact.…”

Introduction: Continuing insights into the healthy and diseased immune system through human genetic investigation

“…Most reviews focus on specific disease entities linked to single gene defects, that are now listed in the Online Mendelian Inheritance in Man (OMIM), such as DOCK8 deficiency (OMIM 611432), Complement hyperactivation, angiopathic thrombosis and protein‐losing enteropathy hyperactivation (CHAPLE, OMIM 226300), CTLA‐4 haploinsufficiency with autoimmunity and inflammation (CHAI, OMIM 616100), autoimmune lymphoproliferative syndrome (ALPS, OMIM six601859) and Ras‐associated lymphoproliferative disease (RALD, OMIM 614470) due to Fas and Ras mutations, respectively, ADA2 deficiency (OMIM 615688), Omenn syndrome (OMIM 603554) and other deficits of the recombinase activating genes RAG1 and RAG2 (OMIM 179615), warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM, OMIM 193670) syndrome due to CXCR4 mutations, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) due to AIRE gene mutations (OMIM 240300), Wisott‐Aldrich syndrome and actin regulatory protein deficiencies due to WAS and WIP mutations, among others . In addition, there are reviews on classes of disorders, such as allergy and atopy, common variable immunodeficiency, early‐onset inflammatory bowel disease, and Chromosome 22.q11.2 and DiGeorge syndrome . Finally, some monographs address specific components of the immune system, such as NK cells, tissue neutrophils, and regulatory T cells .…”

“…Most reviews focus on specific disease entities linked to single gene de- due to CXCR4 mutations, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) due to AIRE gene mutations 12 (OMIM 240300), Wisott-Aldrich syndrome and actin regulatory protein deficiencies due to WAS and WIP mutations, among others. 13 In addition, there are reviews on classes of disorders, such as allergy and atopy, 14 common variable immunodeficiency, 15 early-onset inflammatory bowel disease, 16 and Chromosome 22.q11.2 and DiGeorge syndrome. 17 Finally, some monographs address specific components of the immune system, such as NK cells, 18 tissue neutrophils, 19 and regulatory T cells.…”