Genomic and Immunologic Drivers of Very Early-Onset Inflammatory Bowel Disease

Abstract

Purpose of Review: Inflammatory bowel disease (IBD) is a multifactorial disease caused by dysregulated immune responses to commensal or pathogenic intestinal microbes, resulting in chronic intestinal inflammation. However, a subset of patients with IBD diagnosed <6 years of age, known as very early-onset (VEO)-IBD, can be phenotypically and genetically distinct from older onset IBD. We aim to review the clinical presentation of children with VEO-IBD and recent discoveries that point to the underlying genomic and immunologic drivers of disease, and the significant impact on our therapeutic decisions. Recent Findings: VEO-IBD is increasing in incidence and is associated with more severe disease, aggressive progression, and poor response to most conventional therapies. This article will review some of the genetic findings in this population and the subsequent impact on therapy, with targeted approaches. Summary: Children with VEO-IBD may present with a different phenotype and more severe disease than older children and adults. An integrated approach combining genetics, immunology, and traditional IBD evaluations can lead to the identification of causal defects that directly impact management. These strategies can also be employed in older onset refractory IBD.

The Evolution of Very Early Onset Inflammatory Bowel Disease, Autoimmune Hepatitis, and Primary Sclerosing Cholangitis in a Young Girl

“…Polygenic forms of IBD with hundreds of genetic susceptibility loci have been described in adolescent and adult onset IBD [ 10 ]. In comparison, children 5 years and younger have been reported to have monogenic mutations, including IL10RA, IL10RB, IL10 ligand and receptors, and XIAP [ 10 , 11 ]. IL-10 is an anti-inflammatory cytokine secreted by dendritic cells, natural killer cells, eosinophils, mast cells, macrophages, B-cells, and CD4+ T-cell subsets (Th2 cells, Th1 cells, Th17 cells, and Treg) [ 11 ].…”

The Growing Need to Understand Very Early Onset Inflammatory Bowel Disease

“…These monogenic variants are clinically important and dictate divergent pathways in treatment of VEO-IBD. Monogenic etiologies may underlie 15-20% of VEO-IBD patients (3,(11)(12)(13)(14). To date, the monogenic variants can be classified into 5 distinct groups:…”

“…(1) Epithelial barrier defects; (2) Phagocytic defects; (3) T and B cell defects; (4) T regulatory cells and signaling; and (5) Hyper-and auto-inflammatory conditions (see Table 1) (3,(11)(12)(13).…”

“…In general, therapeutic options are patient specific and are influenced by underlying genetic variation or primary immunodeficiency. Interventions can include nutritional therapies, immunosuppression, as well as hematopoietic stem cell transplantation depending on the underlying genetic variations or primary immunodeficiencies ( 3 , 11 , 12 , 67 ). In addition to nonspecific immunosuppression such as corticosteroids, some targeted treatment options exist and depend on timely diagnosis of the underlying immunologic dysfunction.…”

“…These monogenic variants are clinically important and dictate divergent pathways in treatment of VEO-IBD. Monogenic etiologies may underlie 15-20% of VEO-IBD patients ( 3 , 11 – 14 ). To date, the monogenic variants can be classified into 5 distinct groups: (1) Epithelial barrier defects; (2) Phagocytic defects; (3) T and B cell defects; (4) T regulatory cells and signaling; and (5) Hyper- and auto-inflammatory conditions (see Table 1 ) ( 3 , 11 – 13 ).…”