IBD and Primary Immunodeficiencies

PIDs are a heterogeneous group of genetically inherited diseases affecting the innate and adaptive immune systems that confer susceptibility to infection, autoimmunity and cancer through antibody defects, T cell defects, combined defects of T and B cells, other defects of the immune system and phagocyte dysfunction (Table 1). PID-associated genes include those involved in intestinal epithelial barrier function, phagocyte bacterial killing, autoimmune and autoinflammatory disorders and function of the immune system. Maintenance of the epithelial barrier requires contributions from innate lymphoid cells, and it may be that some immune deficiencies contribute to the pathogenesis of IBD through their effects on the innate lymphoid cell populations. It is also possible that immune deficiencies may affect the microbiota by failing to tune the colonising populations through exaggerated immune responses and also due to frequent antibiotic use. Taken together, these mechanisms explain how PIDs can present as IBD or “IBD-like colitis”, particularly in infants, children and occasionally adults.

Table 1. Categories of primary immunodeficiencies (PIDs)

• Predominantly antibody defects
  • Common variable immunodeficiency (CVID)
  • Selective IgA deficiency
  • Selective deficiency of other Ig isotypes
  • Infantile X-linked agammaglobulinaemia (Bruton’s disease)
  • X-linked immunodeficiency with increased IgM and IgD
  • Secretory component deficiency
  • ID with thymoma
• Predominantly defects of cell-mediated immunity
  • Severe combined immunodeficiency (SCID)
  • IPEX syndrome
  • Chronic mucocutaneous candidiasis
• Combined immunodeficiencies with syndromic features
  • DiGeorge syndrome
  • Wiscott-Aldrich syndrome
  • Ataxia telangiectasia
  • Transcobalamin deficiency
• Defects in phagocytes (number/function/both)
  • Chronic granulomatous disease
  • Systemic mastocytosis

The landmark discovery of mutations involving the cytokine IL-10 and its receptors IL-10RA and IL10RB, which control pro-inflammatory responses of macrophages in the gastrointestinal tract, resulting in severe infantile enterocolitis and perianal disease presenting as fistulating colitis, was the first occasion on which causal genetic defects were identified in patients with VEO-IBD, which is alternatively termed “monogenic IBD”. A defect in intracellular killing of pathogens based on the failure of the NADPH complex to produce oxygen radicals in granulocytes and macrophages in patients with chronic granulomatous disease (CGD) is linked with early-onset IBD-like colitis in about 30% of the patients. CGD may present with intestinal inflammation mimicking Crohn’s Disease that is characterised by multiple granulomas, sometimes necrotising, with or without associated active colitis, and mucosal accumulation of pigmented macrophages during quiescent phases. Several autoinflammatory diseases have also been linked to VEO-IBD. These include mevalonate kinase deficiency, familial Mediterranean fever, Hermansky-Pudlak syndrome and X-linked inhibitor of apoptosis protein (XIAP). XIAP is involved in NOD2-mediated NFKB signalling in monocytes/macrophages and thereby regulates the local inflammatory response, resulting in impaired ability to sense bacteria. XIAP deficiency manifests as early onset IBD in 20% of the affected boys. The deficiency of the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) regulating apoptosis versus necroptosis downstream of TNF and TLR signalling manifests mainly through IBD and arthritis. Defects that affect development or function of B and T cells, as occur with mutations in recombination activating genes (RAG1 or RAG2), in IL-7R (Omenn syndrome) and with the multiple gene defects associated with severe combined immunodeficiency (SCID), may be associated with severe intestinal disease. Patients with DOCK 8 (dedicator of cytokinesis 8 protein) deficiency, a combined T and B cell immunodeficiency syndrome, present with susceptibility to viral, fungal and bacterial infections in association with increased serum levels of IgE. Some patients may present with chronic diarrhoea and severe enterocolitis (Table 2).

Table 2. Genes responsible for VEO-IBD 

• Immunodeficiencies affecting cellular and humoral immunity
  IL2RG, RAG1, RAG2, DCLRE1C, ADA, LIG4, CD3G, ZAP70, DOCK8, LRBA, IL21, CD41LG
• Combined immunodeficiency with associated or syndromic features
  WAS, DKC1, RTEL1, IKBKG, IKBA, TCC7A
• Predominantly antibody deficiencies
  BTK, AICDA, ICOS, PIK3R1
• Diseases of immune dysregulation
  SHD1A, XIAP, FOXP3, IL10, IL10RA, IL10RB, NFAT5, STXBP2, IL2RA, HPS1, HPS4, HPS6
• Congenital defects of phagocyte number, function or both
  CYBB, CYBA, NCF1, NCF2, NCF4, G6PT1, INTGB2
• Defects in intrinsic and innate immunity
  STAT1, PLCG2
• Autoinflammatory disorders
  MEFV, MVK, ADAM17
• Complement deficiencies and others
  MSAP2, SKIV2L, TTC37, COL7A1, FERMT1, GUCY2C, EPCAM, RET

In addition to early onset, diagnosis of monogenic IBD is further supported by the occurrence of IBD in multiple family members, consanguinity, autoimmunity, failure to thrive, conventional treatment failure, endocrine abnormality, recurrent infectious or unexplained fevers, severe perianal disease, macrophage activation syndrome and haemophagocytic lymphohistiocytosis, obstruction and atresia of the intestine, skin lesions and dental and hair abnormalities, and the presence of malignancies.
Histological findings in GI biopsies are very heterogeneous and are characterised by various inflammatory patterns resembling IBD; hence the term “IBD-like (entero)colitis” has been used to identify these cases. Histological patterns seen in gastrointestinal biopsies of monogenic IBD cases can be grouped as follows:

• “Crohn’s disease-like” pattern is characterised by a discontinuous inflammatory infiltrate with eosinophils, neutrophils and plasma cells, transmural inflammation and deep ulceration of mucosa with granulomas in the colon while villous loss with crypt hyperplasia with or without intraepithelial lymphocytosis, chronic active enterocolitis, focal cryptitis, granulomas and pronounced lymphoid hyperplasia are seen in the small bowel.
• “Ulcerative colitis-like” pattern presents with a continuous marked inflammatory infiltrate comprised of eosinophils, monocytes, plasma cells and lymphocytes with or without cryptitis and crypt distortion accompanied by mucosal ulcerations.
• Apoptotic pattern is characterised by extensive apoptosis in the crypt epithelium leading to crypt dropout and eventually severe crypt atrophy accompanied by increased mononuclear inflammation in the lamina propria.

In summary, recent advances in molecular technology have resulted in the discovery of genes and pathways associated with VEO-IBD or monogenic IBD which are different from the genetic variants found in IBD of older children and adults. The diagnosis of these unique disorders rests on the use of next generation sequencing, and their identification not only offers these patients the possibility of “personalised medicine” but also deepens our insight into mucosal immune response.

References

1. Heyman MB, Kirschner BS, Gold BD, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr 2005;146:35–40.
2. Glocker E, Grimbacher B. Inflammatory bowel disease: is it a primary immunodeficiency? Cell Mol Life Sci 2012;69:41–8. 
3. Uhlig HH. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut 2013;62:1795–805.
4. Ashton JJ,  https://www.ncbi.nlm.nih.gov/pubmed/?term=Coelho%20T%5BAuthor%5D&cauthor=true&cauthor_uid=27537055 , et al. Identification of variants in genes associated with single-gene inflammatory bowel disease by whole-exome sequencing. Inflamm Bowel Dis 2016;22:2317–27.
5. Kostel Bal S, Haskologlu S, Serwas NK, et al. Multiple presentations of LRBA Deficiency: a single-center experience. J Clin Immunol. 2017;37:790–800. 
6. Kelsen JR, Sullivan KE.  Inflammatory bowel disease in primary ımmunodeficiencies. Curr Allergy Asthma Rep 2017;17:57. 
7. Ensari A, Kelsen J, Russo P. Newcomers in paediatric GI pathology: childhood enteropathies including very early onset monogenic IBD. Virchows Arch 2018;472:111–23. 
8. Conrad MA, Kelsen JR. Genomic and ımmunologic drivers of very early-onset ınflammatory bowel disease. Pediatr Dev Pathol 2019;22:183–93. 
9. Both T, Dalm V, Richardson SA, et al. Inflammatory bowel disease in primary immunodeficiency disorders is a heterogeneous clinical entity requiring an individualized treatment strategy: A systematic review. Autoimmun Rev 2021;20:102872.
10. Kanegane H. Inflammatory bowel diseases and primary immunodeficiency diseases. Histopathological features of monogenic ınflammatory bowel disease: subanalysis of systematic review. Gastro Hep Advances 2022;1:679–81.