Elena Wen-Yuan Hsieh
Scott B. Snapper
Edwin F. de Zoeten- 1Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- 2Section of Pediatric Allergy and Immunology, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado, Aurora, CO, United States
- 3Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital and Harvard Medical School, Boston, MA, United States
- 4Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado, Aurora, CO, United States
Editorial on the Research Topic
Inborn errors of immunity and mucosal immunity
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the digestive tract which can present at any age, and is separated into two main subtypes, Crohn’s disease (CD) and ulcerative colitis (UC). While the two diagnoses demonstrate overlapping inflammatory pathology and clinical presentation, they have unique disease processes, evidenced both by disease characterization and known pathophysiology. Genome-wide association studies have identified an approximately 30% concordance of IBD-related genetic loci between CD and UC which suggests that the majority of susceptibility genes are unique to each subset (1). While treatment management strategies overlap in many cases between CD and UC, development of disease- and patient-specific precision medicine strategies is the ultimate goal. The discovery and study of inborn errors of immunity (IEI) elucidates mechanisms of human immunity and reveals candidate targets for personalized therapy. Inflammatory bowel disease (IBD) constitutes the primary presentation in up to 40% of IEI that present with auto/hyperinflammatory complications (2). Multiple etiologies contribute to intestinal pathology in monogenic IBD, including infections resulting from impaired antimicrobial immunity and disruptions in central and peripheral tolerance (3). The monogenic forms of IBD are rare, severe, and often refractory to conventional therapies (4, 5). Monogenic etiologies underlie 5-10% of very early onset (under 6 years old) IBD patients (VEO-IBD) (6–12). Monogenic IBD illustrates the importance and need for precision medicine in IBD care, as the underlying etiology dictates therapeutic choice and response. For example, cytotoxic T-lymphocyte associated protein-4 (CTLA-4) haploinsufficiency leads to defects in Tregs and a failed peripheral tolerance, with IBD as one of the manifestations of immune dysregulation (13). Abatacept, a fusion protein containing the extracellular domain of CTLA-4, has been successfully used as long-term therapy or a temporary therapy to quell the inflammation before hematopoietic stem cell transplantation (HSCT) (14–16). How different immunological defects impact intestinal epithelial cell composition, regulation, and function – and hence, intestinal homeostasis and health, is poorly understood. This knowledge gap constitutes a significant hurdle to guide current therapies and provide novel targets. This Research Topic gathers different contributions (research and review articles) describing how the study of different IEI has enlightened our understanding of mucosal immunity, and how such understanding can be translated into pathway-specific therapy in IBD.
In the mini-review by Ouahed, 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 addressed. The molecular mechanisms driving pathogenesis are reviewed along with the personalized therapeutic interventions, including HSCT, gene therapy, and small molecule inhibitors that target specific cellular/molecular pathways. Additionally, the growing multi-omic and interdisciplinary efforts in the study of monogenic IBD is also discussed.
Following the broad IEI and IBD review by Ouahed, Illig and Kotlarz focus their mini-review specifically on monogenic IBD etiologies that result from dysregulated inflammasome activity. Inflammasomes have been shown to play a central role in the defense strategy of intestinal epithelial cells (IEC), which is reflected by the expression of a diverse repertoire of inflammasome sensor proteins including NLR family CARD domain-containing protein 4 (NLRC4), pyrin-domain containing 3 and 6 (NLRP3, and NLRP6) (17). Previous studies have indicated that inflammasomes are implicated in IBD pathogenesis, as mucosal IL-1 production is significantly enhanced during active disease (18). Furthermore, higher IL-1 levels were detected in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) from CD patients and long-standing UC (19). Moreover, IL-1β signatures have been detected in macrophages/monocytes isolated from inflamed intestinal tissues of IBD patients by single-cell transcriptomics and deep immunoprofiling (20). Correspondingly, Liso et al. have recently demonstrated that failure to respond to anti-TNF therapy was associated with increased IL-1β in sera and colonic biopsy specimens from patients with UC (21). Taken together, these studies illustrate the importance of understanding the primary driver of the immunopathology in IBD to match specific therapies that target specific pathways that are dysregulated in specific patients, propelling precision medicine in IBD.
In line with the above mini-review, Shaul et al. demonstrated a positive clinical response in a single center retrospective study of patients with VEO-IBD with autoinflammatory phenotype (AIP) in the absence of monogenic disease treated with anti-IL1β (canakinumab) for >6 months. AIP was defined as confirmed IBD with associated signs of systemic inflammation in the absence of infection, including leukocytosis, markedly elevated inflammatory markers, and extraintestinal manifestations (recurrent fevers, oral ulcers, arthritis). Primary outcomes included clinical response in disease activity indices after 6 months of therapy. Secondary outcomes included rate of AIP signs and symptoms, growth, surgery, steroid use, hospitalizations, and adverse events. This study emphasizes the importance of a precision medicine approach in children with VEO-IBD, to maximize efficacy and minimize toxicity.
The study of genetic contributions to IBD, either as polymorphisms that lead to increased risk or causative genes in monogenic IBD, have served to enlighten our understanding regarding the regulation of such genes. For example, the gene encoding Nod2 is the first susceptibility gene that has been identified for CD (22, 23). However, mutations in NOD2 also underlie Blau Syndrome (BS), an autosomal disorder characterized by granulomatous inflammation of the skin, joints, and eyes, but rarely the GI tract (24, 25). This difference is most likely due to the fact that the CARD15 genetic abnormalities occurring in the two diseases differ with respect to the Card15 domain exhibiting mutational hits: the CD Card15 genetic abnormalities are present in the leucine-rich repeat (LRR) domain of Card15, the domain involved in NOD2 ligand engagement, whereas BS Card15 genetic abnormalities are present in the nucleotide-binding domain (NBD) of Card15, the domain mediating Nod2 oligomerization and interaction with downstream adaptors (26). The study of mutations in NOD2 in Blau Syndrome by Mao et al. demonstrated the loss of Nod2 cross-regulatory function, which provides additional insight into its function of inflammatory disease. This study exemplifies how understanding the impact of different mutations within the same gene set the foundation to differentially immunomodulate in different patients who may otherwise be placed under the same umbrella treatment.
The study of inflammatory disorders due to IEI has shed light onto relative contribution, signaling cross-talks, specificity, and redundancy of each of those components in the orchestration of the immune response. Rodari et al., illustrate this concept nicely in their review of TGF-β signalopathies. Human TGF-β1 deficiency results in VEO-IBD, demonstrating the non-redundant role of TGF-β1 in suppressing intestinal inflammation and supporting the hypothesis that the aberrant TGF-β1/SMAD signaling observed in active lesions of IBD patients participate in disease pathogenesis (27). Importantly, targeting Smad7 by specific antisense oligonucleotides has been assessed, with mixed results, for the treatment of IBD (28–31).
Taken together, this Research Topic illustrates the diverse types/categories of IEI that underlie monogenic IBD. This research exemplifies how these genetic defects alter immune function at the mucosal site and provide novel insight into these immunological pathways, and their potential as novel targets for precision medicine in IBD. We hope that the reader will find this Research Topic a useful reference for the connection between IEI and mucosal immunity, and the utility of such line of research to help optimize therapy selection for IBD patients.
Author contributions
EWYH, EFdZ, and SBC conceived this Research Topic together, edited the articles, and co-wrote the editorial. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature (2011) 474:307–17. doi: 10.1038/nature10209
2. Pazmandi J, Kalinichenko A, Ardy RC, Boztug K. Early-onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms. Immunol Rev (2019) 287:162–85. doi: 10.1111/imr.12726
3. Nambu R, Muise AM. Advanced understanding of monogenic inflammatory bowel disease. Front Pediatr (2020) 8:618918. doi: 10.3389/fped.2020.618918
4. Uhlig HH, Muise AM. Clinical genomics in inflammatory bowel disease. Trends Genet (2017) 33:629–41. doi: 10.1016/j.tig.2017.06.008
5. Muise AM, Snapper SB, Kugathasan S. The age of gene discovery in very early onset inflammatory bowel disease. Gastroenterology (2012) 143:285–8. doi: 10.1053/j.gastro.2012.06.025
6. Collen LV, Kim DY, Field M, Okoroafor I, Saccocia G, Driscoll Whitcomb S, et al. Clinical phenotypes and outcomes in monogenic versus non-monogenic very early onset inflammatory bowel disease. J Crohns Colitis (2022) 16:1380–96. doi: 10.1093/ecco-jcc/jjac045
7. Ouahed J, Spencer E, Kotlarz D, Shoulval DS, Kowalik M, Peng K, et al. Very early onset inflammatory bowel disease: a clinical approach with a focus on the role of genetics and underlying immune deficiencies. Inflammation Bowel Dis (2020) 26:820–42. doi: 10.1093/ibd/izz259
8. Nambu R, Warner N, Mulder DJ, Ktlarz D, McGovern DP, Cho J, et al. A systematic review of monogenic inflammatory bowel disease. Clin Gastroenterol Hepatol (2022) 20:e653–63. doi: 10.1016/j.cgh.2021.03.021
9. Uhlig HH, Henrion C, Kotlarz D, Shoulval D, Schwerd T, Strisciuglio C, et al. Clinical genomics for the diagnosis of monogenic forms of inflammatory bowel disease: a position paper from the paediatric IBD Porto group of European society of paediatric gastroenterology, hepatology and nutrition. J Pediatr Gastroenterol Nutr (2021) 72:456–73. doi: 10.1097/MPG.0000000000003017
10. Kelsen JR, Sullivan K, Rabizadeh S, Singh N, Snapper S, Elkadri A, et al. North American society for pediatric gastroenterology, hepatology, and nutrition position paper on the evaluation and management for patients with very early-onset inflammatory bowel disease. J Pediatr Gastroenterol Nutr (2020) 70:389–403. doi: 10.1097/MPG.0000000000002567
11. Conrad MA, Kelsen JR. Genomic and immunologic drivers of very early-onset inflammatory bowel disease. Pediatr Dev Pathol (2019) 22:183–93. doi: 10.1177/1093526619834807
12. Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology (2014) 147:990–1007 e1003. doi: 10.1053/j.gastro.2014.07.023
13. Schwab C, Gabrysch A, Olbrich P, Patiño V, Warnatz K, Wolff D, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol (2018) 142:1932–46
14. Uhlig HH, Schwerd T. From Genes to Mechanisms: The Expanding Spectrum of Monogenic Disorders Associated with Inflammatory Bowel Disease. Inflamm Bowel Dis (2016) 22:202–12
15. Kiykim A, Ogulur I, Dursun E, Charbonnier LM, Nain E, Cekic S, et al. Abatacept as a Long-Term Targeted Therapy for LRBA Deficienc. J Allergy Clin Immunol Pract (2019) 7:2790
16. Vardi I, Chermesh I, Werner L, Barel O, Freund T, McCourt C, et al. Monogenic Inflammatory Bowel Disease: It’s Never Too Late to Make a Diagnosis. Front Immunol (2020) 11
17. Lei-Leston AC, Murphy AG, Maloy KJ. Epithelial cell inflammasomes in intestinal immunity and inflammation. Front Immunol (2017) 8:1168. doi: 10.3389/fimmu.2017.01168
18. Ligumsky M, Simon PL, Karmeli F, Rachmilewitz D. Role of interleukin 1 in inflammatory bowel disease–enhanced production during active disease. Gut (1990) 31:686–9. doi: 10.1136/gut.31.6.686
19. Lazaridis LD, Pistiki A, Giamarellos-Bourboulis EJ, Georgitsi M, Damoraki G, Polymeros D, et al. Activation of NLRP3 inflammasome in inflammatory bowel disease: differences between crohn’s disease and ulcerative colitis. Dig Dis Sci (2017) 62:2348–56. doi: 10.1007/s10620-017-4609-8
20. Mitsialis V, Wall S, Liu P, Ordovas-Montanes J, Parmet T, Vukovic M, et al. Single-cell analyses of colon and blood reveal distinct immune cell signatures of ulcerative colitis and crohn’s disease. Gastroenterology (2020) 159:591–608 e510. doi: 10.1053/j.gastro.2020.04.074
21. Liso M, Verna G, Cavalcanti E, Santis De S, Armentano R, Tafaro A, et al. Interleukin 1beta blockade reduces intestinal inflammation in a murine model of tumor necrosis factor-independent ulcerative colitis. Cell Mol Gastroenterol Hepatol (2022) 14:151–71. doi: 10.1016/j.jcmgh.2022.03.003
22. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to crohn’s disease. Nature (2001) 411:603–6. doi: 10.1038/35079114
23. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to crohn’s disease. Nature (2001) 411:599–603. doi: 10.1038/35079107
24. Matsuda T, Kambe N, Ueki Y, Kanazawa N, Izawa K, Honda Y, et al. Clinical characteristics and treatment of 50 cases of blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation. Ann Rheum Dis (2020) 79:1492–9. doi: 10.1136/annrheumdis-2020-217320
25. Wouters CH, Maes A, Foley KP, Bertin J, Rose CD. Blau syndrome, the prototypic auto-inflammatory granulomatous disease. Pediatr Rheumatol Online J (2014) 12:33. doi: 10.1186/1546-0096-12-33
26. Proell M, Riedl SJ, Fritz JH, Rojas AM, Schwarzenbacher R. The nod-like receptor (NLR) family: a tale of similarities and differences. PloS One (2008) 3:e2119. doi: 10.1371/journal.pone.0002119
27. Monteleone G, Kumberova A, Croft NM, McKenzie C, Steer HW, MacDonald TT. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest (2001) 108:601–9. doi: 10.1172/JCI12821
28. Di Fusco D, Dinallo V, Marafini I, Figliuzzi MM, Romano B, Monteleone G, et al. Antisense oligonucleotide: basic concepts and therapeutic application in inflammatory bowel disease. Front Pharmacol (2019) 10:305. doi: 10.3389/fphar.2019.00305
29. Boirivant M, Boirivant M, Pallone F, Giacinto Di C, Fina D, Monteleon I, et al. Inhibition of Smad7 with a specific antisense oligonucleotide facilitates TGF-beta1-mediated suppression of colitis. Gastroenterology (2006) 131:1786–98. doi: 10.1053/j.gastro.2006.09.016
30. Monteleone G, Stolfi C, Marafini I, Atreya R, Neurath MF. Smad7 antisense oligonucleotide-based therapy in crohn’s disease: is it time to re-evaluate? Mol Diagn Ther (2022) 26:477–81. doi: 10.1007/s40291-022-00606-1
Keywords: inborn errors immunity, inflammatory bowel diseases, innate immunity, inflammasome, anti-IL1 therapy
Citation: Hsieh EW-Y, Snapper SB and de Zoeten EF (2023) Editorial: Inborn errors of immunity and mucosal immunity. Front. Immunol. 14:1208798. doi: 10.3389/fimmu.2023.1208798
Received: 19 April 2023; Accepted: 24 April 2023;
Published: 09 May 2023.
Edited and Reviewed by:
Isabelle Meyts, KU Leuven, BelgiumCopyright © 2023 Hsieh, Snapper and de Zoeten. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Elena Wen-Yuan Hsieh, ZWxlbmEuaHNpZWhAY3VhbnNjaHV0ei5lZHU=