Inflammatory bowel disease (IBD) is a multifactorial disorder triggered by imbalances of the microbiome and immune dysregulations in genetically susceptible individuals. Several mouse and human ...studies have demonstrated that multimeric inflammasomes are critical regulators of host defense and gut homeostasis by modulating immune responses to pathogen- or damage-associated molecular patterns. In the context of IBD, excessive production of pro-inflammatory Interleukin-1β has been detected in patient-derived intestinal tissues and correlated with the disease severity or failure to respond to anti-tumor necrosis factor therapy. Correspondingly, genome-wide association studies have suggested that single nucleotide polymorphisms in inflammasome components might be associated with risk of IBD development. The relevance of inflammasomes in controlling human intestinal homeostasis has been further exemplified by the discovery of very early onset IBD (VEO-IBD) patients with monogenic defects affecting different molecules in the complex regulatory network of inflammasome activity. This review provides an overview of known causative monogenic entities of VEO-IBD associated with altered inflammasome activity. A better understanding of the molecular mechanisms controlling inflammasomes in monogenic VEO-IBD may open novel therapeutic avenues for rare and common inflammatory diseases.
IL-10 and IL-10 receptor defects in humans Glocker, Erik-Oliver; Kotlarz, Daniel; Klein, Christoph ...
Annals of the New York Academy of Sciences,
December 2011, Letnik:
1246, Številka:
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Journal Article
Recenzirano
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is chronic in nature and is characterized by abdominal pain, diarrhea, bleeding, and malabsorption. ...It is considered a complex multigenic and multifactorial disorder that results from disturbed interactions between the immune system and commensal bacteria of the gut. Recent work has demonstrated that IBD with an early‐onset within the first months of life can be monogenic: mutations in IL‐10 or its receptor lead to a loss of IL‐10 function and cause severe intractable enterocolitis in infants and small children. Both IL‐10 and IL‐10 receptor deficiency can be successfully treated by hematopoietic stem cell transplantation.
Advances in genomic technologies have led to increasing reports of monogenic inflammatory bowel disease (IBD). Here, we systematically review the literature to determine the clinical features, ...genetic profile, and previously used treatment strategies in monogenic IBD.
A systematic review of MEDLINE articles published between January 2000 and December 2020 was conducted. A total of 750 individual monogenic IBD cases were identified from 303 eligible articles.
The most frequently reported monogenic IBD genes were IL10RA/B, XIAP, CYBB, LRBA, and TTC7A. In total, 63.4% of patients developed IBD before 6 years of age, 17.4% developed IBD between ages 10 and 17.9 years, and 10.9% developed IBD after age 18. There was a substantial difference between these age groups and the underlying monogenic disorders. Only 31.7% had any history of extraintestinal comorbidity (EIC) before IBD onset, but 76.0% developed at least 1 EIC during their clinical course. The most common EICs were atypical infection (44.7%), dermatologic abnormality (38.4%), and autoimmunity (21.9%). Bowel surgery, biologic therapy, and hematopoietic stem cell transplantation were performed in 27.1%, 32.9%, and 23.1% of patients, respectively.
Monogenic IBD cases, although rare, have varied extraintestinal comorbidities and limited treatment options including surgery and transplant. Early identification and improved understanding of the characteristics of the genes and underlying disease processes in monogenic IBD is important for effective management.
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Opposing roles have been proposed for IL-22 in intestinal pathophysiology. We have optimized human small intestinal organoid (hSIO) culturing, constitutively generating all differentiated cell types ...while maintaining an active stem cell compartment. IL-22 does not promote the expansion of stem cells but rather slows the growth of hSIOs. In hSIOs, IL-22 is required for formation of Paneth cells, the prime producers of intestinal antimicrobial peptides (AMPs). Introduction of inflammatory bowel disease (IBD)-associated loss-of-function mutations in the IL-22 co-receptor gene IL10RB resulted in abolishment of Paneth cells in hSIOs. Moreover, IL-22 induced expression of host defense genes (such as REG1A, REG1B, and DMBT1) in enterocytes, goblet cells, Paneth cells, Tuft cells, and even stem cells. Thus, IL-22 does not directly control the regenerative capacity of crypt stem cells but rather boosts Paneth cell numbers, as well as the expression of AMPs in all cell types.
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•Optimized culture protocol for human intestinal organoids•Organoids display extensive budding and harbor all cell types•IL-22-mTOR signaling mediates human Paneth cell differentiation•IL-22 induces expression of host defense genes in all cell types
Generating a long-term organoid culture model that displays extensive budding and harbors all cell types of the human small intestine reveals mechanism of human Paneth cell differentiation by IL-22-mTOR signaling.
Genetic analyses showed that mutations affecting the interleukin-10 receptor are associated with early-onset colitis. Further molecular analyses showed that the mutations abrogated interleukin-10 ...signaling. Treatment of one of the affected children by means of allogeneic hematopoietic stem-cell transplantation was successful.
Genetic analyses showed that mutations affecting the interleukin-10 receptor are associated with early-onset colitis. Treatment of an affected child by means of allogeneic hematopoietic stem-cell transplantation was successful.
Inflammatory bowel disease is a heterogeneous group of disorders, classified as Crohn's disease, ulcerative colitis, and indeterminate colitis.
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In most patients, these disorders are manifested in adolescence or adulthood; however, they may present in infancy and may be inherited as an autosomal recessive trait.
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The genetic causes of inflammatory bowel disease are only partly understood. Studies in transgenic murine models
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and genomewide genetic-linkage and association studies have provided insights into the genetic complexity underlying these inflammatory conditions.
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Investigators using these approaches have implicated several genes in the pathogenesis of inflammatory bowel disease; the identity of these genes suggests . . .
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