What is Inflammatory Bowel Disease (IBD)?

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What is Inflammatory Bowel Disease (IBD)?

Inflammatory bowel disease ( IBD ), consisting of ulcerative colitis ( UC ) and Crohn’s disease ( CD ), affects approximately 6 to 8 million people worldwide.

As a chronic, progressive and recurrent intestinal disease, IBD seriously affects the quality of life and daily life of patients and increases the medical burden.

Although it is now generally accepted that IBD is caused by an abnormal immune response to microorganisms in genetically susceptible individuals, its exact pathogenesis is largely unknown.

Currently available IBD treatments include non-targeted therapies ( such as aminosalicylic acid, glucocorticoids, and immunomodulators ) and targeted therapies ( such as anti-TNF, anti-IL-12/IL-23, and anti-α4β7 integrin ).

Although biologically targeted therapies are effective for many patients, up to 30% of patients do not respond to initial therapy, and up to 50% of patients lose response over time.

Therefore, a deep understanding of the operating mechanism of the intestinal immune system and the immune pathogenesis of IBD will help us develop immunotherapeutic drugs for IBD and provide a new means of immunotherapy for IBD.

Gut immune system

What is Inflammatory Bowel Disease (IBD)?

Gut microbiota

The human gut microbiota consists of trillions of species of microorganisms, including fungi, unicellular animals, viruses, archaea and, overwhelmingly, bacteria.

The gut microbiota plays a crucial role in the pathogenesis of IBD by regulating the activation of the innate immune system, affecting host energy metabolism, immune homeostasis and maturation, and maintaining mucosal integrity.

Accumulating evidence indicates that the composition of the gut microbiota is altered in patients with IBD.

For example, Escherichia coli increases in the gut as a pathogen, has the ability to survive and replicate in macrophages, and induces TNF-α secretion and inflammatory responses in IBD.

Furthermore, Faecalibacterium prausnitzii, as a probiotic, stimulated DCs to secrete the anti-inflammatory cytokine IL-10 and suppressed the production of IL-12 and INF-γ in the gut, which were significantly reduced in the gut of IBD patients.

In addition, the metabolites of the gut microbiota in IBD patients are also altered, such as disrupted bile acid metabolism, decreased levels of tryptophan metabolism, decreased SCFA, and increased levels of niacin, taurine, and acylcarnitines. Loss of these metabolites during intestinal inflammation may be a driving force in IBD pathogenesis.

Intestinal epithelial cells (IECs)

The intestinal epithelium is the largest mucosal surface in the human body, acting as a physical and biochemical barrier between the luminal contents and the underlying immune system.

It consists of a single layer of specific endothelial cells of different subtypes, mainly including columnar epithelium, goblet cells and Paneth cells.

Goblet cells, as secretory cells of the intestinal epithelium, can secrete mucus on the luminal surface of the intestinal mucosa, and the mucus layer provides the first line of defense.

Paneth cells are specialized granule-containing cells that reside in the epithelial crypts of the small intestine and play a crucial role in innate intestinal defense and protection of nearby stem cells.

They can produce antimicrobial peptides ( AMPs ), such as α-defensins, lysozyme C, phospholipases, and C-type lectins, which can fight against invading luminal pathogens.

AMP has been shown to be deficient in CD patients.

Another important component of the intestinal epithelium is the apical junction complex, composed of tight junctions ( TJ ), adherens junctions ( AJ ), and desmosomes, which tightly seal the intestinal epithelium to prevent entry of pathogens and regulate response to water, ions and Nutrient permeability.

Mutations in the gene encoding TJ and TJ dysfunction have been elucidated as key pathogenic factors of IBD.

Intestinal immune cells

Gut immune cells can be divided into innate and adaptive immune cells, both of which contribute significantly to the immune response in IBD.

Innate immune cells, such as macrophages, dendritic cells ( DC ), neutrophils, natural killer ( NK ) cells, and innate lymphocytes ( ILCs ), interact and produce cytokines, chemokines, and antibiotics to Inflammation is triggered, leading to phagocytosis, antigen presentation and activation of the adaptive immune system.

Macrophages, dendritic cells, neutrophils, NKT cells and ILCs constitute the first line of defense of the mucosal innate immune system. These immune cells of the innate immune system engage pathogen-associated molecular patterns ( PAMPs ), leading to the activation of multiple signaling pathways and the production of pro-inflammatory cytokines, chemokines, and antimicrobial peptides.

Compared with innate immune cells, adaptive immune cells have a high degree of specificity and immune memory capacity, and they complement each other to eliminate invading pathogens.

A key player in the adaptive immune response is T cells. Upon stimulation with antigens in the gut-associated lymphoid tissue ( GALT ) or mesenteric lymph nodes, naïve T cells are activated and differentiate into distinct subsets that respond to chemokine receptors ( Such as CCR9 and CCR10 ) and integrins and other cell adhesion molecules migrate to the inflammatory site of the intestine.

Nowaday, many drugs that target these receptors are successfully used in clinical practice to block the migration of T cells to the gut to prevent inflammation in IBD patients.

Immunological Pathogenesis of IBD

What is Inflammatory Bowel Disease (IBD)?

IL-22 and IL-6

IL-22 is a pleiotropic cytokine secreted by Th22, Th17, and Th1 cells that activates STAT3 to promote intestinal tissue repair and inhibit intestinal pathogens.

In IBD, IL-22 is ubiquitously expressed in the small intestine induced by microbiota signaling. In addition, IL-22 also promotes the expression of IBD susceptibility genes such as fut2, sec1, bcl2115 and PTPN22.

IL-6 is mainly produced by macrophages and dendritic cells in the lamina propria.

The study found that serum and intestinal IL-6 levels were elevated in CD patients and correlated with clinical disease activity, relapse frequency, and inflammation severity.

After binding to the receptor, IL-6 activates gp130-positive T cells, leading to STAT-3 signal transduction and transcriptional activation, which subsequently activates the transcription of the anti-apoptotic genes Bcl-2 and Bcl-xl.

Currently, the humanized anti-IL-6R monoclonal antibody tocilizumab has been used to treat IBD.

IL-12/IL-23

Both IL-12 and IL-23 produced by dendritic cells belong to the IL-12 family and play an important role in the pathogenesis of chronic inflammatory diseases.

In several models of colitis, pathogenic T cell responses are driven by IL-12 and IL-23.

IL-12 can promote the differentiation of naïve CD4+ T cells into IFN-γ-producing Th1 cells, and promote the proliferation and effector functions of NK cells, NKT cells and cytotoxic T cells.

IL-23 exerts its biological function by enhancing and affecting Th17 cell response, and it also antagonizes anti-inflammatory Foxp3+Treg cell response to promote intestinal inflammation.

IL-17

IL-17 cytokines, including IL-17A and IL-17F, also play an important role in the pathogenesis of IBD.

Genome-wide association studies ( GWAS ) have identified a number of Th17-related IBD susceptibility genes, including JAK2, STAT3, IL-23R, IL-12B, and CCR6.

Clinical studies have found that the intestinal mucosa and lamina propria of IBD patients contain higher levels of Th17 cells, IL-17 and IL-23 compared with healthy controls.

In mouse models, deficiencies in IL-17A and IL-17F were shown to be protective against colitis.

Il-10

IL-10 is the most important cytokine that suppresses the pro-inflammatory response of the immune system and can be produced by a large number of different types of cells, including Tregs, macrophages, dendritic cells, etc.

Mutations in the IL-10R subunit gene are associated with intestinal inflammatory immune responses during the early onset of IBD patients.

In fact, both IL-10 and IL-10R deficient mice can develop spontaneous colitis. In addition, c-MAF inactivation in Treg cells also leads to dysfunctional IL-10 production, leading to the development of idiopathic colitis.

IL-1β Family Cytokines

IL-1β is a pro-inflammatory cytokine secreted by macrophages that synergizes with other pro-inflammatory cytokines such as TNF-α and IL-6 to induce inflammation in IBD.

The study found that IL-10-deficient mice had increased secretion of IL-1β before the onset of spontaneous colitis. Furthermore, genetic deficiency or inhibition of IL-1β and IL-18 signaling alleviates experimental colitis.

TNF and TNF-like ligand 1A (TL1A)

TNF is considered a pro-inflammatory cytokine in the pathogenesis of IBD, which can stimulate the response in the acute phase, promote the secretion of IL-1 and IL-6, and increase the expression of adhesion molecules.

The study found that TNF-α was significantly elevated in the blood, epithelial tissue, and feces of patients with active IBD, and its levels correlated with clinical disease activity in CD patients.

Blocking TNF-α signaling by anti-TNF-α monoclonal antibodies has become an important treatment for patients with moderate to severe refractory IBD.

The TNF family member TL1A has also been found to be a key mediator of intestinal inflammation, and its levels are also elevated in IBD patients.

TL1A mainly exerts its function by binding to death receptor 3 (DR3), and TL1A can also synergistically promote the production of IL-4, IL-12 and IL-23, and increase the expression of DR3 by Th1, Th2 and Th17 cells to promote inflammation .

Immune cell migration

Migration of immune cells to the gut to initiate and maintain immune responses is a key pathogenesis of IBD, of which T cell migration is the most important one.

The complete process of immune cell migration includes tethering, rolling, activation, adhesion, and extravasation, involving various integrins, selectins, chemokines and their ligands or receptors, such as integrins α4β7 that promote migration to the small intestine, α4β1, β2 integrin and CCR9.

A variety of therapeutic approaches targeting different stages of immune cell migration have been applied clinically.

Immunotherapy for IBD

Currently, seven biologics have been officially approved by the U.S. Food and Drug Administration ( FDA ) for the treatment of IBD , and clinical trials of many innovative drug candidates for the treatment of IBD are underway.

What is Inflammatory Bowel Disease (IBD)?

TNF -α

Antibodies against TNF have been widely used for about 25 years.

Currently, four TNF-α inhibitors have been approved for clinical use, including infliximab, adalimumab, golimumab, and certolizumab pegol.

Infliximab, which induces healing of mucosal ulcers, is the first treatment approved for CD perianal fistula and has been shown to be effective in both CD and UC.

Adalimumab was shown to induce mucosal healing in CD, and it was also effective in CD and UC, as well as in CD patients unresponsive to infliximab.

In addition, golimumab and certolizumab pegol are also approved in the United States for the treatment of UC.

Although anti-TNF therapy has shown clinical efficacy, 10-30% of IBD patients do not respond and 20-40% lose response over time.

Targets IL-12/IL-23

Ustekinumab is a monoclonal antibody targeting the p40 subunit of IL-12 and IL-23, which has shown positive effects in the treatment of IBD.

It is currently the only anti-IL-23 therapy approved by the FDA.

Another target, targeting the p19 subunit of IL-23, has also shown clinical efficacy, including risankizumab, brazikumab, guselkumab, and mirikizumab. However, these antibodies are still in clinical trials.

Target JAK

The Janus kinase ( JAK ) family comprises four intracellular tyrosine kinases: JAK1, JAK2, JAK3, and non-receptor tyrosine protein kinase 2, which activate the STAT pathway and play key roles in the pathogenesis of IBD.

Currently, 10 JAK inhibitors have been evaluated for their clinical efficacy on IBD, and Tofacitinib is the only inhibitor with clinical efficacy and approved for the clinical treatment of UC.

Targeting cell adhesion molecules

As important mediators of T cell recruitment and intestinal inflammation, cell adhesion molecules are potential targets in IBD.

For example, the anti-α4β7 integrin antibody vedolizumab and the anti-a4 integrin monoclonal antibody natalizumab have shown good efficacy in the treatment of IBD, and have been approved and widely used clinically.

In addition, etrolizumab ( a monoclonal antibody that selectively binds to the β7 subunit ), abrilumab ( a monoclonal antibody that blocks α4β7 integrin ) and ontamalimab ( a humanized antibody targeting MAdCAM-1 ) have been clinically Efficacy has also been shown in previous data, and clinical trials are still ongoing.

Targeting the NLRP3 inflammasome

Elevated levels of NLRP3 inflammasome and pro-inflammatory cytokines are the main pathological mechanisms of IBD. CD patients have been observed to have high levels of the NLRP3 inflammasome.

Furthermore, activated NLRP3 inflammasome can promote excess IL-1β production and alter TJ expression in colonic epithelium, thereby accelerating disease progression.

Therefore, targeting the NLRP3 inflammasome offers a promising strategy for IBD therapy.

Outlook

In the past few decades, great progress has been made in the immunological mechanism of IBD , which provides new strategies and new ideas for the treatment of IBD .

In the future, alterations in specific genetic loci may be promising treatments for IBD .

In addition, new antibodies or inhibitors, combined treatment regimens and multifactorial blockers are also expected to break the bottleneck of IBD treatment and bring good news to the improvement of IBD patients.

references:

1. Immunology of Inflammatory Bowel Disease: Molecular Mechanisms and Therapeutics. J Inflamm Res. 2022; 15: 1825–1844.

What is Inflammatory Bowel Disease (IBD)?

(source:internet, reference only)

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What is Inflammatory Bowel Disease (IBD)?

What is Inflammatory Bowel Disease (IBD)?