Pathogenesis of inflammatory bowel disease

The inflammatory bowel diseases (IBDs) are chronic intestinal disorders that are typically Crohn’s disease and ulcerative colitis.

Ulcerative colitis is limited to the colon, with superficial mucosal inflammation.

UC extends proximally in a contiguous manner, and can lead to ulcerations, severe bleeding, toxic megacolon, and fulminant colitis. 

Crohn’s disease can affect any part of the digestive tract, often in a noncontiguous manner.

Crohn’s disease  is characterized by transmural inflammation, which can lead to complications such as fibrotic strictures, fistulas, and abscesses.

The pathophysiology of IBD involves complex genetic, environmental, epithelial, microbial, and immune factors. 

Differences between ulcerative colitis and Crohn’s disease have been observed: immune-cell subpopulations differentially enriched,  and genetic variants that increase the risk of Crohn’s disease but may be protective against ulcerative colitis.

The IBD armamentarium includes aminosalicylates, glucocorticoids, and immunomodulators, as well as targeted biologic therapies.

Medications act through one of the following mechanisms: neutralization of cytokines that promote inflammation, promote differentiation and function of specialized immune cells, block signal transduction cascades downstream, or modulation of lymphocyte trafficking.

Neutralization of cytokines that promote inflammation-anti–tumor necrosis factor antibodies.

Promote differentiation and function of specialized immune subsets-anti–interleukin-12 and anti–interleukin-23 antibodies.

Biologic therapies for IBD are effective in many patients, but up to 30% of patients do not have a response to initial treatment.

Biologic therapies for IBD lose their responsiveness in up to 50% of patients, over time. 

The normal intestinal epithelium is comprised of a single layer of epithelial cells linked by tight junctions and intercalated with immune cells.

The intestinal epithelium is a dynamic tissue containing  a series of villi and crypts.

In  ulcerative colitis down-regulation of a colonic goblet-cell–secreted protein, (whey acidic protein four-disulfide core domain 2), may occur.

With a reduction in  acidic protein four-disulfide core domain 2 

 (WADC2) there are abnormalities in mucus layer formation, increased colonization  of the microbiota, and breakdown of the epithelial barrier.

WFDC2 produced by goblet cells might be protective in ulcerative colitis.

Fibroblasts, myofibroblasts, and perivascular pericytes in the lamina propria play important roles in fibrosis and wound healing. 

Fibroblasts subpopulations exacerbate ulcerative colitis, by increasing  expression of  chemokines CCL19 and CCL21, and interleukin-33, which induce certain immune-cell subsets to produce type 2 cytokines.

The heritable risk that is greater for Crohn’s disease than for ulcerative colitis.

There is a higher incidence of IBD in first-degree relatives of patients with IBD than in the general population.

Only 8 to 13% of Crohn’s disease and 4 to 7% in ulcerative colitis can be explained by known IBD genetic risk loci.

Genetic factors may be important in children with very-early-onset IBD: variants in the antiinflammatory interleukin-10 signaling pathway.

The gastrointestinal tract, particularly the distal ileum and colon, contains the largest number and diversity of bacteria, and gut microbes maintain health by metabolizing dietary components such as cellulose. 

Gut microbes produce essential components such as vitamin K, an important cofactor in blood clotting, and short-chain fatty acids, an energy source for colonic epithelial cells. 

Commensal bacteria and their products also have an essential role in the normal development and functioning of the immune system. 

The presence of commensal bacteria interferes with the ability of pathogens to colonize and invade the gut, in part because of competition for space and nutrients. 

When  the integrity of the mucosal barrier is compromised, innocuous commensal bacteria can become pathogenic.

By crossing the epithelium commensal bacteria may eliciting an immune response and intestinal inflammation.

Crohn’s disease and ulcerative colitis are associated with reduced total number, and diversity of microbial species. 

Studies of microbiota have the potential to identify specific microbes or groups of microbes that may promote or mitigate intestinal inflammation owing to effects on the mucosal immune system.

Innate immune cells express receptors that detect microbial products or patterns, include granulocytes, macrophages, and dendritic cells.

Adaptive immune cells include B cells and T cells, which express variable receptors that recognize specific antigens, and mucosal-associated invariant T cells, which express antigen receptors with more limited diversity. 

The mucosal immune system represents the largest component of the immune system, containing approximately 75% of all lymphocytes and producing the majority of immunoglobulin in healthy persons.

The mucosal immunity must balance the opposing demands of providing protective immunity against pathogens while preventing excessive immune responses against innocuous food antigens and commensal microbes.

Immune cells can be found in organized secondary lymphoid structures of the gut mucosa.

These gut-associated lymphoid tissues, as well as in intestinal draining mesenteric lymph nodes are embedded between surface epithelial cells, and within the underlying connective tissue. 

Macrophages under the epithelium, kill invading microorganisms and dispose of pathogens and infected  mucosal cells targeted by adaptive immune cells. 

Innate lymphoid cells regulate tissue homeostasis, repair, remodeling, and microbial defense.

Subsets of these cells can be defined by their cytokine production.

Dendritic cells initiate and shape immune responses in mucosal tissues by acquiring antigen from microfold cells or by directly capturing and sampling luminal antigens, using membranous processes between epithelial cells. 

Dendritic cells that acquire antigens remain in Peyer’s patches or migrate to mesenteric lymph nodes to interact with naive T cells.

Naive B cells encountering antigens in the follicular areas of Peyer’s patches and mesenteric lymph nodes undergo activation and differentiation into antibody-secreting plasma cells, germinal center B cells, or memory B cells. 

IgG is able to fix and activate the complement cascade can result in cell lysis, inflammation, and tissue destruction.

Inflamed IBD tissue has a pronounced IgG predominance, in contrast to the IgA predominance characteristic of healthy gut tissue.

This suggests a paucity of IgA, an increase in IgG, or both might be pathogenic. 

IgG predominance observed in IBD tissue could lead to intestinal inflammation by recruitment of inflammatory immune cells and activation of complement, resulting in cell lysis.

Naive T cells undergo activation by antigen-bearing dendritic cells in the gut associated lymphatic tissues or mesenteric lymph nodes and up-regulate homing receptors that allow for T-cell redistribution to mucosal surfaces. 

Activated T cells can differentiate into effector, regulatory, and memory subset cells.

Effector cells produce inflammatory cytokines,  provide protection from microbial infection, dampen inflammation, and memory cells are long-lived and provide durable immunity.

Effector CD4+ T cells are, influenced by the cytokine microenvironment in which naive cells are activated.

Interleukin-12, a heterodimeric cytokine comprising interleukin-12p35 and interleukin-12p40 subunits, induces up-regulation of the transcription factor T-bet and promotes differentiation of type 1 helper T (Th1) cells, which produce interferon-γ and recruit macrophages, natural killer cells, and CD8+ T cells.

Interleukin-6, TGF-β, and interleukin-1 induce up-regulation of interleukin-23R and a network of transcription factors.

This up regulation of interleukin-23R enables responsiveness to interleukin-23, a heterodimeric cytokine, facilitating differentiation of Th17 cells, which recruit neutrophils and produce interleukin-17A, interleukin-17F, and interleukin-22. 

Interleukin-17 is produced not only by T cells but also by several other type 17 innate immune cells.

Anti–interleukin-12p40 antibodies targeting both interleukin-12 and interleukin-23 have been shown to be effective in the treatment of Crohn’s disease and ulcerative colitis.

Antibodies against the interleukin-23p19 subunit, targeting the interleukin-23 receptor, have also been shown to be effective in the treatment of Crohn’s disease and ulcerative colitis.

Janus kinase (JAK) inhibitors, such as tofacitinib, which block signals from interleukin-12, interleukin-23, and other cytokines by virtue of inhibiting downstream signaling pathways, are effective in ulcerative colitis.

Antibodies against interleukin-17A or the interleukin-17 receptor subunit interleukin-17RA have not been effective, at least in Crohn’s disease.

Effects of interleukin-17A: induce inflammation, promotes intestinal epithelial barrier function and repair, acts in an autoregulatory loop to limit Th17-cell pathogenicity, and provides protection against commensal fungi.

Targeting type 1 and type 17 immunity by lymphocyte trafficking or cytokine signaling with antibodies against interleukin-12 and interleukin-23 and JAK inhibitors are major components of the current IBD treatment.

There is an an increase in Treg cells in inflamed tissue from patients with IBD.

There are enriched numbers of FOXP3+ Treg cells in inflamed tissue from patients with Crohn’s disease, which were capable of producing interleukin-17A and interferon-γ while still retaining suppressive function.

It is difficult to determine whether the Treg-cell phenotypes are a cause or consequence of intestinal inflammation.

Activated CD4+ and CD8+ T cells can give rise to subsets of effector and Treg cells, and tissue-resident subsets of memory cells.

Tissue-resident memory T (TRM) cells are characterized by high expression of CD69 and CD103 in the gut mucosa.

TRM cells positioned at key barrier surfaces, such as the skin and intestinal, genital, and respiratory mucosa, diminish the microbial load in the earliest by directly recognizing antigen, augmenting innate immunity, and recruiting circulating memory T cells.

Tissue-resident immune cells (TRM) may play a pathogenic role in organ-specific autoimmune and inflammatory diseases.

Crohn’s disease is often manifested as skip lesions,and is reminiscent of psoriasis, in which exacerbations tend to affect the same region of skin and have been linked to clonally related  tissue-resident immune cells-like cells.

Crohn’s disease tends to recur at the site of surgical anastomosis after ileocolectomy raises the possibility that TRM cells are involved. 

The numbers of TRM-like cells are increased in both ulcerative colitis and Crohn’s disease. 

Increased numbers of intestinal interleukin-17A–producing, commensal microbiota–reactive CD4+ T cells with a CD154  memory phenotype have been observed in both patients with ulcerative colitis and those with Crohn’s disease, as compared with healthy controls.

Increased numbers of CD4+CD69+CD103+ Tissue-resident immune  cells are seen in intestinal tissue from patients with ulcerative colitis and those with Crohn’s disease, as compared with healthy controls.

Data suggest long-lived memory T-cell populations, particularly tissue-resident subsets, may contribute to the chronicity of IBD and represent a potential target for therapy.

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