UC PATHOPHYSIOLOGY

The pathway to inflammation

Ulcerative colitis (UC) is an immune-mediated inflammatory disorder affecting the colon.1–4 

It is characterised by relapsing and remitting mucosal inflammation, which usually involves the rectum and extends proximally to a variable extent through the colon.1,4

In UC, inflammation is continuous throughout the area of colon affected and is limited to the colon’s mucosal and submucosal layers.1,3


What is ulcerative colitis?

The incidence of UC is similar between men and women.1,4 While the onset can occur at any age,1 UC most commonly first presents in early adulthood and its prevalence is rising dramatically worldwide.1,4

The key symptoms of UC are bloody diarrhoea, faecal urgency, tenesmus (cramping rectal pain) and pain in the lower abdomen.5

UC can cause fibrosis and structural changes in the colon, which are associated with additional risks, such as surgery and cancer.3

While UC can be effectively managed with treatment, there is no cure.1,4



Under-recognition of the disabling and
progressive nature of UC means it is often
treated suboptimally3

UC disease localisation and subtypes by
extent of colon inflammation4

Figure reproduced from: Yeshi K, Ruscher R, Hunter L et al. J Clin Med 2020;9(5):1273.







Drivers of IBD pathophysiology

Professor Charlie Lees summarises the current understanding of the factors driving the development of IBD, and what we hope to learn in the next few years.



What causes UC?

The pathophysiology of UC is complex, and understanding continues to evolve.1,2 Multiple interdependent factors may drive the disease pathophysiology.1,2,4,6,7

In UC, the activity of pro- and anti-inflammatory mediators is dysregulated, provoking an exaggerated immune response and initiating a chronic cycle of inflammation.6-8

Impairment of the epithelial and mucus layer barrier in the colon due to dysregulation of inflammatory mediators such as interleukin (IL)-13 is strongly implicated in UC pathogenesis.1,2,4,6,7

Impaired barrier function increases the permeability of the epithelial layer of the intestine.1,2,4,6 This causes aberrant activation of antigen-presenting cells (APCs) in response to normally harmless intestinal bacteria (commensal microbiota), which initiates an inappropriate inflammatory response.1,2,4,6,7


Numerous cells and inflammatory processes

are implicated in UC pathophysiology4,7



Key cell types implicated in UC pathogenesis include:1,2,4,9,10
  • Cell type

  • Colonocytes (colonic epithelial cells)

  • APCs (macrophages and dendritic cells)

  • T cells

  • Circulating leukocytes

  • Role in UC pathogenesis

  • Increased gut permeability


  • Triggering of the inflammatory response, resulting in increased production of pro-inflammatory cytokines (magnified by increased APC activation and sensitivity in UC)

  • Dysregulation of different T cell types leading to increased inflammatory cytokine production; impaired wound healing 

  • Recruitment of circulating immune cells to the intestinal mucosa leads to increased production of pro-inflammatory cytokines



Other factors known to contribute to or increase the risk of development of dysregulated inflammation in UC1,4,7,9


Genetic factors1,4,7,9
  • Family history is the greatest risk factor for UC; first-degree relatives of patients with UC have a four-fold higher risk of developing the condition compared with the general population
  • Numerous genetic risk loci have been identified for UC, many of which are related to gut immunity
Environmental and lifestyle factors1,4
  • A range of environmental and lifestyle factors are associated with UC, although their roles remain unclear
Microbial influences1,4,9
  • Commensal gut bacteria are essential to intestinal homeostasis and health, and disruption is associated with intestinal inflammation
  • The gut microbiome of patients with UC is dysregulated, with evidence for an absence of certain bacteria important for gut health; however, it is not yet clear what role this plays in UC pathogenesis
  • Numerous environmental and dietary factors can impact the gut microbiome
Factors thought to contribute to the development of UC

Figure reproduced from Yeshi K, Ruscher R, Hunter L, et al. J Clin Med. 2020;9(5):1273. 


Cytokines and signalling pathways

A number of different inflammatory cytokines and pathways are implicated in UC; key areas of therapeutic interest include:1,2,6–8

  • Cytokines

    • Interleukins
    • TNFα
  • Signalling pathways

    • The JAK-STAT pathway

Treatment targets in IBD

Professor Séverine Vermeire introduces some of the key targets of current and future IBD treatments. 


Cytokines

Cytokines enable cell–cell communication and play an important role in the immune system.11 They are produced in response to cell activation, e.g. by detecting an immune threat and binding with cytokine receptors on target cells. This stimulates intracellular pathways to produce appropriate cellular responses.11,12


Interleukins

Interleukins are a family of cytokines with an essential role in activation and differentiation of immune cells.12 Numerous interleukins are implicated in UC, with roles including:1,4

  • Inducing differentiation and proliferation of pro-inflammatory T cells
  • Stimulating expression of inflammatory and cell survival genes
  • Triggering apoptosis of epithelial cells
  • Interrupting tight junctions

Interrupting interleukin signalling may help limit inflammation in UC.4


TNFα15,16

TNFα is a pro-inflammatory cytokine, that plays a pivotal role in the inflammatory cascade - this leads to chronic intestinal inflammation in UC.

  • Synthesised by monocytes, macrophages and natural killer cells
  • Induces signalling through NF-κB and MAPK
  • Causes cell proliferation and macrophage differentiation
  • Induces expression of pro-inflammatory cytokines including IL-6 and IL-12, and stimulates self-propagating TNFα expression
  • May also decrease mucosal barrier function by stimulating apoptosis of intestinal epithelial cells

Elevated TNFα in UC leads to an aberrant pro-inflammatory response that is associated with dysregulation of mucosal immune cells and tissue damage. Inhibiting the action of TNFα can help mitigate these effects.

Key interleukins implicated in UC include:4,13,14
  • IL-4

    Differentiation of naïve T cells into Th2 cells

  • IL-5

    Eosinophil activation and B cell growth

  • IL-6

    Induces Th17 cell differentiation in presence of TGF-β

  • IL-9

    Prevents mucosal healing and disrupts mucus layer

  • IL-13

    Promotes fibrosis, and induces apoptosis and degradation of tight junctions in intestinal epithelial cells leading to ulceration

  • IL-17A

    Increases release of pro-inflammatory cytokines, chemokines and mediators including matrix metalloproteinases and granulocyte-macrophage colony-stimulating factor

  • IL-21

    Helps stabilise Th17 cell differentiation

  • IL-23

    Works with TGF-β, IL-6 and IL-21 to induce Th17 cell differentiation, and stimulates innate lymphoid cells and invariant natural killer T cells



Signalling pathways

Cytokines act through a number of different signalling pathways:17,18

  • Type I cytokine receptors
  • Type II cytokine receptors
  • Tumour necrosis factor receptor family
  • Chemokine receptors
  • TGF-β receptor family

 


These pathways mediate the expression and downstream effects of key inflammatory mediators.19

The JAK-STAT pathway is a critical signalling pathway as it is involved in the action of multiple cytokine families.9,20–22

JAK-STAT has been implicated in the pathogenesis of a number of inflammatory diseases, including inflammatory bowel disease (IBD).6,20

The JAK-STAT pathway

The JAK-STAT pathway represents a point of convergence common to multiple pathways of inflammation.8,20
Four JAK proteins form pairs that mediate cytokine signalling: JAK1, JAK2, JAK3 and TYK2.23
Many of the pro-inflammatory cytokines implicated in UC signal through the JAK-STAT pathway by binding to their associated receptors.21,23,24

The role of cytokine signalling through the JAK-STAT pathway in IBD pathogenesis*

Selective JAK pairing mediating cytokine signalling
Role in IBD pathogenesis
Cytokines signalling through this JAK pairing
Selective JAK pairing mediating cytokine signalling
image
Role in IBD pathogenesis
  • Inflammation25
  • Deleterious impact on wound healing26
  • Pro-inflammatory cytokine signalling in mucosal immune cells27
Cytokines signalling through this JAK pairing
  • IL-2, IL-4, IL-7, IL-9, IL-15, IL-2120
Selective JAK pairing mediating cytokine signalling
image
Role in IBD pathogenesis
  • Chronic intestinal epithelial inflammation26
  • Pro-inflammatory cytokine production26
  • Increased permeability of intestinal epithelial barrier14,26,28
  • Intestinal epithelial cell apoptosis and ulceration13,14
  • Epithelial cell proliferation and tumour growth (colorectal carcinogenesis)7,29
Cytokines signalling through this JAK pairing
  • IL-6, IL-10, IL-11, IL-13, IL-19, IL-22, oncostatin20
Selective JAK pairing mediating cytokine signalling
image
Role in IBD pathogenesis
  • Lymphocyte differentiation14
  • Inflammatory cytokine production14
Cytokines signalling through this JAK pairing
  • IL-12, IL-2320
Selective JAK pairing mediating cytokine signalling
image
Role in IBD pathogenesis
  • Epithelial cell death7,14
  • Disruption and loss of epithelial barrier function13,14
Cytokines signalling through this JAK pairing
  • IFNγ20

*Not an exhaustive list.


JAK-STAT signalling in UC


In UC, excessive signalling through the JAK-STAT pathway results in aberrant cytokine production and a cycle of chronic, relapsing inflammation and potential damage.6,8

Modulating JAK signalling affects adaptive and innate immune responses.20 Many of these signalling pathways mediate the downstream effects of cytokines implicated in UC pathogenesis, including T cell activation, and differentiation and recruitment of inflammatory cells.14,20

The JAK-STAT pathway mediates pathological inflammatory pathways as well as normal physiological functions.6,15,16,20

Emerging research continues to improve our understanding of how the JAK-STAT pathway plays important roles in inflammatory diseases such as UC, as well as in homeostasis.6,23,24

Current evidence suggests that excessive signalling through JAK1-containing pairs is important in the pathogenesis of IBD, whereas the roles of other JAK pairs are less clear and still being explored. Research is ongoing to evaluate if treatment with molecules that demonstrate preferential JAK inhibition will lead to differences in efficacy and safety profile.30



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