Etiopathogenesis

Introduction

Ulcerative colitis (UC) is a systemic, chronic, idiopathic, inflammatory disorder characterized by relapsing-remitting mucosal inflammation, starting in the rectum and extending to proximal segments of the colon. The exact etiopathogenesis of UC remains unknown; however, studies have implicated genetic factors, environmental triggers, and immunoregulatory dysfunction as contributing factors.

Genetic Factors

Family History

A family history of inflammatory bowel disease (IBD) is present in approximately 8% to 14% of patients with UC, with first-degree relatives being at four times greater risk for developing the disease. In families with a high incidence of IBD, approximately 75% are concordant, that is, affected members have either UC or Crohn’s disease (CD). The remaining 25% are not concordant, with certain family members having UC and others having CD. Heritability studies have found a higher concordance rate among monozygotic twins compared to dizygotic twins for both UC and CD; however, concordance rates for UC are lower than for CD, suggesting that the genetic contribution in CD is more pronounced. In CD, concordance rates range from 37% to 58% in monozygotic twins compared to 3.9% to 12% in dizygotic twins. In UC, concordance rates range from 6% to 17% and 0% to 5% in monozygotic and dizygotic twins, respectively. These findings indicate that genetic factors do contribute to the pathogenesis of IBD, particularly CD; however, the low concordance rates indicate that other factors play important roles as well.

In a 5-year population-based cohort study of 454 patients with UC, no significant differences in medical therapy outcomes, indications for colectomy, or disease extent were found between patients with and without a family history of UC. However, the study did find that relapse rates were greater in familial cases. In an analysis of 46,114 UC cases, Kuwahara and colleagues found that although the age of onset was lower in patients with a family history of UC, the clinical course of patients was not affected. Similar results were found in a retrospective study of 411 children with IBD, 244 of whom had UC.

Susceptibility Loci

Recent advances have been made in genetic testing and deoxyribonucleic acid (DNA) sequencing, thus permitting genome-wide association studies in IBD. One study of more than 75,000 patients with IBD and controls identified 163 susceptibility loci for IBD, with 110 contributing to both Ulcerative colitis and CD phenotypes, 30 unique to CD and 23 unique to UC. UC and CD are therefore hypothesized to be heterogenous polygenic disorders sharing many, but not all, susceptibility loci. Human leukocyte antigen variants appear most strongly associated with UC.

Other identified genes involved in UC include those associated with barrier function, such as HNF4A, CDH1, and LAMB1 and those that encode cytokines and inflammatory markers, such as IL1R2, IL7R, TNFRSF15, TNFRSF9 and IL8RaIRB. As of August 2018, over 240 risk gene loci have been associated with the presence of IBD. So far, identified loci individually contribute only a small percentage to expected heritability. Therefore, the presence or absence of a mutated gene does not appear to have predictive value for determining who will develop UC or disease severity in those who do eventually develop UC.

Environmental Factors

Although patients with IBD are genetically predisposed to develop their disease, it is not sufficient for the onset of inflammation, reinforcing the importance of environmental factors on its development. The rising incidence of UC in less-developed regions of the world supports this. Current hypotheses posit that genetically predisposed individuals, upon exposure to environmental triggers, develop a dysregulated immune response that leads to gastrointestinal inflammation. Environmental factors including tobacco smoking history, drug exposure (e.g., oral contraceptives, nonsteroidal anti-inflammatory drugs (NSAIDs)), diet, pollution, geography, stress and lifestyle, sleep, dysbiosis and breastfeeding have been investigated as contributing factors in the development of UC. These and other environmental factors will be covered in more detail in Environmental Risk and Protective Factors.

Pathogenesis

Several processes have been proposed to be responsible for triggering chronic mucosal inflammation, including a defective mucosal barrier, immunoregulatory defects, infection with specific pathogens and dysbiosis. These will each be discussed below.

Colonocytes and Barrier Integrity

The human gut harbors greater than 10 organisms belonging to 500 species of organisms. In healthy individuals, the presence of potentially proinflammatory intestinal bacteria is tolerated without neutrophil recruitment. One mechanism by which excessive inflammatory response may be prevented is through controlled activation of triggering receptor expressed on myeloid cells 1(TREM-1) on myeloid cells. When activated, TREM-1 amplifies the inflammatory response by enhancing degranulation and secretion of proinflammatory cytokines. However, the ligand for TREM-1 is expressed on less than 10% of macrophages within the intestinal lamina propria.

The tight junctions present between healthy gut epithelial cells provides an effective barrier against luminal microbes and antigens. However, in instances of compromised barrier integrity, bacteria may cross the mucosal barrier and encounter immune cells, triggering an adaptive immune response, leading to the production of a variety of inflammatory cytokines and the recruiting of additional cells into the intestinal wall. Epithelial and mucous barrier defects are strongly associated with the pathogenesis of UC. Patients with UC have depleted colonic goblet cells and as a result, a compromised mucus barrier. Polymorphisms in trefoil factors, goblet cell-produced proteins that contribute to the mucosal barrier, have also been described in UC patients. Increased epithelial permeability may lead to continuous stimulation of the mucosal immune system and the chronic inflammation characteristic of UC.

Immunoregulatory Dysfunction

In healthy individuals, exposure to commensal bacteria is hypothesized to block activation of the NF-kB pathway, therefore inhibiting a potential inflammatory immune response to the plethora of antigens the epithelial cells are exposed to. However, in IBD, this symbiotic relationship is lost and exposure to gut microbes triggers a destructive immune response. Expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), a negative regulator of NF-kB-dependent inflammation, is reduced in colonocytes of UC patients, representing one possible mechanism by which inflammation could be triggered. Another potential driver of disease pathogenesis is the innate lymphoid cell (ILC), a major mediator of chronic intestinal inflammation. ILCs isolated from UC patients show elevated expression of key cytokines, including IL17A and IL22, transcription factors RAR-related orphan receptor C (RORC) and aryl hydrocarbon receptor (AHR) and cytokine receptors, including IL23R.

Elevated concentrations of immunoglobulin M (IgM), immunogloulin A (IgA) and immunoglobulin G (IgG) have been reported in patients with IBD, with a marked increase of IgG1 antibodies in patients with UC. However, it is not known whether B cell involvement is a cause or consequence of barrier disruption.

The Janus kinase (JAK) family consists of the four tyrosine kinases JAK1, JAK2, JAK3 and TyK2. These intracellular enzymes transmit signals from cytokine or growth factor-receptor signaling to influence gene expression. In this signaling pathway, cytokine or growth factor binding triggers the pairing of JAKs (e.g., JAK1/JAK3) and the subsequent phosphorylation and activation of signal transducers and activators of transcription (STATs), which in turn modulate intracellular activity relating to hematopoiesis and immune cell function. The JAK-STAT pathway regulates signaling for multiple relevant immune mediators implicated in the pathogenesis of IBD, such as type I interferon, interferon-γ and interleukins 2, 4, 6, 7, 9, 12, 15, 21, 23 and 27. JAK inhibitors, such as tofacitinib, prevent the phosphorylation and activation of STATs, thus impairing the transmission of signals from the cell surface to the nucleus.

Infection

Infection with a ≥1 specific pathogen has been proposed as being causative of IBD. Interest in this hypothesis stems from the observation that disease onset and activity are elevated during winter, a season of high bacterial, viral and parasitic infections. Implicated pathogens include Mycobacterium paratuberculosis, M paramyxovirus, Listeria monocytogenes and Helicobacter hepaticus, but no single organism has been conclusively associated with disease onset to date.

Dysbiosis

A decrease in gut biodiversity has been reported in patients with UC, with a lower proportion of Firmicutes and an increase in Deltaproteobacteria, Gamma-proteobacteria and Enterobacteriaceae. Although dysbiosis is observed in patients with UC, it is unclear whether it plays a role in triggering UC or occurs following disease onset.

Overview

In summary, UC is associated with damage to the intestinal barrier, which facilitates the ability of gut microbes to trigger a sustained and uninhibited inflammatory response (Figure 2-1). Regardless of the mechanism, neutrophils likely play an early role in the inflammatory process. Once neutrophils have infiltrated tissues through gaps in vascular endothelium, they release antimicrobial peptides and reactive oxygen species, which may further damage tissue. Neutrophils also produce chemokines and proinflammatory cytokines, such as TNFα, IL-1b, IL-6 and IL-8, which serve to recruit and activate other white blood cells (WBCs), including antigen-presenting cells.

Adaptive immunity plays an important role in the pathogenesis of UC. T cells are important participants in the regulation of the immune response in patients with UC. T cells proliferate in the peripheral blood and when they become stimulated in the presence of antigens. The T cell response, precipitated by antigen-presenting cells, has been studied extensively in IBD pathogenesis. The main subtypes of T_H cells are T_H1, T_H2, T_H17 and regulatory T cells. Each of these subtypes has relevant immune functions. For example, T_H1 cells eliminate pathogenic agents present in the cells; T_H2 cells control allergic reactions and protects the body from parasites; T_H17 remove extracellular bacteria and fungi; regulatory T cells promote tissue repair.

Evidence indicates that the adaptive immune response can follow one of two pathways: a T_H1-driven response in CD and a T_H2-driven response in UC. An excessive T_H2 response is characterized by increased secretion of IL-4, IL-5, IL-10 and IL-13, contributing to a self-sustaining cycle of activation. In support of an excessive T_H2 response in UC, IL-5–producing, T_H2-polarized T cells were identified in the colonic lamina propria of patients with UC. Additionally, rectal biopsies from patients with UC were found to have significantly elevated IL-4 and IL-13 mRNA levels compared to controls. A population of IL-9–producing, CD-4–positive T_H cells have also been identified as contributors to the development of UC, with IL-9 increasing tissue concentrations of TNFα and inhibiting cellular proliferation and repair, thus having a negative impact on intestinal barrier function.

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