Immunopathogenesis of inflammatory bowel disease

Abstract

Crohn's disease and ulcerative colitis are chronic relapsing immune mediated disorders that results from an aberrant response to gut luminal antigen in genetically susceptible host. The adaptive immune response that is then triggered was widely considered to be a T-helper-1 mediated condition in Crohn's disease and T-helper-2 mediated condition in ulcerative colitis. Recent studies in animal models, genome wide association, and basic science has provided important insights in in the immunopathogenesis of inflammatory bowel disease, one of which was the characterization of the interleukin-23/Th-17 axis.

Figure 1

Working hypothesis of inflammatory bowel disease. A defect occurs in sampling of gut luminal antigen, possibly mediated by enhanced Toll-like receptor activity and controlled by other genetic factors (mutations in DLG5 and OCTN). Over-response to antigens results in stimulated dendritic cells (DC) that recruits and generates various T-cell subtypes, which then initiate a cascade of immunologic events leading to mucosal inflammation. Adhesion molecules such as intercellular cell adhesion molecule 1 (ICAM1) are important for circulating mononuclear and polymorphonuclear cells to adhere and migrate to the inflamed gut mucosa. Crohn’s disease (CD) is a predominately Th1 and Th17 mediated process, while ulcerative colitis (UC) appears to be predominately mediated through Th2 and NK T-cells.

Figure 2

PRRs and their corresponding ligands. Toll-like receptors on the cell membrane (TLR-1, -6, -10, and -11) and intracellular (TLR-7, -8, and -9) selectively bind to various bacterial, viral, or fungal components. A major convergent pathway is through myeloid differentiation primary response protein MyD88, which activates NF-κB. The death domain of MyD88 then recruits downstream IL-1 receptor-associated kinase (IRAK) to the receptor complex. IRAK is then autophosphorylated and in turn recruits TNF receptor-associated factor 6 (TRAF6). TRAF6 then activates kinases including NF-κB-inducing kinase (NIK) and mitogen-activated protein kinase/ERK kinase kinase 1 (MEKK1). Inhibitor of NF-κB degradation (IκB) is subsequently phosphorylated and degraded, resulting in NF-κB nuclear translocation. NF-κB then activate genes involved in inflammatory response including IL-1b, TNF, IL-6, IL-8, and ICAM1. Toll-inhibitory protein (Tollip) is one of the negative regulators of the innate immunity. Activation of typeI IFN (IFN-α/β) also has anti-inflammatory function in colitis.

Figure 3

Th1 Polarization Pathway. Polarization of naïve T-cells towards Th1 cell subtype is initially induced by IL-12, a heterodimer of the p40 and p35 subunits. Activation of signal transducer and activator of transcription-1 (STAT1) and its stimulation of transcription factor T-bet, a TH1 “master switch” that upregulates and stabilizes the expression of IL-12. IL-12 can then amplify TH1 response by upregulating IL-18 on T-cells. IL-18 then stimulates NF-κB and AP1, and in synergy with STAT4 (activated by IL-12), transactivates IFN-γ expression.

Figure 4

Differentiation of T-cell Subsets. Upon stimulation, naïve CD4+ T-cells differentiate into 3 main subsets, Th1, Th2, and Th17 cell. IL-12 induces the formation of IFN-γ producing Th1 cells. IL-23 promotes the development of an IL-17 producing CD4+ helper T cells. IL-4 induces STAT6 activation, promoting the expression of GATA-3, which feed forward to induce IL-4 expression and Th2 cell differentiation. An EBI3-associated cytokine was hypothesized to be necessary for activation of IL-13 producing NK T-cells. Tregs, an immune-modulating subset of CD4+ T-cells, can suppress the differentiation and function of Th1 and Th2 cells. Interestingly, in the presence of IL-6, Treg-derived TGF-β can induce the differentiation of Th17 cells.