Key points

Introduction

Inflammatory bowel disease (IBD), specifically Crohn disease (CD) and ulcerative colitis (UC), are autoimmune diseases whose incidence and prevalence are increasing worldwide. Over the last few decades, substantial progress has been made in understanding the pathophysiology of IBD, which has been translated into newer, more effective therapies (biologics) that have reduced flares, brought more patients into remission, and improved the quality of life of patients with IBD. IBD is considered to be an immune-mediated disease that involves a complex pattern/interplay of host genetics and environmental influences. Our knowledge of the immune system and its homeostatic imbalance is derived from mouse models of colitis and human studies involving clinical and laboratory experiments.

The immune system evolved in multicellular organisms/metazoans as a defense mechanism against pathogens like bacteria, protozoa, parasites, and fungi. The human immune system can be broadly categorized into innate and adaptive based on the differences in timing of the response and specificity. The immune system comes in contact with a foreign challenge, which could be food, commensal flora, microbial pathogens, and xenobiotics at different sites like the skin, mucous membrane of lungs, gastrointestinal tract, and so forth. The human gastrointestinal tract, with a total surface area roughly equal to that of a tennis court (400 m ² ), serves as the largest area of interface with the external environment. The gut mucosal immune system, which interacts with this large antigenic load, thus, has the most varied immune cells in the body. In a disease-free host, there is a fine balance between a protective and deleterious response of the immune system, which becomes perturbed in patients with IBD. To understand these perturbations in IBD that produce a disease state, it is necessary to first understand how the intestinal immune system works. In this review, the authors divide their article into subsections of innate and adaptive immunity and link it with the currently identified abnormalities in these pathways in IBD. In addition, the authors have summarized in Table 1 the current and emerging therapies for IBD that target specific molecules in the immune system.

Introduction

Inflammatory bowel disease (IBD), specifically Crohn disease (CD) and ulcerative colitis (UC), are autoimmune diseases whose incidence and prevalence are increasing worldwide. Over the last few decades, substantial progress has been made in understanding the pathophysiology of IBD, which has been translated into newer, more effective therapies (biologics) that have reduced flares, brought more patients into remission, and improved the quality of life of patients with IBD. IBD is considered to be an immune-mediated disease that involves a complex pattern/interplay of host genetics and environmental influences. Our knowledge of the immune system and its homeostatic imbalance is derived from mouse models of colitis and human studies involving clinical and laboratory experiments.

The immune system evolved in multicellular organisms/metazoans as a defense mechanism against pathogens like bacteria, protozoa, parasites, and fungi. The human immune system can be broadly categorized into innate and adaptive based on the differences in timing of the response and specificity. The immune system comes in contact with a foreign challenge, which could be food, commensal flora, microbial pathogens, and xenobiotics at different sites like the skin, mucous membrane of lungs, gastrointestinal tract, and so forth. The human gastrointestinal tract, with a total surface area roughly equal to that of a tennis court (400 m ² ), serves as the largest area of interface with the external environment. The gut mucosal immune system, which interacts with this large antigenic load, thus, has the most varied immune cells in the body. In a disease-free host, there is a fine balance between a protective and deleterious response of the immune system, which becomes perturbed in patients with IBD. To understand these perturbations in IBD that produce a disease state, it is necessary to first understand how the intestinal immune system works. In this review, the authors divide their article into subsections of innate and adaptive immunity and link it with the currently identified abnormalities in these pathways in IBD. In addition, the authors have summarized in Table 1 the current and emerging therapies for IBD that target specific molecules in the immune system.

Innate intestinal immunity

Epithelial Barrier

The gastrointestinal tract has a continuous layer of single epithelial cells that are derived from a common progenitor LGR5+ intestinal stem cell. The epithelial cells comprise enterocytes (intestinal absorptive cells), goblet cells, neuroendocrine cells, Paneth cells, and microfold (M) cells. The epithelial cells are sealed with intercellular tight junctions that serve a barrier function and regulate the trafficking of macromolecules between the luminal environment and the host. The tight junctions are composed of a meshwork of proteins like occludin, claudin family members, and the junctional adhesion molecule, with zonulin as one of the physiologic modulators (of tight junctions) that controls intestinal permeability. The luminal surface is covered by a thick layer of mucus, which is produced by goblet cells. Mucus is rich in secreted immunoglobulin A (IgA) antibodies, proteins with antibacterial activity (ie, α- and β-defensins), and proteolytic and glycolytic enzymes that form the first line of defense against invasion by foreign pathogens. In spite of this barrier, gut bacteria and luminal antigens do enter the subepithelial lamina propria (an extracellular matrix compartment that contains a variety of immune and nonimmune cells), with some entering through unwanted breaks but most through the specialized, follicle-associated epithelium (FAE) that overlies the organized lymphoid tissue of the gut (gut-associated lymphoid tissue [GALT]). GALT consists of organized lymphoid compartments (Peyer patches, mesenteric lymph nodes, isolated lymphoid follicles, cryptopatches) and dispersed lymphoid cells in lamina propria and intraepithelial spaces. The FAE overlies the large lymphoid aggregates called Peyer patches and, compared with other parts of intestinal epithelium, is devoid of goblet cells and has a lower concentration of brush border enzymes. The FAE also contains unique highly specialized epithelial cells called M cells that actively pinocytose or endocytose selected luminal macromolecules into underlying lymphoid follicles, thus, facilitating transepithelial transport. M cells, in comparison with enterocytes, have irregular microvilli, decreased alkaline phosphatase activity, and no IgA secretory component. Immediately below the FAE is the subepithelial dome region that overlies the lymphoid follicle containing large numbers of dendritic cells (DCs). The antigens and microorganisms transported through M cells are captured by these DCs, which then present antigenic peptides to interfollicular T cells or naïve T cells within the mesenteric lymph nodes ( Fig. 1 ). Paneth cells are epithelial cells found at the base of the small intestinal crypt that can sense luminal microbiota and antigens to secrete antimicrobial peptides and contribute to innate host immunity.

Basic organizational structure of the small intestine mucosal immune system. On the left of the figure is FAE. The main functional component of the FAE is the M cell, which is specialized in transepithelial antigen transport. DCs and antigen-presenting cells (APC) take up these transported antigens and then present them to naïve T cells. A single layer of epithelial cells that are derived from a common progenitor LGR5+ intestinal stem cell (SC) act as a barrier against the pathogens and foreign antigens. The Paneth cells are found in base of small intestine crypts and secrete antimicrobial peptides (AMP). Goblet cells secrete mucus that limits exposure of intestinal epithelium to bacteria. Immune cells present in the mucosa include macrophages, DCs, T cells, intraepithelial lymphocytes, IgA-secreting plasma cells, atypical lymphocytes, B cells, and stromal cells. The right side of the figure depicts the likely pathways through which bacterial antigens can activate mucosal T cells: (1) apoptosis of infected epithelial cells; (2) luminal sampling and acquisition of bacteria by mucosal DCs; and (3) direct contact of translocated bacteria with T cells mediated by Toll-like receptor (TLR) recognition. APCs like the DC on activation migrate through the efferent lymphatics to the mesenteric lymph nodes, where they interact with naïve T cells and induce 2 surface molecules, α4β7 integrin and the chemokine receptor CCR9, that induce homing of T cells back to the gut (site of activation of DC). MLN, mesenteric lymph node.

Evidence for innate immune cellular dysfunction in the pathogenesis of IBD

There are multiple lines of evidence that indicate a major role for innate immune cells in the perpetuation of human chronic intestinal inflammation. The most recent meta-analysis of genome-wide association studies (GWAS) in IBD has implicated multiple susceptibility genes involved in innate mucosal defense (NOD2, CARD9, REL, SLC1A) and antigen presentation (ERAP2, LNPEP). Indeed, one of the strongest genetic associations to date with small bowel CD is the loss-of-function polymorphisms in the bacterial sensing gene CARD15/NOD2. The dysfunction secondary to NOD2 mutation has been reported in Paneth cells and monocytes. It seems that dysregulation in the detection of and/or responsiveness to enteric bacteria by innate immune and epithelial cells promotes chronic inflammation in this subgroup of patients. More evidence for their role rests in the efficacy of immune therapy targeted against proinflammatory cytokines produced by innate immune cells. Activated macrophages produce large quantities of TNF-α and IL-12, which are 2 cytokines responsible for the recruitment and activation of pathogenic effector T cells. The efficacy of anti–TNF-α therapy in IBD is well established, and promising anti–IL-12/23 studies are ongoing.

Another feature in patients with CD is a defective inflammatory response to injury and bacterial products, as evidenced by decreased neutrophil infiltration, lower production of proinflammatory interleukins (IL-8 and IL-1β), and reduced vascular flow as compared with healthy individuals. In addition to defective acute response, there is failure of clearance of bacteria and inflammatory debris, which indicates a disruption in the autophagy pathway. Autophagy (or self-eating) is a process that involves degradation and recycling of intracellular contents and removal of intracellular microbes and is mediated by lysosomes. The GWAS first pointed to the role of autophagy in CD pathogenesis, with many CD-associated genetic loci lying within the category of autophagy homeostatic function (eg, ATG16L1 and IRGM). Homozygosity for the ATG16L1 risk allele contributes to Paneth cell dysfunction in mice and humans, but mice do not develop spontaneous intestinal inflammation. Another pathway interconnected with autophagy and that affects intestinal epithelial cells of patients with IBD is unfolded protein response (UPR) from endoplasmic reticulum (ER) stress. Most of the secreted and membrane proteins enter the ER where they fold and assemble with only properly folded proteins exiting the ER via vesicles. When the unfolded proteins accumulate in the ER, it may lead to ER stress and activation of signaling pathways collectively known as UPR that help mitigate the stress. Not only the intestines of patients with IBD have evidence of endoplasmic reticulum (ER) stress but multiple ER stress-related genes like XBP1 have been associated with IBD. Genetic deletion of XBP1 in the intestinal epithelial cells of mice results in the depletion of Paneth cells, inflammatory hyperresponsiveness to TNF-alpha, and spontaneous enteritis.

Evidence for barrier dysfunction and epithelial injury in the pathogenesis of IBD

Numerous studies have shown that disruption of the epithelial barrier may either initiate or perpetuate chronic intestinal inflammation. Abnormal intestinal permeability has been established among patients with CD and their healthy first-degree relatives and may represent a primary abnormality predisposing to excessive antigen uptake, continuous immune stimulation, and eventually mucosal inflammation. Animal models like SAMP1/YitFc have increased intestinal permeability before the development of spontaneous ileitis, and GWAS studies have identified as a CD risk locus MUC19, whose product comprises the intestinal mucous layer. Barrier dysfunction has been directly observed by confocal endomicroscopy in a cohort of patients with IBD, and this dysfunction is predictive of IBD relapse within 12 months of microscopy. The etiologic factors for barrier dysfunction in CD may be environmental or genetic. Diet and nonsteroidal antiinflammatory drugs can affect gut permeability and are variably associated with IBD. Furthermore, polymorphic variants in several IBD-associated genes (DLG5, JAK2, HNF4A) seem to primarily affect epithelial permeability and may lead to inappropriate exposure of the mucosal immune system to luminal antigens. Additionally, epithelial cell death, particularly of Paneth cells, has been demonstrated to induce terminal ileal inflammation in mice with conditional deletion of caspase-8 in the intestinal epithelium and is associated with CD in humans.