Maneesh Dave, MBBS, MPH, Konstantinos A. Papadakis, MD, PhD and William A. Faubion, Jr., MD∗faubion.william@mayo.edu, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
∗Corresponding author.
Inflammatory bowel disease (IBD) is an immune-mediated disease and involves a complex interplay of host genetics and environmental influences. Recent advances in the field, including data from genome-wide association studies and microbiome analysis, have started to unravel the complex interaction between host genetics and environmental influences in the pathogenesis of IBD. A drawback of current clinical trials is inadequate or lack of immune phenotyping of patients. However, recent advances in high-throughput technologies provide an opportunity to monitor the dynamic and complex immune system, which may to lead to a more personalized treatment approach in IBD.
Introduction
Inflammatory bowel disease (IBD), specifically Crohn disease (CD) and ulcerative colitis (UC), are autoimmune diseases whose incidence and prevalence are increasing worldwide.1 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.2–4 IBD is considered to be an immune-mediated disease that involves a complex pattern/interplay of host genetics and environmental influences.5 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.6 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 m2), 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.
Table 1
Some of the key biologic molecules in active use or under study for treatment of IBD
| CCR9 | CCX282-B | Inhibition of CCR9 | CD |
| CCX 025 | Inhibition of CCR9 | CD |
| IL-21 | PF 05230900 | IL-21 receptor antagonist | CD |
| IL-13 | QAX576 | IL-13 antagonist | CD |
| Anrukinzumab | IL-13 antagonist | UC |
| Tralokinumab | IL-13 antagonist | UC |
| IL-17 | Vidofludimus | Inhibitor of IL-17 A and IL-17F | Both |
| IL-12/23 | Ustekinumab | Blockade of IL-12/23 | CD |
| IL-18 | GSK1070806 | Blockade of soluble IL-18 | CD |
| IL-6 and IL-6R | Tocilizumab | Inhibitor of IL -6 | CD |
| PF04236921 | Inhibitor of IL -6 | CD |
| IP-10 | MDX 1100 | Blockade of interferon-γ inducible protein (IP-10 or CXCL10) | UC |
| IRAK4/TRAF6/MyD88 | RDP58 | Disrupts IRAK4/TRAF6/MyD88 signaling and reduces production of proinflammatory cytokines | Both |
| JAK3 | Tofacitinib | Inhibition of JAK3 | Both |
| MAdCAM-1 | PF-547659 | Blocks MAdCAM-1 | Both |
| NF-κB | HE3286 | Synthetic steroid that modulates NF-κB activity | UC |
| NKG2D | NN8555 | Anti-NKG2D receptor monoclonal antibody | CD |
| PKC | AEB071/Sotrastaurin | PKC inhibitor | UC |
| T Cell | Laquinimod | Reduces IL-17 level and interferes with migration of T cells | CD |
| TLR | DIMS0150 | Blockade of Toll-like receptor | UC |
| BL-7040 | Blockade of Toll-like receptor | UC |
| TNF-α | Infliximab | Neutralization of TNF-α | Both |
| Adalimumab | Neutralization of TNF-α | Both |
| Certolizumab pegol | Neutralization of TNF-α | CD |
| Golimumab | Neutralization of TNF-α | UC |
| Debiaerse | Vaccine against TNF-α consisting of a TNF-α derivative TNF-α kinoid | CD |
| Effector T cells, B cells | Antigen specific Type 1 regulatory cells (OvaSave) | Autologous ova expanded regulatory T cells injected | CD |
| α4 integrin | AJM-300 | Blockade of α4 integrin | CD |
| α4 integrin | Natalizumab | Blockade of α4 integrin | Both |
| α4β7 integrin | Vedolizumab | Blockade of α4β7 integrin | Both |
| β7 integrin | Etrolizumab (aka rHuMab β7) | Anti-β7 integrin | UC |
Abbreviations: aka, also known as; CCR9, chemokine receptor 9; IL, interleukin; IP, inducible protein; IRAK-4, interleukin-1 receptor-associated kinase 4; JAK3, Janus kinase 3; MAdCAM-1, human mucosal addressin cell adhesion molecule-1; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor-κB; PKC, protein kinase C; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-α; TRAF6, TNF receptor-associated factor 6, E3 ubiquitin protein ligase.
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.7 The epithelial cells comprise enterocytes (intestinal absorptive cells), goblet cells, neuroendocrine cells, Paneth cells, and microfold (M) cells.7 The epithelial cells are...
EPUB (Adobe DRM)
