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Updates in mucosal immunology for inflammatory bowel diseases

2018; Lippincott Williams & Wilkins; Volume: 34; Issue: 6 Linguagem: Inglês

10.1097/mog.0000000000000484

1531-7056

María T. Abreu,

Immunodeficiency and Autoimmune Disorders

The current issue of Current Opinion in Gastroenterology is devoted to mucosal immunology. The reader will see that the topics have more relevance to inflammatory bowel diseases (IBD) than perhaps other topics within mucosal immunology. When one considers immunology of the gastrointestinal tract, it is no longer a primary focus on B and T cells as it once may have been nor is the focus only on bacteria. In choosing the topics, I wanted to focus on new concepts in immunology and even new types of colitis. The topics also set the stage for new immune-based therapies that are in the pipeline for treating inflammatory diseases of the intestine. The reader will enjoy a review on colitis because of immune-based therapies for oncology. For many types of solid tumors including melanoma and lung cancers, biologic therapy directed at stimulating an immune response to tumor antigens had a dramatically beneficial effect. As a consequence, however, patients may experience a range of autoimmune side-effects including colitis. Siakavellas and Bamias describe the pathogenesis of checkpoint inhibitor colitis and evolving management strategies. In their article (pp. 377–383), we learn that CTLA4 and PD1/PDL-1 have been implicated in IBD. Polymorphisms in CTLA4 are found in IBD. In animal models, PD-1-mediated inhibitory signals limit the severity of colonic inflammation. We are now learning what aspects of the microbiota predispose to checkpoint inhibitor colitis. Perhaps not surprisingly, oncologists and gastroenterologists have resorted to treatment paradigms used in IBD to treat these patients. In spite of expanding therapies for IBD, we still have no good way of predicting who will respond to what therapy. Moreover, we know that animal models have failed us in many ways when we try to translate findings from mice to humans. Swanson et al. (pp. 384–391) describe an emerging strategy to help predict responses to diverse therapies using mucosal biopsies. They provide the data on the use of mucosal biopsies to test new and existing compounds to treat IBD. Although the limitation of this strategy is its deployment to the bedside in non-IBD centers. They also discuss models using gut on a chip technologies and stem cell cultures as other strategies to predict responses to therapy. T cells have long been the center stage in mucosal inflammation and bacteria the focus of the microbiome. The genetics of IBD, however, point to innate immune defects and genes expressed by macrophages. There are also significant polymorphisms in the genes for fungal receptors such as Dectin-1 and their downstream adaptors such as CARD9. The pioneering work of Iliev et al. demonstrate that intestinal phagocytes are at the critical interface between the microbiota –including fungi, and intestinal homeostasis. In the current issue, he and his colleagues discuss how macrophages respond to fungi and bacteria and the implications for IBD pathogenesis. To complement, Leonardi et al. description of phagocyte function (pp. 392–397), Limon et al. dive into mucosal immune responses to fungi (pp. 398–403). One of the earliest biomarkers of Crohn's disease is antibody responses to the fungus Saccharomyces cerevisiae antibodies, that is ASCA. Numerous studies are now pointing us towards fungi as key players in the dysregulated immune response in IBD. The first hurdle is defining the 'normal' fungome using modern molecular techniques. And more recently defining the abnormal fungome in IBD. Candida albicans is a common fungus that can be found as a commensal in the gastrointestinal tract and also as an opportunistic pathogen. The IBD fungome as represented in stool is characterized by an increase in different Candida species. CX3CR1+ mononuclear phagocytes (MNP) in the intestine recognize fungal antigens and are responsible for generation of ASCA. The immune response to fungal antigens may under certain circumstances be detrimental and impair barrier function. There are likely also effects of the metabolites produced by fungus. To date, however, antifungal strategies have not clearly been effective in treating IBD. Nevertheless, diet and alcohol consumption may have specific effects on fungal populations and these interventions may be used to modify the immune response in IBD. In addition to exposure of the mucosal immune system to bacterial and fungal antigens, the gut is exposed to other potentially toxic xenobiotic and endobiotic substances. In the piece by Chen and Sundrud (pp. 404–412), they describe the immunologic – largely tolerogenic role, of short-chain fatty acids (SCFAs) generated by the microbiota in response to the metabolism of carbohydrates. Receptors for SCFAs, that is, GPR43, GPR41 and GRP109A are expressed in both intestinal epithelial cells (IECs) and leukocytes, and generally have anti-inflammatory effects including induction of regulatory T cells. Bile acids are also immunologically active compounds. Bile acids are endobiotic byproducts of heme metabolism generated in the liver and secreted into the intestine to facilitate fat absorption. Through work from the Sundrud laboratory, we now know that secondary bile acids generated by bacterial metabolism of primary, liver-derived bile acids when reabsorbed in the ileum can lead to oxidative stress of lamina propria immune cells and pro-inflammatory cytokine production. To mitigate this, CD4 T cells, once they migrate to the ileum upregulate expression of the multidrug resistance xenobiotic transporter MDR1. MDR1 indirectly serves to protect against oxidative stress and inhibits inflammation. In the absence of MDR1 function, ileal CD4+ T cells induce a Crohn's-like disease. Not only can this pathway be targeted, we now have agonists of the farsenoid X receptor (FXR) in clinical trials for cholestatic liver disease. FXR serves as the master regulator of bile acids homeostasis such that agonists may decrease bile acid synthesis but have other effects on intestinal inflammation. The article by Blander (pp. 413–419) tells the compelling story of the role of the IEC as a dynamic barrier that participates in innate immune response in various ways. Cells can die through apoptosis and extrusion of the cell into the lumen. However, accelerated apoptosis or inflammatory necroptosis leads to microerosions that compromise barrier function and trigger inflammation. Key kinases involved in necropstosis are increased in IBD. Tumor necrosis factor (TNF) induces RIPK1-mediated apoptosis or necroptosis. A20 and its binding partner ABIN-1 (TNIP-1) inhibit inflammation by inhibiting NF-kB signaling, RIG-1 signaling, and NLRP3 inflammasome activation. These proteins protect IECs from apoptosis and necroptosis downstream of RIPK1. Thus, a mechanism for mucosal healing in the context of anti-TNF therapy is protection against IEC apoptosis. Currently, inhibitors of RIPK1 are in clinical trials for IBD and protection from IEC damage is one plausible mechanism of action. One could imagine that bolstering A20 or ABIN-1 expression or function may also serve as a protective benefit. But there is another role for apoptotic IECs and that is to generate tolerance to cell antigens. Apoptotic cells are sampled by lamina propria phagocytes, both macrophages and dendritic cells. Once engulfed, these phagocytic cells decrease expression of inflammatory genes and enhance expression of anti-inflammatory pathways including A20. Sampling of apoptotic IECs by CD103+ dendritic cells can also induce FoxP3+ regulatory T cells. If one could harness the power of these tolerogenic phagocytes, one could enhance current treatment of IBD. In the composite, the intestinal immune response is carefully orchestrated to integrate signals from a variety of external and internal stressors including bacteria, fungi, nutrients, and bile acids. In most people, this occurs seamlessly but, in the case of IBD, perturbations in some or all of these facets may impact disease. Acknowledgements None. Financial support and sponsorship This work was supported by grants from National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases R01DK099076 & R01DK104844. Additional funding was provided by The Micky & Madeleine Arison Family Foundation Crohn's & Colitis Discovery Laboratory and Martin Kalser Chair in Gastroenterology at the University of Miami. Conflicts of interest M.T.A. has consulted or served on scientific advisory boards for the following companies: Abbvie Laboratories, Gilead Sciences, Prometheus Laboratories, Takeda, Pfizer, Janssen, Eli Lilly Pharmaceuticals, Shire Pharmaceuticals, Roche Pharmaceuticals, and Boehringer Ingelheim Pharmaceuticals.