Innate Immunity in the Gastrointestinal Tract

Electronics Repair Manuals

Schematic Diagrams and Service Manuals

Get Instant Access

Intestinal epithelial cells lining the small and large bowel are an integral part of the gastrointestinal innate immune system, involved in responses to pathogens, tolerance to commensal organisms, and antigen sampling for delivery to the adaptive immune system in the gut. There are several different types of intestinal epithelial cells, all derived from a common precursor found in the crypts of intestinal glands. Among these are the mucus-secreting goblet cells, which reside at the top of the intestinal villi; cytokine-secreting absorptive epithelial cells; antigen-sampling M cells, found in specialized dome structures overlying lymphoid tissues; and antibacterial peptide-secreting Paneth cells, found at the bottom of the crypts. All these cell types contribute in different ways to the barrier function of the mucosa, as we will discuss later.

Innate immune protection in the gut is mediated in part by the nonspecific physical and chemical barrier provided by the mucosal epithelial cells and their mucus secretions. Adjacent intestinal epithelial cells are held together by proteins that form tight junctions, including zonula occludens 1 and claudins, and these block the movement of bacteria and pathogen-associated molecular patterns (PAMPs) between the cells into the lamina propria. In addition, mucosal epithelial cells produce antimicrobial substances, and several cell types located in the mucosa, including epithelial cells, DCs, and macrophages, are capable of mounting inflammatory and antiviral responses. Most of these responses are induced by pattern recognition receptor engagement of PAMPs, which we discussed in Chapter 4. Interestingly, some innate immune receptors that promote inflammation in other parts of the body have anti-inflammatory actions in the gut. In this section, we will describe features of innate immunity that are unique to the intestines.

Several different extensively glycosylated proteins, called mucins, form a viscous physical barrier that prevents microbes from contacting the cells of the gastrointestinal tract. Mucins contain many different O-linked oligosaccharides and include secreted and cell surface glycoproteins. The secreted mucins, including MUC2, MUC5, and MUC6, form a hydrated gel ranging from 300 to 700 |m in thickness that can prevent microbial contact

Adiposse Tissue Expansion

Intestinal lumen

Mucosal epithelium

Lamina propria

Mesentary

FIGURE 13-1 The gastrointestinal immune system. A, Schematic diagram of the cellular components of the mucosal immune system in the intestine. B, Photomicrograph of mucosal lymphoid tissue in the human intestine. Similar aggregates of lymphoid tissue are found throughout the gastrointestinal tract.

Intestinal lumen

Mucosal epithelium

Lamina propria

Mesentary

FIGURE 13-1 The gastrointestinal immune system. A, Schematic diagram of the cellular components of the mucosal immune system in the intestine. B, Photomicrograph of mucosal lymphoid tissue in the human intestine. Similar aggregates of lymphoid tissue are found throughout the gastrointestinal tract.

with the epithelial lining cells and also serves as a matrix for display of antimicrobial substances produced by the epithelial cells. Some mucins act as decoy molecules, which can be shed from the epithelial cells and bind to the adhesin proteins that pathogenic bacteria use to attach to host cell membranes. In addition to the secreted mucus, the apical surface of gastrointestinal epithelial cells is coated with membrane-bound mucin proteins, including MUC1, MUC3A/b, MUC12, MUC13, MUC17.

These membrane-bound mucins combine with various glycolipids to form a dense macromolecular layer at the epithelial cell surface called the glycocalyx, which ranges from 30 to 500 nm in thickness in different locations in the gut. The glycocalyx, like the secreted mucus, serves as a physical barrier to prevent microbial contact.

A remarkable property of the mucous barrier of the intestine is its rapid turnover and responsiveness to various environmental and immune signals, which allows rapid increases in mucosal barrier function. Mucins are constitutively produced both by the surface epithelial cells in the gastrointestinal tracts and by submucosal glands and are replaced by newly synthesized molecules every 6 to 12 hours. Several different environmental and immune stimuli can induce dramatic increases in mucin production. These stimuli include cytokines (IL-1, IL-4, IL-6, IL-9, IL-13, tumor necrosis factor [TNF], and type I interferons), neutrophil products (such as elastase), and microbial adhesive proteins. These stimuli not only increase mucin gene expression but also alter the glyco-sylation of the mucins because of induced changes in the expression of glycosyltransferase enzymes. The changes in quantity and glycosylation of mucins are thought to increase barrier function against pathogens.

Defensins produced by intestinal epithelial cells provide innate immune protection against luminal bacteria, and defects in their production are associated with bacterial invasion and inflammatory bowel disease. Defensins are peptides produced by various cell types in the body that exert lethal toxic effects on microbes by inserting into and causing loss of integrity of their outer phospholipid membranes (see Chapter 4). In the small bowel, the major defensins are the a-defensins, including human defensin 5 (HD5) and HD6, produced constitutively as inactive precursor proteins by Paneth cells located at the base of crypts between microvilli. Active HD5 and HD6 peptides are generated by proteolytic cleavage mediated by trypsin, also produced by Paneth cells. In the colon, P-defensins are produced by absorptive epithelial cells in the intestinal crypts, some constitutively and others in response to IL-1 or invasive bacteria. In addition, neutrophil granules are rich in a-defensins, which likely contributes to their antimicrobial functions in the setting of infections of the bowel wall. Several studies have identified defects in defensin production by epithelial cells in affected regions of bowel in Crohn's disease, a chronic inflammatory disease that can involve the entire gastrointestinal tract. Because there is a significant inheritable risk for development of Crohn's disease, it is possible that a genetically determined defect in production of defen-sins may be a predisposing factor for the disease, and reduced expression of defensin genes has been associated with a subset of Crohn's disease.

Toll-like receptors (TLRs) and cytoplasmic Nod-like receptors (NLRs) expressed by intestinal epithelial cells promote immune responses to invasive pathogens but are also regulated to limit inflammatory responses to commensal bacteria. In Chapter 4, we defined TLRs and NLRs as cellular receptors that recognize PAMPs produced by microbes and generate signals that promote inflammatory and antiviral responses by the cells. Most luminal bacteria of the gut are nonpathogenic if they are retained outside the epithelial barrier, yet they may express the same array of PAMPs that pathogenic bacteria express, such as lipopolysaccharide, peptidoglycans, CpG DNA, and flagellin. Because inflammatory responses that involve the intestinal epithelial cells can impair barrier function and can lead to bacterial invasion and pathologic inflammation, it is not surprising that stringent control mechanisms have evolved to limit TLR-induced proinflammatory responses to commensal bacteria.

Intestinal epithelial cells express a wide range of TLRs, including TLRs 2, 4, 5, 6, 7, and 9, with different receptors expressed in different regions of the gut. Ligation of some TLRs results in the phosphorylation and reorganization of zona occludens 1 and increased strength of the tight junctions between epithelial cells, and TLR signaling also increases intestinal epithelial motility and proliferation. These functional responses to TLR signaling increase barrier function but not inflammation. TLR responses in the gut appear also to be regulated by levels of expression or compartmentalized expression in only certain sites (Fig. 13-2). For example, TLR5, which recognizes bacterial flagellins, is exclusively expressed on the basolateral surface of intestinal epithelial cells, where it will be accessible only to bacteria that have invaded through the barrier. Similarly, NLR family receptors for flagellins (e.g., NAIP and IPAF-1) are expressed in the cytoplasm of intestinal epithelial cells and will activate inflammatory responses only when pathogenic bacteria or their products gain access to the cytosol. There is also evidence that regulators of TLR signaling inside intestinal epithelial cells maintain a higher threshold for activation of inflammatory responses compared with epithelial cells and DCs in other tissues (see Fig. 13-2).

In healthy individuals, lamina propria DCs and macrophages in the gut inhibit inflammation and serve to maintain homeostasis. Overall, intestinal macrophages have a unique phenotype that enables them to phagocytose and kill microbes but at the same time to secrete anti-inflammatory cytokines, such as IL-10. This pheno-type is apparently induced in the local mucosal environment by transforming growth factor-P (TGF-P). TLR4 expression on both macrophages and DCs in the lamina propria is lower than in other tissues, and inflammatory gene expression in these cells is often inhibited by micro-bial products. This may be an evolved mechanism to prevent damaging inflammation in response to commensal bacteria and bacterial products that may traverse the epithelial barrier.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment