Genetic Variants Associated with CD and UC

Polymorphisms in cytokine genes and cytokine pathway genes are associated with both CD and UC. Duerr and colleagues completed the first large-scale GWAS in IBD of 308,332 SNPs 68 . A non-synonymous SNP (rs11209026 Arg381Gln) in the interleukin 23R gene conferred significant protection against IBD. Heterozygous carriage of the glutamine allele confers an approximately threefold increase in protection against developing CD, with a more modest protective effect observed in UC. Several other SNPs...

Innate Signals Dictating Homeostasis

Microorganisms have inhabited Earth for at least 2.5 billion years, and the power of the immune system is a result of co-evolution in which especially commensal bacteria have shaped host defense in a state of mutualism 10, 14 . The prevailing mucosal homeostasis in the gut mucosa is indeed remarkable because of the large surface area to be defended - continuously being exposed to at least 1,000 different bacterial species (Figs. 3.1 and 3.10). The gut microbiome is perhaps 100 times larger than...

Effects of Genes vs the Environment

The increasing incidence of immune-mediated diseases in affluent societies indicates that susceptibility genes for dysregulation are quite universal, such that they can be induced readily with environmental change. Epigenetics is an active research field providing novel understanding of how the environment can have heritable genomic effects and promote disease 86, 207, 227 . A number of early life exposures, including dietary nutrients and microbial exposure in utero, have been recently shown...

Role of IgA and Breastfeeding in Immune Control

The level of SIgA appears to contribute to an individual's threshold for hypersensitivity reactions to exogenous antigens 12 . Thus, the risk of contracting allergy seems increased when the development of the IgA system is retarded and the SIgA-dependent barrier function insufficient ) 145 . Minor dysregulations of both innate and adaptive immunity (especially IgA) have been observed in children with multiple food allergy 146 . These clinical observations are in accordance with the...

Additional IgA Antibody Functions

Antibody production by the numerous intestinal pIgA+ PCs may also be important for homeostasis within the lamina propria as a result of several anti-inflammatory mechanisms. IgA lacks ordinary complement-activating properties 93 and can therefore block nonspecific biological amplification triggered by locally produced or serum-derived IgG antibodies (Fig. 3.7) , which may actually increase the penetration of exogenous bystander antigens through the surface epithelium 94 . This is important in...

Mucosal Tolerance Induction

In healthy human gut mucosa, resident APCs are quite inert in terms of immune-productive stimulatory properties 172 . and they hardly express detectable surface levels of TLR2 or TLR4 111 . Also, only negligible expression of the LPS co-receptor CD14 is normally observed on these cells, and their proinflammatory cytokine response is usually low after LPS stimulation 102, 173 . Nevertheless, the phagocytic and bacteriocidal activity of mucosal macrophages is maintained 174 , which would be...

Epithelial Permeability and Secretory Immunity

In fetal life, murine gut epithelial cells are sensitive to microbial factors such as LPS (endotoxin) because they express intracellularly a PRR for this MAMP, namely TLR4 91 . Exposure to LPS in the vaginal tract during birth activates the neonatal gut epithelium via TLR4 and temporarily upregulates microRNA-146a, which leads to degradation of the TLR signaling molecule IL-1R-associated kinase 1 (IRAK1). Such translational repression of IRAK1 protects the epithelium from microbiota-induced...

Recognition of Microbial Components

Final cellular conditioning for oral tolerance in MLNs appears to depend on appropriate stimulation of the migrating mucosal APCs by certain MAMPs derived from commensal bacteria (Fig. 3.12), which induce the signaling molecules and transcription factors dictating the differentiation pathways and cytokine profiles of the activated T cells 11, 12, 198 . Components of intestinal parasites such as helminths can exert similar immune modulation 10, 14, 199-201 - apparently to some extent through...

Activation and Homing of Intestinal B Cells

Antigens are presented to T cells in GALT and MLNs by APCs after intracellular processing 1 . The activated helper T (Th) cells release mediators (cytokines), and especially transforming growth factor (TGF)-b induces the switch of B cells from surface membrane expression of IgM to IgA in GALT follicles 2, 6, 31 . Memory effector cells migrate rapidly via lymphatics to MLNs where B cells may be further differentiated to plasmablasts, which then reach peripheral blood via the thoracic duct and...

How Decisive Are Commensal Bacteria

Indigenous gut bacteria play a central role in the extended hygiene hypothesis. Thus, the intestinal microbiota of young children in Sweden was found to contain a relatively large number of Clostridium spp., whereas high levels of Lactobacillus spp. and Eubacterium spp. were detected in 234 an age-matched population from Estonia this difference might contribute to the lower incidence of allergy in the Baltic countries compared with Scandinavia 235 . A Finnish study likewise reported that...

Nutrition and Diet

Considerable efforts have been made in the search for nutritional factors related to, and maybe even responsible for the development of IBD. The methodology of this research has been hampered by the problems of confounding factors and the fact that many patients will change their nutritional habits as a consequence of the disease. There are many studies in small cohorts of patients, who claim that intake of certain diet constituents like fat, refined sugar, fruits, vegetables, and fiber affect...

Inductive Gut Associated Lymphoid Tissue Structures

Talus Anatomy

Intestinal immune cells are located in three compartments GALT, the mucosal lamina propria, and the surface epithelium (Fig. 3.2). GALT comprises Peyer's patches, the appendix, and numerous ILFs 2, 6, 30 . These organized lymphoid structures represent inductive sites for intestinal immune responses, while the lamina propria and epithelial compartment principally constitute effector sites but may nevertheless contribute to retention, proliferation, and differentiation of immune cells 31 . Fig....

Mechanisms Promoting Homeostasis

Crohn Disease Mechanism

Numerous genes regulate both the innate and adaptive arms of the immune system. Human immu-nogenetics has evolved to identify danger under the pressure of a dirty environment, even long beyond the hunting-gathering period. In this evolutionary process the intestinal immune system has generated its two adaptive anti-inflammatory strategies immune exclusion performed by SIgA to control surface colonization of microorganisms and inhibit mucosal penetration of potentially dangerous agents and oral...

The Epithelial Barrier Function

Epithelial Barrier Oral

Although so-called gut closure normally occurs in humans mainly before birth, the mucosal barrier may be inadequate up to 2 years of age the mechanisms involved remain poorly defined 73 , but the development of secretory immunity is probably one decisive variable. Importantly in this context, pIgR-deficient knockout mice that lack SIgA and SIgM exhibit aberrant mucosal leakiness 74 and have increased uptake of food proteins and commensal bacteria 75 . A thick virtually microbe-devoid inner...

Micronutrients and Microparticles

Both in food and water supply, metals and minerals, as well as other microparticles, are abundant, and as such more common as part of pollution in industrialized areas. These particles may act in different ways with the immune system, causing primary or secondary effects. It has been suggested that exposure to xenobiotic-like metals may induce immune responses in autoimmune diseases. Such reactions have been related to effects of mercury 105 , cobalt, zirconium, beryllium, silver, and aluminum...

Contents

1 The Genetics of Inflammatory Bowel 3 2 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease 17 3 The Intestinal Immune System in 41 4 Understanding the Epithelial Barrier in Inflammatory Bowel Disease 75 Emily M. Bradford, Emily S. Turner, and Jerrold R. Turner 5 Intestinal Microbiology and Ecology in Inflammatory Bowel Disease 85 6 Microbial Recognition and Pathogen-Associated Molecular Pattern Kenya Honda, Koji Atarashi, and Junko Nishio 7 Inflammasomes in Inflammatory...