Immunology Update: Role Diet and Mucosal Gut on Health and Disease

Mucosal surfaces are lined by epithelial cells. These cells establish a barrier between sometimes hostile external environments and the internal milieu. However, mucosae are also responsible for nutrient absorption and waste secretion, which require a selectively permeable barrier. These functions place the mucosal epithelium at the centre of interactions between the mucosal immune system and luminal contents, including dietary antigens and microbial products. Recent advances have uncovered mechanisms by which the intestinal mucosal barrier is regulated in response to physiological and immunological stimuli. These discoveries along with evidence that this regulation shapes mucosal immune responses in the gut and, when dysfunctional, may contribute to health and disease.

The mucosal surfaces of the gut and airways have important barrier functions and regulate the induction of immunological tolerance. The rapidly increasing incidence of chronic inflammatory disorders of these surfaces, such as inflammatory bowel disease and asthma, indicates that the immune functions of these mucosae are becoming disrupted in humans. Recent data indicate that events in prenatal and neonatal life orchestrate mucosal homeostasis. Several environmental factors promote the perinatal programming of the immune system, including colonization of the gut and airways by commensal microorganisms. These complex microbial-host interactions operate in a delicate temporal and spatial manner and have an important role in the induction of homeostatic mechanisms.

The anatomical basis of intestinal immunity.

It remains unclear how and where unresponsiveness to fed antigens is induced. This “oral tolerance” is probably necessary to prevent the array of immune effector mechanisms required to counteract pathogens of the mucosae from being misdirected against food antigens or commensal flora. It will obviously be important to dissect where, when, and how such immunological homeostasis is maintained in the gut, but it will also be necessary to determine whether similar inductive and effector mechanisms are required for the therapeutic applications of oral tolerance systemically.

This may be influenced by anatomical and microenvironmental effects on the phenotype and/or activation state of the antigen-presenting cell (APC), which presents orally delivered antigen. Fed antigen passes from the intestinal lumen either via the villus epithelium and M cells in the Peyer’s patches (PP) or the mucosal lamina propria to the organized lymphoid tissues of the PP and mesenteric lymph nodes (MLN). In addition, there is evidence that mucosally administered antigen also gains access directly to peripheral lymphoid organs. Each of these sites contains distinctive populations of APCs and has unique local microenvironments that may influence the immune response in different ways.

The lymphoid tissues associated with the intestine are exposed continuously to antigen and are the largest part of the immune system. Many lymphocytes are found in organised tissues such as the Peyer’s patches and mesenteric lymph nodes, as well as scattered throughout the lamina propria and epithelium of the mucosa itself. These lymphocyte populations have several unusual characteristics and the intestinal immune system is functionally and anatomically distinct from other, peripheral compartments of the immune system.

The anatomical and molecular basis of these differences, with particular emphasis on the factors which determine how the intestinal lymphoid tissues discriminate between harmful pathogens and antigens which are beneficial, such as food proteins or commensal bacteria. These latter antigens normally provoke immunological tolerance, and inappropriate responses to them are responsible for immunopathologies such as food hypersensitivity and inflammatory bowel disease. The interactions between local immune cells, epithelial tissues and antigen-presenting cells may be critical for the induction of tolerance and the expression of active mucosal immunity. In addition, the possibility that the intestine may act as an extrathymic site for T-cell differentiation is discussed.

Under physiological conditions, immune responses to food antigens and commensal bacteria are prevented by common regulatory mechanisms, in which transforming growth factor beta plays a critical role.

The intestine is the largest lymphoid organ in the body by virtue of lymphocyte numbers and quantity of immunoglobulin produced. This is largely related to the enormous antigen load to which these cells are exposed on a daily basis. However, despite this, the mucosa-associated lymphoid tissue appears to be regulated by unique mechanisms, and this is reflected in specific phenomena (oral tolerance, controlled or physiologic inflammation) as well as unusual lymphoid populations (intraepithelial lymphocytes) that respond to alternative pathways of activation. This, coupled with the existence of novel antigen-presenting cells (intestinal epithelial cells) sets the scene for distinct immune responses.

The feeding antigen in high doses may induce clonal anergy, deletion, or altered differentiation because it gains direct access to resting APCs in the T cell areas of both the gut-associated lymphoid tissues (GALT) and peripheral lymphoid organs, with presentation occurring in the absence of productive costimulation. By contrast, low doses of tolerizing antigen may be taken up and presented preferentially by APCs in the GALT, where the local environment may favor the induction of regulatory T cells. This is consistent with our own and others findings, using adoptive transfer of TcR tg T cells.

These studies have shown that antigen-specific CD4(+) T cells are activated simultaneously in all peripheral and gut-associated lymphoid organs after feeding high doses of proteins, but that this may be more restricted to local tissues when lower doses are used. Another level of anatomical control is imposed within lymphoid organs, where migration of T cells through distinct anatomical compartments can affect their differentiation. We find that, in contrast to orally primed T cells, orally tolerized T cells are unable to migrate into B cell follicles during their initial exposure to antigen. This affects their differentiation as upon subsequent challenge with antigen in adjuvant, tolerized T cells can be found in follicles but are unable to provide the B cell help that primed T cells can deliver. The initial defective migration of tolerized T cells prevents them from receiving signals from antigen-specific B cells in follicles and results in abortive differentiation. Thus, both gross and fine anatomical location of fed antigen presentation may be important in mucosal immunoregulation.

It is these distinct regulatory factors that support immunosuppression or tolerance rather than active immunity at a site juxtaposed to the external environment. These novel interactions and suggests how alteration in normal function may result in allergic or inflammatory responses. A clearer understanding of mucosal immunoregulation may lead to new therapeutic approaches for these diseases.

Innate and adaptive mechanisms to control pathological intestinal inflammation.

The intestine is the home of a tremendous number of commensal organisms that have a primary role in host metabolism. As a consequence, the gut mucosa has evolved multiple layers of protection. Both innate and adaptive mechanisms that prevent bacterial invasion and abnormal intestinal inflamamation, how a failure of these mechanisms may be involved in the pathogenesis of inflammatory bowel diseases, and discusses new findings implicating dendritic cells as central to the induction of active mucosal tolerance to commensal bacteria.

DCs are specialized APCs that orchestrate innate and adaptive immune responses. The intestinal mucosa contains numerous DCs, which induce either protective immunity to infectious agents or tolerance to innocuous antigens, including food and commensal bacteria. Several subsets of mucosal DCs have been described that display unique functions, dictated in part by the local microenvironment. The distinct subtypes of DCs and their distribution in the gut; examine how DC dysfunction contributes to intestinal disease development, including inflammatory bowel disease and celiac disease; and discuss manipulation of DCs for therapy.

Many different pathways contribute to the maintenance of tolerance to harmless antigens in the intestine. When these important pathways are compromised, chronic intestinal inflammation can develop. In particular, naturally occurring CD4+CD25+ regulatory T cells have been shown to play an important role in the prevention and cure of colitis in animal models of intestinal inflammation.

These regulatory T cell responses may be influenced by the local environment in the intestine. For example, functionally specialised populations of dendritic cells exist in the intestine which may favour regulatory type responses. Understanding how these pathways intersect may lead to the development of more specific therapies for the treatment of inflammatory bowel disease.

The antigen-rich environment of the gut interacts with a highly integrated and specialized mucosal immune system that has the challenging task of preventing invasion and the systemic spread of microbes, while avoiding excessive or unnecessary immune responses to innocuous antigens. Disruption of the mucosal barrier and/or defects in gut immune regulatory networks may lead to chronic intestinal inflammation as seen in inflammatory bowel disease. The T-cell populations of the intestine play a critical role in controlling intestinal homeostasis, and their unique phenotypes and diversities reflect the sophisticated mechanisms that have evolved to maintain the delicate balance between immune activation and tolerance at mucosal sites. In this article, we will discuss the specialized properties of mucosal T cells in the context of immune homeostasis and inflammation.

Regulation of homeostasis and inflammation in the intestine

The gastrointestinal tract is the largest immune interface with the environment. Exposure to large numbers of dietary and microbial antigens requires complex and highly regulated immune responses by different mucosal cell types, which result in the induction and maintenance of intestinal homeostasis. Defects in this equilibrium can disrupt the homeostatic mechanisms and lead to chronic intestinal inflammation. We review the cell populations and mechanisms involved in the control of intestinal homeostasis and inflammation, focusing on inflammatory bowel diseases.

Some aspects of gut immunity that could alter the delicate balance between inflammatory and tolerogenic responses and result in chronic gastrointestinal tract inflammation in patients.

Regulation of mucosal immune responses in effector sites.

In human disease and rodent models, immune responses in the intestinal mucosa can be damaging. Damage is characterised by villus atrophy, crypt hyperplasia and reduced ability to digest and absorb nutrients. In normal individuals active responses to harmless environmental antigens associated with food and commensal bacteria are controlled by the development of immunological tolerance. Similar pathological changes occur in piglets weaned early from their mothers. Active immune responses to food antigens are observed in these piglets, and we and others have hypothesised that the changes occur as a result of transient allergic immune responses to novel food or bacteria antigens. The normal mechanism for producing tolerance to food antigens may operate at induction (Peyer’s patches and mesenteric lymph nodes) or at the effector stage (intestinal lamina propria). In studies piglet studies immunological tolerance occurs despite the initial active response. Together with evidence from rodents, this observation suggests that active responses are likely to be controlled at the effector stage, within the intestinal lamina propria. Support for this mechanism comes from the observation that human and pig intestinal T-cells are susceptible to apoptosis, and that this process is accelerated by antigen. These studies suggest that the role of the normal mature intestinal lamina propria is a balance between immunological effector and regulatory function. In neonatal animals this balance develops slowly and is dependant on contact with antigen. Immunological insults such as weaning may tip the balance of the developing mucosal immune system into excessive effector or regulatory function resulting in transient or chronic allergy or disease susceptibility.

Immunity, inflammation, and allergy in the gut.

The gut immune system has the challenge of responding to pathogens while remaining relatively unresponsive to food antigens and the commensal microflora. In the developed world, this ability appears to be breaking down, with chronic inflammatory diseases of the gut commonplace in the apparent absence of overt infections. In both mouse and man, mutations in genes that control innate immune recognition, adaptive immunity, and epithelial permeability are all associated with gut inflammation.

This suggests that perturbing homeostasis between gut antigens and host immunity represents a critical determinant in the development of gut inflammation and allergy.

The recognition that immune responses in the intestine differ from those seen systemically has led to a search for novel pathways involved in mucosal immunoregulation. One cell type that has surfaced as a prime candidate for such a regulatory role is the intestinal epithelial cell. A number of laboratories have documented that intestinal epithelial cells sample luminal antigens and process and present these to primed T cells. However, several unique features have emerged, making their potential role as antigen-presenting cells a critical part of mucosal homeostasis.

Mucosal T cells in gut homeostasis and inflammation

The antigen-rich environment of the gut interacts with a highly integrated and specialized mucosal immune system that has the challenging task of preventing invasion and the systemic spread of microbes, while avoiding excessive or unnecessary immune responses to innocuous antigens. Disruption of the mucosal barrier and/or defects in gut immune regulatory networks may lead to chronic intestinal inflammation as seen in inflammatory bowel disease. The T-cell populations of the intestine play a critical role in controlling intestinal homeostasis, and their unique phenotypes and diversities reflect the sophisticated mechanisms that have evolved to maintain the delicate balance between immune activation and tolerance at mucosal sites. The specialized properties of mucosal T cells in the context of immune homeostasis and inflammation.

Potential diet-modifiable feature of gut inflammation and autoimmunity.

The small intestine is an organ responsible for nutrient absorption, barrier functions, signal recognition/transduction, and the production of bioactive compounds. These functions are known to be regulated by such factors as hormones and cytokines, but substances contained in the daily diet are also thought to play roles as major modulators of intestinal functions. Intestinal epithelial cells (IECs), which form a monolayer covering the inside surface of the intestinal tract, are particularly important in this modulation, because they directly interact with intestinal contents, including food substances, their digests, and gut microbial components.

Using cell-based in vitro assays, some studies investigated the food-IEC interactions at the cellular and molecular levels, and found that a variety of food substances affected the transporter activity, tight junction permeability, metabolic enzyme expression, immune functions, and so on.

The gastrointestinal tract represents the largest immune interface with the environment. Exposure to large numbers of dietary and microbial antigens requires complex and highly regulated intestinal immune responses by different immune cell types for the maintenance of oral tolerance. Defective immune homeostasis can cause gut barrier dysfunction and breakdown of tolerance, leading to chronic inflammation and autoimmunity. The key immune cell populations involved in oral tolerance. Diet-modifiable aspects of gut immunity that alter the intricate balance between inflammatory and tolerogenic immune responses in the gut and contribute to disease development. Modulation of the intestinal functions by dietary substances is therefore essential to promote health.

Commensal bacteria, mucosal immunity and chronic inflammatory and autoimmune diseases.

Commensal microflora (normal microflora, indigenous microbiota) consists of those micro-organisms, which are present on body surfaces covered by epithelial cells and are exposed to the external environment (gastrointestinal and respiratory tract, vagina, skin, etc.). The number of bacteria colonising mucosal and skin surfaces exceeds the number of cells forming human body. Commensal bacteria co-evolved with their hosts, however, under specific conditions they are able to overcome protective host responses and exert pathologic effects. Resident bacteria form complex ecosystems, whose diversity is enormous. The most abundant microflora is present in the distal parts of the gut; the majority of the intestinal bacteria are Gram-negative anaerobes. More than 50% of intestinal bacteria cannot be cultured by conventional microbiological techniques. Molecular biological methods help in analysing the structural and functional complexity of the microflora and in identifying its components. Resident microflora contains a number of components able to activate innate and adaptive immunity. Unlimited immune activation in response to signals from commensal bacteria could pose the risk of inflammation; immune responses to mucosal microbiota therefore require a precise regulatory control.

The mucosal immune system has developed specialised regulatory, anti-inflammatory mechanisms for eliminating or tolerating non-dangerous, food and airborne antigens and commensal micro-organisms (oral, mucosal tolerance). However, at the same time the mucosal immune system must provide local defense mechanisms against environmental threats (e.g. invading pathogens). This important requirement is fulfilled by several mechanisms of mucosal immunity: strongly developed innate defense mechanisms ensuring appropriate function of the mucosal barrier, existence of unique types of lymphocytes and their products, transport of polymeric immunoglobulins through epithelial cells into secretions (sIgA) and migration and homing of cells originating from the mucosal organised tissues in mucosae and exocrine glands. The important role of commensal bacteria in development of optimally functioning mucosal immune system was demonstrated in germ-free animals (using gnotobiological techniques). Involvement of commensal microflora and its components with strong immunoactivating properties (e.g. LPS, peptidoglycans, superantigens, bacterial DNA, Hsp) in etiopathogenetic mechanism of various complex, multifactorial and multigenic diseases, including inflammatory bowel diseases, periodontal disease, rheumatoid arthritis, atherosclerosis, allergy, multiorgan failure, colon cancer has been recently suggested. Animal models of human diseases reared in defined gnotobiotic conditions are helping to elucidate the aetiology of these frequent disorders.

An improved understanding of commensal bacteria-host interactions employing germ-free animal models with selective colonisation strategies combined with modern molecular techniques could bring new insights into the mechanisms of mucosal immunity and also into pathogenetic mechanisms of several infectious, inflammatory, autoimmune and neoplastic diseases. Regulation of microflora composition (e.g. by probiotics and prebiotics) offers the possibility to influence the development of mucosal and systemic immunity but it can play a role also in prevention and treatment of some diseases.

Immuno-bacterial homeostasis in the gut.

The intestinal mucosa is the interface between the immune system and the massive antigenic load represented by the commensal enteric bacteria. These commensal bacteria drive the development of the mucosal immune system, and in turn most of the lymphocytes in the intestinal mucosa appear to be specific for enteric bacteria antigens. Proper regulation of the responses of these anti-bacterial lymphocytes are extremely important because T cell effectors reactive to enteric bacterial antigens have been shown to cause chronic intestinal inflammation in an adoptive transfer system.

The cells and molecules important in regulating mucosal immune response are now being identified. Insights into the mechanisms of mucosal regulation have come from a number of genetically manipulated mouse strains which develop inflammatory bowel disease in response to the enteric bacterial flora. CD4(+)T cells with regulatory function in the mucosa are being identified; other cell types such as CD8(+)T cells. NK cells, and B cells may also have a role in mucosal immune regulation. A model for T cell-immune homeostasis in the intestinal mucosa is presented.

The impact of perinatal immune development on mucosal homeostasis and chronic inflammation

The mucosal surfaces of the gut and airways have important barrier functions and regulate the induction of immunological tolerance. The rapidly increasing incidence of chronic inflammatory disorders of these surfaces, such as inflammatory bowel disease and asthma, indicates that the immune functions of these mucosae are becoming disrupted in humans. Recent data indicate that events in prenatal and neonatal life orchestrate mucosal homeostasis. Several environmental factors promote the perinatal programming of the immune system, including colonization of the gut and airways by commensal microorganisms. These complex microbial-host interactions operate in a delicate temporal and spatial manner and have an important role in the induction of homeostatic mechanisms.

References:
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