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Editorial overview: Immunology section

2010; Lippincott Williams & Wilkins; Volume: 26; Issue: 6 Linguagem: Inglês

10.1097/mog.0b013e32833fa744

1531-7056

W. Allan Walker,

Digestive system and related health

Introduction Again this year a large number of seminal studies have been published which underscore the interaction of gut microbiota with the gastrointestinal tract resulting in the expression of important immunology functions which have been implicated in gastrointestinal disease states such as Helicobacter pylori gastritis, celiac disease and inflammatory bowel disease (IBD). Because of the extensive observations reported this year, we have obtained an unprecedented seven reviews on various aspects of microbial–epithelial/lymphocyte ‘crosstalk’ as the basis for gut inflammatory and infectious diseases. These reviews provide an excellent background for gastroenterologists to understand the pathophysiology of intestinal clinical disease states. In addition to the topics reviewed in the immunology section of Current Opinion in Gastroenterology, several additional reviews will be briefly considered to provide a comprehensive overview of the role of mucosal immunology in gastrointestinal disease. In Nature Reviews Immunology, Abreu [1] carefully considers the function of the gut epithelium as a mucosal barrier and sensor of commensal bacteria colonizing the gut. The author emphasizes that ligation of Toll-like receptors (TLRs) on the intestinal epithelial cells by bacterial molecular patterns results in enterocyte proliferation, the secretion of polymeric immunoglobulin A (IgA) and antimicrobial peptides which results in microbial-induced epithelial cell homeostasis and repair of the intestine. In contrast, a dysfunctional microbial–epithelial interaction can result in either chronic inflammation or excessive epithelial proliferation leading to colorectal cancer. In another important review by Slack et al.[2], the authors consider how innate and adaptive immunity flexibly coordinate to maintain a host-microbial mutualism. They suggest that flexible innate and adaptive immune responses help to control the number and distribution of colonizing bacteria in various compartments of the small and large intestine. To study this association, they used mice with knockout of components of the innate immune system to determine how the adaptive immune system compensates to maintain a normal microbiota-epithelial mutualism. This approach may help to understand how dysfunction in the innate or adaptive immune systems leads to alteration in the intestinal homeostasis with disrupted microbiota and the expression of disease. In another review in Mucosal Immunology, Lavelle et al.[3] consider the important role of epithelial receptors mediating innate immunity in homeostasis that exists in a gut free of disease despite enormous exposure to microbial and dietary antigens. They suggest that interaction of commensal bacteria with the gut epithelium results in the stimulation of a broad range of epithelial genes that maintain epithelial integrity, create a self-limited inflammatory response to invading pathogens and mediate antimicrobial peptides to establish homeostasis. The loss of receptors or the presence of receptor polymorphisms can alter this homeostasis resulting in chronic inflammation. A better understanding of this process may be helpful in the future to either prevent or treat chronic inflammatory conditions of the gut. Finally, Imager and Medzhitov [4] review our most recent understanding of how a pathogen-induced innate immune response can result in the activation of an antigen-specific adaptive immunity. They suggest that pattern recognition receptors (PRRs), for example, TLRs, are present on dendritic cell phagosomes along with major histocompatibility complex (MHC) class II molecules and help to select the bacterial antigen to be presented to T cells resulting in an antigen-specific adaptive T-cell and B-cell response. This and other observations intimately link the innate immune response to a specific adaptive response that maintains long-term protection against intestinal antigens. These brief reviews of additional publications during the last year along with enclosed reviews help the gastroenterologist understand the role of mucosal immunity in gastrointestinal disease states. Update on mucosal immunoglobulin A in gastrointestinal disease This study reviews previous and current observations on the role of mucosal IgA in the pathogenesis of gastrointestinal diseases. Polymeric IgA (pIgA) has recently been implicated in immunologic homeostasis by a variety of mechanisms including immunoexclusion at mucosal surfaces of potential pathogens and noxious antigens and anti-inflammatory effects after transepithelial migration of pathogens, including viruses and allergens, which cross the epithelial barrier under normal luminal conditions by complexing with these molecules before they interact with proinflammatory neutrophils and macrophages to elicit inflammatory cytokines. The same mechanism, pIgA-commensal bacterial complexes, occurring in the intestinal lumen can direct these organisms to appropriate lymphoid cells and Peyer's patches. Finally, Per Brandtzaeg (pp. 554–563) summarizes the role of mucosal IgA in specific disease states. In IBD, less pIgA is produced against commensal bacteria causing an increase in mucosal adherence and translocation at sites of inflammation, partly due to decreased expression of the joining chain (J chain) necessary to create pIgA and a shift to less stable pIgA2 from pIgA in secretions as well. In addition, a higher percentage of celiac disease patients are pIgA deficient than the general population. All these changes in pIgA function lead to less mucosal immunohomeostasis and a defective mucosal barrier. In celiac disease, although not as apparent, pIgA antibodies to tissue transglutaminase are thought to be the immunopathogenesis basis for villous atrophy associated with the untreated condition or pIgA–gluten complexes actually contribute to mucosal inflammation. In addition, less IgA is transported to the gastric surface in H. pyloric gastritis and patients with food allergy produce less pIgA to inhibit the uptake of food allergic peptides. Accordingly, the secretory IgA immune system can be implicated in a variety of common intestinal disease states. The role of mucosal immunity and host genetics in defining intestinal commensal bacteria In this review, Sartor et al. (pp. 564–571) expand our current understanding of the mechanisms by which commensal bacterial populations are influenced by host genetic factors and innate/adaptive immune responses, including release of antimicrobial peptides by enterocytes. They provide published evidence that host factors contribute to the composition of microbiota in the fully colonized intestine and that these microbiota are unique to the individual host. This observation is particularly true for subtle genetic or acquired changes in mucosal immune function, for example, presence of inflammation, in altering the composition of large families of bacteria (phyla), or in the degree of diversity of individual bacterial species, a necessary component for colonization resistance. Furthermore, in conditions such as IBD, quantities of specific microbial species such as Escherichia coli in their intestinal contents are removed. Adaptive immunity also influences commensal microbiota colonizing the gut. This is illustrated by the production of pIgA against colonic microbiota that, by immune exclusion, influence their attachment and penetration across the intestinal epithelium. In the absence of pIgA, that is, pIgA deficiency, an increased abundance of anaerobic microbiota has been noted. This same difference has been observed in knockout animals that lack either T or B cells. An important recent observation in TLR5 knockout mice suggests that this innate immune dysfunction can result in metabolic syndrome, an example of the innate immune system influence on intestinal microbiota which in turn influences disease. This same result has been shown when microbiota from TLR5 deficient animals were transferred to other wild type animals. The same passive process was noted when microbiota from nucleotide-binding oligomerization domain (NOD)-2-deficient mice are given to wild type animals. Finally, antimicrobial peptides, produced by Paneth cells and enterocytes, have a profound effect on the composition of intestinal microbiota and subsequent gut physiologic responses. Studies to suggest the importance of the genetic profile of humans and their intestinal microbiota composition have shown greater similarity between dizygotic and monozygotic twins. Thus, this review suggests that immune innate and adaptive function, as well as genetic factors help provide an individualized, stable microbiota in the human gut. How the intestinal epithelium safeguards mucosal barrier immunity through the inflammasome and beyond This review by Cario (pp. 583–590) underscores the contributions of the epithelium in the collective defense of the intestinal barrier. The epithelium acts as a ‘gate keeper’ to distinguish potentially harmful luminal from innocuous factors affecting submucosal lymphoid cells and disrupting homeostasis leading to inflammation and disease. PRRs such as TLRs and NODs are charged with this task. Disruption of these receptors has been associated with disease, for example, IBD, and metabolic syndrome. An important new protein complex, the inflammasome has been identified in epithelial and lymphoid cells which regulates the processing and secretion of cytokines in response to microbial stimuli of PRR and secondarily affects tight junction proteins altering intercellular transport. Furthermore, the communication of enterocytes with other adjacent enterocytes through gap junction channels has been shown to be necessary to complete the ‘gate keeper’ effect. In addition to the ‘gate keeper’ effect of PRRs, these same receptors are charged with the repair of epithelial disruption after epithelial-induced damage mediated through TLR4-activated cyclooxygenase and prostaglandins synthesis and trefoil factor secretion by goblet cells. The inflammasome and the cytokine interleukin (IL)-18 are necessary components of this repair process. TLRs and NODs have also been shown to influence autophagy, an innate immune process which acts to maintain cellular homeostasis. Autophagy and inflammasomes have also been shown to be linked in host defense. As this is a new observation, it is unclear the exact mechanism of this interaction. It is also important to determine the role of inflammasomes–autophagy dysfunction in the progression to intestinal malignancy. The current theory is that this interaction may be an important suppressor of the progression of chronic inflammation to malignancy. This progression from homeostasis to inflammation to malignancy may also be mediated in part by an alteration in the microbiota of the inflamed gut. Paneth cells and innate mucosal immunity This review by Ouellette (pp. 547–553) considers the importance of the subset of enterocytes, Paneth cells, in disrupted homeostasis leading to IBD. It is suggested that Paneth cell endoplasmic reticulum is sensitive to stress responses and that these and other environmental factors, as well as genetic polymorphisms of key molecules may contribute to the chronicity of IBD. The secretion of antimicrobial peptides and additional host defense proteins by Paneth cells as an innate immune response helps control the number of colonizing microbiota in the small intestine. Paneth cells reside in the distal crypt region near stem cells and respond to microbial intervention by releasing defensins, lysozyme and β-catenin which contributes to not only an innate immune response but also to the composition of colonizing bacteria, a contributing factor in the propagation of IBD. Although the ontogeny of Paneth cells is independent of microbial colonization, granules in these cells respond to microbial molecular patterns. Polymorphisms in autophagy genes in Paneth cells can contribute to the incidence and severity of Crohn's disease. Factors affecting the productive capacity of Paneth cells to colonization in premature vs. mature infants provide a possible basis for the condition necrotizing enterocolitis (NEC), an example of inadequate intestinal homoeostasis. Thus, this review helps to explain the role of genetic or environmentally disrupted Paneth cells in human inflammatory conditions such as IBD and NEC. The role of the macrophage in sentinel responses in intestinal immunity Intestinal macrophages represent the largest number of such cells in any organ system and are uniquely adapted to interface with the enormous number of microbiota that colonize the gut. These macrophages have the enhanced capacity to phagocytose microbes penetrating the mucosal barrier and to destroy them intracellularly without extensive inflammation in order to maintain mucosal immunohomeostasis. Monocytes, destined to become macrophages, enter the circulation and home to various sites, including the intestine where they respond to innate and adaptive immunity to provide an appropriate defense of mucosal surfaces with remarkable plasticity. The principal role of intestinal macrophages is to ingest luminal bacteria that routinely cross the mucosal barrier by the process of autophagy. Mutations in the macrophage autophagic process have been associated with an increased risk for Crohn's disease. A unique feature of intestinal macrophages is that they also have the capacity to regulate immune responses and participate in tissue repair. This is due to intestinal microenvironmental factors including the presence of transforming growth factor (TGF-β). In addition, intestinal macrophages can help to regulate a balance in the T helper cell response. Thus, the intestinal macrophage uniquely functions at mucosal surfaces as another ‘gate keeper’ to help evoke the appropriate response to invading microorganisms, for example, tolerance vs. inflammation. Altered function of intestinal macrophages in IBD has been increasingly demonstrated recently. Vitamin D and mucosal immune function A great deal of interest has been generated in medicine over the last several years suggesting that most individuals are mildly vitamin D deficient because of reduced exposure to sunlight. In addition, vitamin D has extensive functions beyond simply affecting calcium deposition in bone. In this review, Sun (pp. 591–595) underscores the importance of vitamin D in mucosal immune function. For example, vitamin D and its receptors have been shown to affect the T-cell antigen receptor, thus altering immunoregulation in a nonclassical fashion. Furthermore, adequate levels of vitamin D and vitamin D receptors help to downregulate subsets of helper T cells (TH1 and TH17) and their cytokines to modulate inflammation via suppression of the nuclear factor (NF-κB) pathway. In addition, evidence exists that the active form of vitamin D, vitamin D3, stimulates T regulatory activity. Finally, the presence of vitamin D nuclear receptors in the intestine is necessary for the transcription of antimicrobial peptides by Paneth cells. The consequences of these observations with regard to disease are that vitamin D and its receptors have been associated with a reduction in the expression of autoimmune diseases, for example, IBD, type 1 diabetes and chronic allergy (asthma), and may help prevent certain cancers through its antiproliferative effects. The exact mechanism of these effects requires further investigation. Innate and adaptive immune connections in inflammatory bowel disease In the last review of this section, Rakoff-Nahoum and Bousvaros (pp. 572–577) consider the current understanding of connections between the innate and adaptive immune systems in the pathogenesis of IBD. Attainment of immune homeostasis in the gut requires the creation of a balance between the stimulus of colonizing bacteria and host defense. Currently, several studies suggest that IBD may result from a breakdown in innate vs. immune adaptive balance. Colonizing bacteria, through conserved molecular patterns, interact with PRRs (e.g., TLRs, etc.) on enterocytes or lymphoid cells triggering signal transduction and the transcription, as well as translation of cytokines and chemokines which mediate the adaptive immune system which has the capacity to respond to pathogens with an acute, self-limited inflammatory response or to commensal bacteria with immune tolerance. This immune homeostasis requires a coordinated innate immunity leading to adaptive immune response which provides appropriate host defense in the absence of chronic inflammation. In animal models for IBD, the disruption of PRR (e.g., TLRs or NODs) can enhance the likelihood of prolonged enterocolitis. The mechanisms for this prolonged inflammatory response are varied and include a reduced production of anti-inflammatory cytokines and an altered tolerogenic response. Thus, suggesting that PRR may be involved in both positive and negative recognition of the innate adaptive response appearing to be important in the pathogenesis of IBD. Finally, patients with IBD have been shown to have an increase in certain commensal bacteria which in these patients cause an aberrant immune response thought to be related to the chronicity of IBD. These seem to be mediated through PRRs that affect both innate and adaptive immune function. This review strongly suggests that derangements in various genes/molecules that mediate innate/adaptive immunity can result in the phenotypic expression of chronic inflammation in the small or large intestine, for example, IBD. With the capacity to pinpoint the disruption, we may be in a better position to prevent/treat pleomorphic causes of IBD in the future. Conclusion In this year's immunology section of Current Opinion in Gastroenterology, we have attempted through an extended overview and several comprehensive reviews to cover the very active field of mucosal immunology as it pertains to gastrointestinal function and diseases states. Each of the reported publications points out the importance of microbial–intestinal interaction in establishing and maintaining immunologic homeostasis. We now know that immunologic dysfunction can result in an altered gut microbiota which in turn can predispose to unappreciated disease states like metabolic syndrome [5]. We are also aware of the observation that altered microbiotia can result in inflammation leading to colorectal cancer and that inflammation per se can facilitate the proliferation of specific pathogens that contribute to disease. These observations reviewed in this section have helped to understand the pathogenesis of idiopathic gastrointestinal disease states.