In 2012 it has been 60 years from the 1952 Summer Olympics in Helsinki. Outstanding marathon run of Emil Zatopek was one of the most memorable events in the 1952 Olympics. Our own, European Champion and Boston marathon winner, Veikko Karvonen finished in the 4th place.
It's late November and pubmed allready offers us a possibility to see latest on immune tolerance and inflammation collected nicely by scientists from the Rockefeller University in N.Y.
The mucosal surface of the intestine alone forms the largest area exposed to exogenous antigens as well as the largest collection of lymphoid tissue in the body. The enormous amount of nonpathogenic and pathogenic bacteria and food-derived antigens that we are daily exposed sets an interesting challenge to the immune system: a protective immune activity must coexist with efficient regulatory mechanisms in order to maintain a health status of these organisms.
Interface between the Outside and Inside Environments
The intestinal mucosa forms the largest area of the body in direct contact with the exterior environment. If expanded, the surface of the small intestine alone can reach roughly the size of a tennis court, or 100 times the area of the skin. In the skin, several layers of cells, including stratified epidermis, and dermis, generate a physical barrier that separates the internal components of the body from the outside. On the other hand, in the intestine, a single layer of absorptive epithelial cells forms an interface between the lumen (outside environment) and the lamina propria (inside environment). If one sees our body as a target for attack from infectious and pathogenic organisms, the structure of intestinal epithelia is counterintuitive, since the intestine is exposed to constant colonization by bacteria and is a host to an enormous quantity and diversity of microbes, including commensals and potential pathogens. More than 100 trillion microbial cells colonize the human gut, which amounts to ten bacteria for every one human cell. The vast majority of these bacteria are not pathogenic, but rather perform a variety of beneficial functions to the host. A recent study estimated that the human microbiome contains more than 1000 bacterial species, with more than 160 different species generally present in each person. These results highlight a high degree of person-to-person variation, possibly influenced by a distinct host genetic landscape and environmental conditions.
Other mucosal surfaces also harbor a diverse microbiota. For instance, over 200 genera of bacteria were identified in a human skin microbiome study. However, the intestinal mucosa is peculiar since it has to deal with intense bacterial colonization and at the same time absorption and digestion of nutrients. In that regard, it should be noted that the large intestine contains most of the microbiota while the small intestine is the main place for absorption and digestion of nutrients.
In addition to the exposure to innocuous antigens, the intestine is also a place where many different types of infections can occur, including infection by viruses, bacteria, parasites, and fungi. Commensal bacteria, generally involved in symbiotic interactions with the host, have also been correlated with the development of inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease. Similarly, dietary proteins can trigger food allergies and celiac disease. Therefore, it is reasonable to argue that the great majority of processes in the gut are not generated towards “defense” against invading organisms, but are rather a consequence of chronic exposure to large amounts of harmless and often beneficial antigens. This scenario poses an interesting challenge to the immune system, since most of the “nonself” interactions should probably be tolerized as “self”. How does the immune system associated with the intestine influence and assimilate the perturbations from the environment without generating pathology?
The Intestinal Context: Microbiota
Commensal microorganisms actively interact with the absorptive intestinal mucosa and influence the basal activity of the immune system as well as the amplitude of the immune response. The microbiota is able to modulate the activity of innate immune cells, including antigen presenting cells and innate lymphoid cells, in the lamina propria. Commensal bacteria-derived ATP has been shown to directly activate lamina propria T cells to produce IL-6, IL-23, and TGF-β and induce local differentiation of Th17 cells.
A contrasting example of a bacterial metabolite that contributes to the mucosal immunity is the short-chain fatty acids (SCFAs), which is produced by fermentation of dietary fiber . SCFAs bind to G-protein-coupled receptor 43 (GPR43, also known as FFAR2) and inhibit inflammatory responses during DSS-induced colitis by suppressing the differentiation of IL-17 producing cells in the lamina propria of conventional mice, suggesting that germ-free mice are more susceptible to this model of colitis due to reduced SCFA in the intestinal environment
The commensal bacteria Bacteroides fragilis is associated with suppression of Th17 and other inflammatory responses in the intestine by expression of polysaccharide A (PSA) via IL-10 production. A recent study showed that PSA is recognized by TLR2-expresing T cells and promotes their production of IL-10. Furthermore, PSA-treated Tregs are more efficient at suppressing activated T-cells in vitro, and Bacteroides fragilis mono-colonized recipient-mice induce higher numbers of Treg cells and show reduced Th17 responses after naïve CD4 adoptive transfer. In a recent report by Atarashi and coworkers identified Clostridium spp., a genus of gram-positive bacteria, belonging to the Firmicutes phylum, as a major inducer of Tregs in the colon of conventional mice. These results show that microbial-derived mechanisms can affect both innate and adaptive immunities and promote immune-regulation in the intestinal surface.
The Intestinal Context: Diet
Although much of the focus in mucosal immunology in recent years was given to the microbiota, most of the immune system antigen interaction in the gut is associated with the small intestine, where the nutrients are absorbed.
Beside the microbiota, the exposure to food proteins has also been shown to play a crucial role in the development and maintenance of the intestinal immune system as well as in susceptibility to systemic infection. The importance of food proteins to systemic immunity can also be appreciated by the fact that we ingest around 100 grams of protein daily, and up to 0.5% (500 mg/day) of ingested proteins can be found intact in blood circulation a few hours after ingestion.
Similarly to the microbiota, food proteins are potentially immunogenic and help to maintain the “immunological tonus”. Nevertheless, in general, the exposure to dietary antigens does not generate pathological responses. Indeed, mucosal exposure to antigens efficiently inhibits the development of immune responses to subsequent challenges with the same antigen, a phenomenon described as oral tolerance. It was demonstrated that peripheral generation of Foxp3-expressing Treg cells by TGF-β is a crucial event in oral tolerance induction in mice harboring monoclonal repertoire by both B and T cells (TBmc). Moreover, using the same experimental model, Curotto de Lafaille et al. showed that lack of functional Foxp3 results in abrogation of oral tolerance induction.
In addition to their regulatory role, it was also demonstrated that mucosal DCs from mesenteric lymph nodes (MLNs) and Peyer’s Patches (PPs) are unique in their capacity of degrading vitamin A to generate retinoic acid (RA). RA, in a TGF-β-dependent process, was proposed to play a crucial role in iTreg induction, demonstrating that diet-derived factors are also part of immune regulatory mechanisms involved in the prevention of aberrant immune responses towards the diet itself and other environmental antigens.
When oral tolerance is abolished, inflammatory processes generally arise resulting in the development of food allergies and other diseases. An example of food-related gut disorder is celiac (or coeliac) disease (CD), a condition that damages the lining of the small intestine and prevents it from absorbing nutrients. The damage is due to a lack of tolerance to gluten, a group of proteins found in wheat, barley, rye, and possibly oats. The break in tolerance leads to an exacerbated (mostly) Th1 immune response to specific gluten antigens (gliadin) in the small intestine after ingestion of gluten. The genetic background together with the intestinal context, in which the gluten protein is presented to T-cells, are the main factors in the balance between tolerance and inflammation in CD development. The differentiation of pathogenic, rather than regulatory, CD4+ T cells is thought to be induced by proinflammatory cytokines, including IL-15 and IFN-α, that are present in the intestinal mucosa from celiac disease patients.
Concluding remarks for the beginning of the year 2012
The dilemma faced by the mucosal immune system to induce tolerance to antigens (rule) or to engage an inflammatory immune response (exception) is daily dealt with through multidirectional interactions between the immune cells and environmental factors that permeate the mucosal surfaces. The identification of cellular and molecular mechanisms involved in this process will likely contribute to new approaches for prevention and treatment of systemic inflammatory diseases.
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