Brunner, Thomas

RERO DOC Digital Library

INTRODUCTIONLiving on the edge: immune cells and immunopathologyin the intestinal mucosaThomas BrunnerPublished online: 3 June 2009# Springer-Verlag 2009The uptake and distribution of nutrients is a vital task of thegastrointestinal tract. Digested food is absorbed by intesti-nal epithelial cells and transported to underlying tissue fromwhere it is distributed to the rest of the body. In order tooptimize the nutrient transport from the intestinal lumen tothe inside of our body, the epithelial surface is dramaticallyenlarged by macro- and mico-folds, villi, and finally thebrush border on the absorptive epithelial cells, similar to atree with branches and leaves. The simple single-cell layerarchitecture of the intestinal epithelium permits efficientuptake of nutrients and direct delivery to nearby bloodvessels.While this direct contact of our body to nutrients makesabsorption more efficient, it also represents a riskybusiness. The luminal side of the intestinal epithelial layercontains not only essential nutrients but also a plethora ofcommensal bacteria and potential pathogenic microorgan-isms. A disruption of this single-cell epithelial layerprovides easy access of these microorganisms to theunderlying tissue and eventually to the rest of the body, aprocess which may result in fatal bacteremia and has to beavoided by any costs. Not surprisingly, the intestinalmucosa is home to the largest and likely also most compleximmune systems of our body with the difficult task toprevent invasion of the host by pathogens. Figure 1illustrates the high density of different leukocyte subsetsin the human colon, representing a complex and extensiveimmune cell defense line. Under most circumstances, theintestinal immune system seems to do quite a good job.Although the single-cell epithelial layer is relatively leaky,in particular during inflammation, and specialized epithelialcells, so-called M cells, are even capable of transportingintact bacteria across the epithelial layer, invasion of thebody by intestinal bacteria is relatively rare, demonstratingthe effective protection by the local immune cells.Efficient effector functions of local immune cells protectthe host from invasion by pathogens. On the other hand,successful activation of immune effector cells often leads toinflammation-associated immunopathologies and bystandertissue damage. Various inflammatory diseases in humansdemonstrate what happens when intestinal immuneresponses go over the top. It is currently well accepted thatdevelopment of inflammatory bowel disease, i.e., ulcerativecolitis and Crohn′s disease, critically involves uncontrolledresponse of immune cells against commensal bacteria.Similarly, in food allergies and celiac disease, overreactionto otherwise harmless food antigens causes severe inflam-mation and associated pathologies. Chronic inflammatoryresponses in the gut may even result in the development ofcolonic cancer, e.g., as seen in many inflammatory boweldisease patients. It is currently not completely clear to whatextent resident immune cells contribute to these pathologiesand what is mediated by infiltrating inflammatory cells.Often, it may be even difficult to distinguish between them,as resident leukocytes under homeostatic conditions have adifferent phenotype than under inflammatory conditions,which may closely resemble that of their correspondinginfiltrating counterparts. Detailed phenotypical and func-tional characterization of local intestinal immune cells is,thus, a must to understand their respective roles in healthand disease. This phenotypic and functional adaptation isclearly evident when analyzing intestinal macrophages. Asdiscussed in this issue, intestinal macrophages have main-tained a high phagocytic activity, which is likely crucial forSemin Immunopathol (2009) 31:143–144DOI 10.1007/s00281-009-0162-7T. Brunner (*)Division of Immunopathology, Institute of Pathology,University of Bern,Murtenstrasse 31,3010 Bern, Switzerlande-mail: tbrunner@pathology.unibe.chpreventing bacterial spreading but lack many markers andcell surface receptors associated with the recognition ofmicroorganisms, e.g., Toll-like receptors and immunoglob-ulin receptors. Clearly, this adaptation leads to a functionalunresponsiveness to factors constantly present in theintestinal mucosa, thereby preventing uncontrolled andexaggerated immune responses.Functional unresponsiveness of resident immune cells is,however, insufficient to prevent inflammatory responsesagainst luminal antigens by infiltrating leukocytes. Physicaland chemical damage of the intestinal epithelial layer willimpair its barrier function. Thus, microbial products willfurther penetrate into the body and reach tissues whereimmune cells do not have such a functional adaptation as inthe gut and may easily become activated by these potenttriggers. When these primed and activated immune cellsfind their way to the source of antigen and microbialtriggers, the associated inflammatory response will evident-ly lead to severe tissue damage, further access to luminalantigen, and initiation of a viscous cycle of inflammation.While this is likely the case in inflammatory bowel diseaseand maybe also other forms of intestinal inflammation, it isalso clear that in the healthy individual, the activation ofresident as well as infiltrating leukocytes is controlled atvarious levels, including regulatory T cells, suppressivecytokines, and other factors. Last but not least, presentationof antigen occurs in a “suppressed” environment, whicheducates immune cells to develop in a biased manner.Critically, under physiological conditions, intestinal immunecells of the adaptive immune system, i.e., T and B cells arenot unresponsive to luminal antigen but rather developimmune effector function, which are generally not harmful tothe tissue and its functions, e.g., synthesis of regulatorycytokines and switch to IgA-producing plasma cells.This issue of Seminars in Immunopathology on thegastrointestinal immune system contains nine reviewsdiscussing various aspects of mucosal immunology andimmunopathology. Although given the size and complexityof the gastrointestinal immune system, this is more a glancethan an in-depth overview; the different articles demon-strate the enormous developmental, functional, and regula-tory adaptation of the intestinal immune cells to thispeculiar environment. Finally, they make clear how difficultthe appropriate balance between immune protection andimmune tolerance in the gastrointestinal tissue can be, oftendeciding between war and peace.Fig. 1 Immune cells in theintestinal mucosa. Immunohis-tochemical detection (brownstaining) of total leukocytes(CD45+), macrophages(CD68+), T lymphocytes(CD3+), and B cells (CD20+) inthe same section of the humancolonic mucosa144 Semin Immunopathol (2009) 31:143–144

Living on the edge: immune cells and immunopathology in the intestinal mucosa

http://doc.rero.ch/record/321576/files/281_2009_Article_162.pdf

Living on the edge: immune cells and immunopathology in the intestinal mucosa

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library