The mucosa: at the frontlines of immunity

The immune system is presented with many challenges in its day-to-day duties, but no part of it is subjected to greater demands than those associated with the body’s mucosal surfaces. Not only are mucosal surfaces generally the first point of entry for pathogens and hence require a prompt and robust immune response, but they are also exposed to an enormous volume of irrelevant or innocuous antigens that need to be effectively ignored. Mounting an appropriate response therefore represents a key decision-making dilemma for the mucosal immune system. The mucosal surfaces of the gut, respiratory tract, reproductive tract, and eye represent a complex immunological network structured to resolve this dilemma. With this single topic issue of Trends in Immunology we have gathered together nine articles covering the breadth of mucosal immunology including the development of mucosal lymphoid tissues, lymphocyte recruitment, probiotics, vaccination, immunopathology, and tolerance mechanisms. It is heartening to see how investigators from diverse backgrounds have been drawn to this field and this should surely lead to fertile research and novel insights.The gut is arguably the body’s largest lymphoid compartment both in terms of cell numbers and size. This is likely a reflection not only of the gut’s large surface area but also the heavy antigen traffic passing through it. A particularly striking property of the gut is its ability to induce so-called oral tolerance, whereby harmless antigens presented to the gut immune system result in systemic unresponsiveness specific for that antigen. This ability enables gut immunity to navigate a path between inappropriate activation and dangerous inaction. Noriko Tsuji and colleagues (Tsukuba, Japan) detail the unique populations of antigen presenting cells, lymphocytes and effector molecules present within the gut associated lymphoid tissue (GALT) that initiate and control the process of oral tolerance. How the gut recruits and becomes populated by lymphocytes is the core theme of the article by William Agace (Lund, Sweden).The gut also plays host to a huge and fantastically diverse population of microbes. Some of these species are simple commensals neither helping nor harming the host, whereas others seem to play a more active and positive role by aiding digestion, hindering colonisation by pathogenic microbes, or fine tuning the immune system. Probiotics are cultured strains of bacteria that attempt to replicate the mutualistic functions of particular gut microbes and much has been reported about their potential benefits to human health. There is already a large and growing body of literature related to the beneficial effects of probiotics in infectious disease, atopy, and various inflammatory ailments, however some aspects of the data remain murky. Much of the confusion seems to arise from variability in the probiotic strains, dosing regimen, and differences in patient microflora. Another problem is surely an incomplete understanding of the immune response triggered by probiotics. Hironobu Nanno and colleagues (Yakult, Tokyo, Japan) take an encompassing look at this topic and attempt to offer immunological insights into how the immune system recognises and responds to probiotics. What seems to be clear though is that gut microfloral diversity and number needs to be kept at an optimum level to maintain human health. Sidonia Fagarasan and colleagues (RIKEN, Yokohama, Japan) describe here how the synthesis of IgA by B cells of the GALT regulates and is in turn regulated by the host microflora. Indeed the development of some key immunological architecture responsible for IgA production in the gut is dependent on microbial signals. This IgA feedback mechanism not only fine-tunes the gut microflora but also acts as a critical barrier to colonisation by pathogenic bacteria. Another important but more evolutionarily ancient mechanism of defence at the gut mucosa is via the production of antimicrobial proteins. Geraldine Canny (Lausanne, Switzerland) and colleagues describe one such protein, BPI (bactericidal/permeability-increasing protein), which is produced by gut epithelial cells and has both potent antimicrobial and endotoxin neutralising effects. These properties make BPI and related proteins attractive targets for biopharmaceutical development.The respiratory tract represents another major mucosal frontline and Hiroshi Kiyono and colleagues (Tokyo, Japan) illustrate how it is subjected to many of the same pathogenic and antigenic challenges as the gut. Indeed, they reveal that many of the induction and regulation systems for immunological responses appear to be shared between the gut and respiratory mucosa even though the developmental processes differ. The eye provides a further interesting example, which is often overlooked despite it being another critical mucosal surface. Joan Stein-Streilein describes how the eye’s delicate nature and its key impact on evolutionary fitness have imposed exacting constraints on the kinds of immune responses that can occur here; namely it needs to resist infection but collateral damage needs to be kept to an absolute minimum. The eye achieves this in part via a process called ACAID (anterior chamber associated immune deviation); a phenomenon uncannily similar to that of oral tolerance. Therefore both the eye and respiratory mucosa present striking examples of the parsimonious nature of the immune system.A failure of oral tolerance coupled with the heavy microbial burden of the gut, can lead to a number of debilitating conditions including inflammatory bowel disease (IBD). Although much is known about the lymphocyte culprits and pathology of IBD the role of other cell types has been less studied. Silvio Danese (Milan, Italy) attempts to address this in a wide-ranging review that draws together the current state of knowledge on the role of nonlymphoid components in the induction and pathogenesis of IBD. Clearly we need to look in often surprising and hitherto unexplored areas before we can obtain a comprehensive picture of this disease.Due to their heavy exposure to the external environment, mucosal surfaces tend to be primary targets for pathogens and often act as a nidus for infection and microbial persistence. For instance the reproductive mucosa is generally the initial site of HIV infection and the gut subsequently becomes the most important reservoir of viral replication. The regional specialisation of the immune system implies that targeted boosting of specific immune compartments should therefore be more effective than systemic immunisation, and indeed this fact might underscore the failure of the current generation of HIV vaccines. Igor Belyakov and colleagues (NIAID, USA) demonstrate how a number of promising mucosal immunisation strategies might more efficiently target and control HIV infection. Another related and appealing vaccine approach described by Hiroshi Kiyono and colleagues is the incorporation of vaccines into genetically engineered cereal plants such as rice. This approach could obviate the need for a vaccine cold-chain as well as ensure the timely and regular boosting of immunity without using needle and syringe. In the years to come, targeting the various mucosal surfaces of the body should lead to a more efficacious second generation of vaccines. Such a future however depends on a detailed understanding of the interrelated cells and mechanisms that comprise the mucosal immune system. We hope this single topic issue on mucosal immunology can convey some of the excitement and potential of this fascinating topic.