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The Future of Mucosal Immunology: Studying an Integrated System-Wide Organ COMMENTARY The future of mucosal immunology: studying an integrated system-wide organ Navkiran Gill, Marta Wlodarska & B Brett Finlay Over the next 10 years, it will be important to shift the focus of mucosal immunology research to make further advances. Examination of the mucosal immune system as a global organ, rather than as a group of individual components, will identify and characterize relationships between mucosal sites. he term ‘common mucosal immunological Tsystem’ was coined by John Bienenstock a nearly 40 years ago. He suggested the con- cept when the bronchus-associated lymphoid tissues his group described were found to be Oral Airway epithelium Antigen epithelium similar to those in the gastrointestinal tract. Fibroblasts Ironically, appreciation of the importance of Smooth muscle T 2T this term is only now truly beginning. Since H reg Treg DC then, the mucosal immune system has received MHC B B Mast cell a great deal of attention and is described as an integrated network of tissues, cells and effector Cervical AMPs Lumen molecules that protect the host from infection Virus epithelium b Intestinal and environmental insult at mucous membrane epithelium Health Disease surfaces. Mucosal surfaces are immunologically Goblet cell Signals Microbial unique, as they act as the primary interface TH2 T 1 H B cell community between the host and the physical environ- T cell T 17 © 2010 Nature America, Inc. All rights reserved. All rights Inc. America, Nature © 2010 H ment yet also have key barrier functions. It Treg has become increasingly evident that mucosal surfaces are also the main sites of interaction IEC- Mucins between the host and its associated commen- Tolerance Inflammation associated microbial Lamina sal microbial community. In the past 40 years, Health Disease sensors propria the field of mucosal immunology research has Vicari Katie exploded and understanding of this key com- ponent of the immune system has flourished. Figure 1 The mucosal immunological system. (a) Recent advances suggest that mucosal sites function Many important findings have come from this together as a system-wide organ. Various mucosal sites throughout the body act as an interface between the physical environment (food, airborne, viral and commensal antigens) and host mucosal defenses. research and have aided in the understanding (b) The intestinal mucosal interface, a complex system that must integrate interactions among the of immune deficiencies and associated diseases microbiota, mucus layer, associated protective compounds, epithelial cells and underlying immune and facilitated the design of effective vaccines. cells of the lamina propria. Notably, it has become clear that both the state of the microbial community The next decade will be important in determin- and underlying immune cells contribute to the health or disease of the host. T, T cell; Treg, regulatory T cell; MHC, major histocompatibility complex; B, B cell; DC, dendritic cell; IEC, intestinal epithelial cell; Navkiran Gill and Marta Wlodarska are with the AMP, antimicrobial peptide. Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada. ing how the knowledge gained is synthesized of the system. For example, the mechanisms B. Brett Finlay is with the Michael Smith and which directions future studies take. responsible for initiating immune responses Laboratories, Department of Microbiology and to invading pathogens in the gastrointestinal Immunology, and Department of Biochemistry and A global organ system have been characterized. Similarly, the Molecular Biology, University of British Columbia, Much of the research undertaken in the past means by which the respiratory tract deals with Vancouver, British Columbia, Canada. several decades on the mucosal immune system bacterial and viral infections have also been e-mail: [email protected] has focused on specific individual components established. However, the mucosal immune 558 VOLUME 11 NUMBER 7 JULY 2010 NATURE IMMUNOLOGY COmmentarY system has yet to be examined from a holistic Immune responses viewpoint as a global organ (Fig. 1). Although much knowledge has been derived from study DC Foxp3+ of the individual components of the mucosal Stressor immune system, future research should exam- Treg cells ine how the different components affect each other and how crosstalk is achieved between Large intestine Lung individual components and, more importantly, Microbiota between various mucosal sites. As many fea- tures are shared by distal mucosal compart- ments, it is likely that these aspects may have Lymph compelling roles in mucosal immunity, and node there could be unappreciated levels of com- munication between mucosal compartments. There is ample evidence suggesting that Immune the mucosal immune system is a system-wide Compositional shift development organ. Studies have demonstrated that stimu- Vicari Katie lation in one compartment of the mucosal Figure 2 Reexamining the hygiene hypothesis. Investigations that take into consideration the cyclic immune system can lead to changes in distal relationship between the mucosal immune system and the microbial community make it possible to areas. For example, intranasal immunization identify previously unknown mechanisms of disease onset. Changes in the microbiota could result in differences to downstream immune responses or, alternatively, immune development. Both of these results in vaginal protection against genital aspects can affect immune mechanisms in distal mucosal sites, such as the lung, and result in asthma. infection with herpes simplex virus type 2 (ref. Alternatively, deficiencies in the immune system can affect the microbiota composition, which can then 1). Clinical studies of patients infected with again have an effect on distal mucosal sites and have a role in the development of atopic conditions. human immunodeficiency virus have shown that high concentrations of human immunode- ficiency virus–specific immunoglobulin A are architecture and the immune system4,5. Despite tissues. The interaction of the microbiota with found in various mucosal secretions, includ- increasing knowledge in this field, important the mucus layer and the role of the micro- ing the vaginal secretions, nasal washes, saliva questions still remain unanswered: Given the biota in modulating the production of both and endocervical secretions2. Furthermore, diversity of the microbiota and the signals the mucus layer and the biologically active the use of antibiotics in neonates has been they can produce, what methods are used to molecules sequestered therein are intriguing associated with a greater risk of developing interact with the host? Furthermore, how are concepts that require future clarification. The asthma3, which suggests that alterations in these interactions monitored and controlled? mucus layer is truly at the interface between the microflora of the gut can have an effect on Studies using knockout mice defective in the microbiota and host, which emphasizes its the lungs and highlights the potential for an mucus production, germ-free mice, and pro- importance. undetermined link between mucosal immune biotics suggest that the mucus layer is a major As there is a new appreciation of the impor- compartments. Collectively, such studies sug- mediator of interactions between epithelial tance of the microbiota, knowledge of the gest that the mucosal immune system is actu- cells and microbes and that its function is mucosal immune system and immune devel- ally one large interconnected network and that affected largely by the microbiota. The mucus opment must be reexamined. There has already © 2010 Nature America, Inc. All rights reserved. All rights Inc. America, Nature © 2010 the individual components are very efficient at layer in the large intestine consists of two strati- been a great deal of research on the importance sharing information distally. fied layers, composed mainly of the secreted of the microbiota in immune development in Understanding the communication between mucin Muc2, which is heavily 0-glycosylated the germ-free mouse model. These mice lack mucosal sites is fundamental to the next phase with complex oligosaccharides6, a character- commensal microbes and have poorly devel- of disease characterization and vaccine devel- istic that is crucial to its structure and func- oped mesenteric lymph nodes, Peyer’s patches, opment. Appreciation of the mucosal immune tion7. The inner layer has a dense composition cryptopatches and isolated lymphoid follicles, system as a global organ will involve determin- and is devoid of commensal bacteria, whereas the four main structures that make up the gut- ing what factors link one area of the mucosal the outer layer is built as a loose matrix hous- associated lymphoid tissue8. Studies have shown immune system to another and the intricacies ing commensal bacteria6. Future studies will that colonization with a single bacterial species of this communication. This aspect needs to be be crucial for further characterization of the is able to reverse those defects8. Furthermore, addressed sooner rather than later. mucus layer and its function in binding to various groups have demonstrated a role for and sequestering growth factors, differentia- the microbiota in intestinal epithelial homeo- The immune system and the microbiota tion factors and mediators of inflammation7 stasis, angiogenesis and the development of It is known that mammals contain millions of (Fig. 1b). Stimuli that result in the
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