[Frontiers in Bioscience S4, 685-698, January 1, 2012]
Innate and adaptive immunity in host-microbiota mutualism
Andrew J. Macpherson1, Markus B. Geuking1, Kathy D. McCoy1
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TABLE OF CONTENTS
1. ABSTRACT
Healthy individuals live in peaceful co-existence with an immense load of intestinal bacteria. This symbiosis is advantageous for both the host and the bacteria. For the host it provides access to otherwise undigestible nutrients and colonization resistance against pathogens. In return the bacteria receive an excellent nutrient habitat. The mucosal immune adaptations to the presence of this commensal intestinal microflora are manifold. Although bacterial colonization has clear systemic consequences, such as maturation of the immune system, it is striking that the mutualistic adaptive (T and B cells) and innate immune responses are precisely compartmentalized to the mucosal immune system. Here we summarize the mechanisms of mucosal immune compartmentalization and its importance for a healthy host-microbiota mutualism.
2. INTRODUCTION
The lower intestine is a habitat for one of the highest densities of microbial consortia on the planet (1). An enduring question is exactly how this load of microbes (reaching 1012 organisms/g of intestinal contents) can be accommodated without damaging the host, given that the barrier between the lumen of the intestine and host tissues is composed of a simple epithelial layer, one cell thick. It is clear that although commensal microbes generally lack pathogenicity genes that characterise pathogens, which encode for proteins that facilitate adhesion, penetration of the epithelium, facultative persistence within host cells or toxin formation, they do share prokaryotic molecular patterns that are powerful activators of the innate immune system.
This question of how commensal microbial mutualism with the host is induced and maintained is also medically important for several reasons. First, about 2 in every 1000 people in industrialised countries suffer from inflammatory bowel disease (IBD) (2). This can manifest in two forms - ulcerative colitis (UC) and Crohn's disease. Table 1 provides an overview of the major differences in immunity between UC and Crohn's disease. Both probably depend on abnormal mucosal immune responsiveness to commensal intestinal microbes: the evidence for a dysregulated handling of intestinal commensals in Crohn's disease is particularly strong on the basis of clinical data (3), the genes that give a genetic susceptibility in the human population (4-6) and animal models of the disease (Table 2). Secondly, many infections in immunocompromised patients, such as in individuals treated with chemotherapy, are from commensal intestinal bacteria.
In this review we will focus on the compartmentalisation of the immune system in responding and adapting to the presence of commensal intestinal microbes with an emphasis on the induction of IgA against commensals as a method of dissecting host-microbial immune mechanisms. Because of the ability to precisely control and manipulate the intestinal microflora in mouse models, the majority of the data discussed here is derived from animal studies. However, where data is available we have added evidence from human studies.
3. ADAPTATION OF THE HOST TO THE COLONISATION OF THE INTESTINE WITH A COMMENSAL MICROBIOTA
The gut is a tube from mouth to anus, so luminal bacteria are not, strictly speaking, inside the body tissues. The evidence that the host has to adapt to the presence of the commensal intestinal microbes comes from studies that have compared germ-free animals with the same animal strain colonised with intestinal bacteria. An alternative approach is to follow the changes in host immunity and other body systems, as intestinal bacteria are introduced to germ-free animals (7).
Germ-free rodents were first derived nearly a century ago, stimulated by the question of whether animal life was possible in the absence of commensal microbes (8). Initially rodents were delivered aseptically and hand reared for short periods: later it became possible to interbreed the germ-free adults, and this is now standard technology (7, 9-11). Because in vivo experiments are easy with mice and many different genetic backgrounds and targeted genetic lesions are available, most germ-free experimentation is with this species. Today, it is convenient to maintain strains in plastic flexible film isolators, introducing sterile food, water and bedding from a sterilised drum connected to the isolator with a plastic sleeve. The inside of the sleeve is sterilised with a 2% peracetic acid mist before the inner door of the isolator is opened and the seal of the drum is broken to access the sterilised contents (7). Although some units still use aseptic Caesarian section to re-derive different genetic strains of mice germ-free, this is a cumbersome and unreliable procedure compared with aseptic embryo transfer into germ-free pseudopregnant females, which then deliver and foster the pups (7).
There are enormous differences between germ-free mice and their colonised counterparts in almost every body system (7). Immunity of the gut is shaped by the introduction of intestinal commensal bacteria through increase in the cellularity and organisation of secondary lymphoid structure of the gut (Peyer's patches and isolated lymphoid follicles) and systemic immune system (spleen, lymph nodes), the induction and secretion of IgA from intestinal lamina propria plasma cells, increase in the content of lamina propria CD4 T cells, and general increase in serum immunoglobulin levels, especially the IgG isotypes (12-14). Paradoxically, IgE levels are abnormally high in germ-free mice and are decreased when the animals become colonised with commensal intestinal bacteria (15).
It is clear from the manifold changes in immunity and other body systems as the intestines of germ-free animals become colonised, that mammals adapt to the presence of commensal intestinal bacteria (14). We assume that these adaptations are functionally relevant, although this is still a developing area as discussed below.
4. UNCOUPLED MUCOSAL AND SYSTEMIC IMMUNE RESPONSES TO COMMENSAL INTESTINAL MICROBES
If pathogens are eliminated from colonies of mice (so they are designated 'specific pathogen free' or SPF) they still have a commensal intestinal microbiota. Such SPF mice mount a strong mucosal response to their intestinal commensals, manifested by the secretion of specific intestinal IgA across the mucosa, but the systemic immune system remains ignorant of these intestinal microbes and no specific serum antibodies or T cells are induced (16, 17). This 'ignorance' of the systemic immune system can easily be broken experimentally by injecting a single dose of a commensal bacteria prepared from pure culture into the tail vein and measuring the appearance of a specific antibody response approximately 14 days later (16).
This shows experimentally that, in unmanipulated SPF animals containing a microbiota, the mucosal immune system mounts responses against commensal microbes quite independently of the systemic immune system (16, 17). As one might expect, the systemic immune system can very easily mount a response provided that the microbes reach systemic secondary lymphoid structures in sufficient numbers (16, 18). In other words immune compartmentalisation is responsible for mutualism with commensal microbes, and there is little or no evidence for systemic immune tolerance (19).
We have recently been able to refine the way in which antibacterial antibodies are detected. Earlier methods of using Western blots of bacterial lysates or binding whole bacteria to plastic and then using enzyme linked (ELISA) methods to detect bound antibodies detect non species-specific binding (16). Although these antibodies are probably functionally relevant, they are presumably of relatively low affinity against bacterial epitopes. Using a flow-cytometric (FACS) assay, we have been able to detect antibodies bound to bacteria with high specificity, for example although Salmonella and Escherichia coli are closely related bacterial species, antibodies raised by priming with the different organisms in vivo do not cross-react in the FACS assay (18).
A further advance has been the ability to use genetically modified bacteria containing auxotrophic mutations for synthesis pathways of bacterial compounds that are not found in eukaryotes. These bacteria (HA107) can be grown in culture in the lab (with media containing the appropriate chemical supplements), but they cannot survive in animals, so germ-free mice can be exposed to these bacteria and become germ-free again after about 72 hours (20). This has allowed us to study induction of commensal intestinal immune responses in germ-free animals uncoupled from colonisation.
Germ-free mice treated with E.coli HA107, that become germ-free again, develop a specific intestinal IgA response against HA107 that is extremely long lasting (>16 weeks) even though the exposure to live bacteria is very short (72 hours). This shows, in a clean experimental system, that the anti-commensal IgA response in the intestine is very specific (20).
The HA107 tool has also allowed us to show that the threshold for an IgA response in the intestine is very high (>109 organisms are required for experimental induction) and does not show the prime-boost memory effect that is characteristic of systemic immune priming. Indeed the overall anti-commensal IgA response is rather an integral of the total amount of bacterial exposure. This suggests that in this system memory seems to be achieved by persistence of the IgA response, which will eventually be displaced when a new IgA response is induced to a different intestinal commensal (20).
5. THE MUCOSAL IMMUNE FIREWALL
Since there is a separation of mucosal and systemic immune responses to commensals, the question of the mechanism of how a mucosal response to commensals can be induced in the absence of a systemic response arises. We, and others, have shown that intestinal dendritic cells (DC) sample commensal bacteria at the mucosal surface (21, 22). The small intestine is thought to contain two main types of DC distinguished by the expression of CD103 (also known as alphaE-integrin) (reviewed in 23). The CD103+ DC subset is thought to be conditioned by factors in the intestinal microenvironment, such as TGF-beta, retinoic acid, microbial antigens, and IL-10, and then migrate via C-C chemokine receptor type 7 (CCR7) to the mesenteric lymph nodes (MLN) where they can promote regulatory T cell development and induction of CCR9 and alpha4beta7 expression on T cells (24-26). This population also seems to be conserved between mouse and man (27). In contrast, the CD103- DC population has been implicated in T helper 17 (Th17) cell induction (28) and expresses CX3C chemokine recptor 1 (CX3CR1), which allows them to extend dendrites between the tight junctions of the intestinal epithelial cells and sample microorganisms (21, 29). DC can also capture microorganisms that transcytose through specialized M cells in the follicle-associated epithelium of the Peyer's patches (reviewed in 30). Sampling of the commensal microflora occurs across the length of the small intestine under steady-state conditions but may increase, especially in the terminal ileum, following infection with pathogenic bacteria (29, 31). Compared with other host phagocytes, DC have rather poor biocidal activity so the live bacteria are retained for up to several days. The bacterially-loaded DC are capable of inducing IgA B cells and can migrate to reach the MLN but do not penetrate beyond the MLN to reach central body tissues. This means that induction of mucosal immunity by commensals is largely restricted to mucosal inductive sites in animals, provided that the immune system is functioning normally (22).
Of course the restriction of immune induction against commensals to mucosal secondary lymphoid structures does not preclude dissemination of the response across the mucosal immune system, because induced B and T cells recirculate through the lymph to the thoracic duct, where they join the blood stream and home back to mucosal tissues (32, 33). It is important for this recirculation that the induced lymphocytes are programmed to express the necessary homing receptors. Induction of CCR9 and alpha4beta7 on intestinal B and T cells is triggered through constitutive expression of retinoic acid by intestinal dendritic cells (34).
Commensal bacteria (and presumably other elements of the intestinal commensal microbiota) are efficiently phagocytosed. There are several lines of evidence for this.
1. It has been shown that intestinal bacterial pathogens (such as Salmonella, Shigella and Yersinia) frequently employ mechanisms to subvert entry into, or they trigger mechanisms of biocidal compartments of phagocytes, in order to maintain a facultative intracellular existence (35, 36). Since such subversion is required for pathogenicity, it follows that non-pathogenic commensals that penetrate mucosal defences allow themselves to be killed by phagocytes as a part of host-microbial mutualism.
2. When biocidal mechanisms of phagocytes are experimentally rendered deficient as a result of genetic manipulation in mice, the consequence is a severe phenotype with a susceptibility to fatal sepsis from intestinal commensals that starts soon after weaning (37).
3. In experiments with isolated intestinal loops, we asked whether commensal bacteria could penetrate to the mesenteric lymph nodes in a free state, or whether they had to be carried there contained within intestinal dendritic cells (22). The experimental setup is shown in Figure 1. Two segments of small intestine were disconnected surgically, without disturbing the lymphatic or vascular supply, and the main small intestine was reanastomosed at the positions marked "xx" to restore continuity. The disconnected small intestinal loops were brought out onto the skin with external stomas (although the loops are shown close together on the diagram for convenience, in fact they were constructed on separate sides of the abdominal wall). We then pulsed one loop with a commensal (Enterobacter cloacae) carrying a naladixic acid antibiotic resistance, and the other loops with Enterobacter cloacae carrying rifampicin resistance. After 18 hours the dendritic cells were plated out at single cell density from disaggregated mesenteric leukocytes. Our reasoning was that if the free bacteria penetrated through the lymphatics some DCs would contain bacteria carrying both resistances. On the other hand, if the bacteria were exclusively taken up by DC at the mucosal surface and then carried to the mesenteric lymph nodes, because the bacterial exposure is in separate loops each with a different bacterial resistance, DC in the mesenteric lymph nodes would only carry Enterobacter cloacae containing one antibiotic resistance. This latter situation turned out to be the case. As a control the antibiotic resistant preparations were mixed and put into one or both loops, when mesenteric DC then contained bacteria with both antibiotic markers (22).
In one sense, therefore, the mesenteric lymph nodes are an immunological firewall that protects the systemic immune system from unnecessary exposure to commensals. The system works because microbes are very efficiently phagocytosed: in most cases they will be killed by macrophages or neutrophils, but some can persist in intestinal DC to assist in the induction of anti-commensal immunity. These DC have a relatively short lifespan, and are arrested within the mesenteric lymph nodes: presumably the live commensal bacteria that are released from effete DC in the mesenteric lymph nodes are rapidly destroyed by biocidal activity from the abundant numbers of macrophages present. Since sepsis from commensal bacteria would be potentially serious (for example mastitis in breast-feeding mothers) it is better to have mucosal immune responses that are characterised by distinct immune geography, rather than any system of immune tolerance to these organisms.
6. THE ROLE OF INNATE IMMUNITY IN MUTUALISM WITH INTESTINAL MICROBES
We have described how the normal immune system is able to compartmentalise responses to commensal intestinal microbes with induction within secondary lymphoid tissues of the gut. Three levels of indirect evidence were cited above to show that biocidal activity of the innate immune system is an important part of this compartmentalization.
In fact, it is experimentally possible to allow breaches in the mesenteric lymph node firewall, by surgically removing the mesenteric lymph nodes. Following this operation, the mesenteric lymphatics spontaneously heal and reanastomose, so that the continuity of lymphatic draining is restored within a few weeks: this can be shown by gavaging the animal with olive oil, following which lymphatics appear a (continuous) brilliant white from the micelle emulsion of fat digestion. Whereas central secondary lymphoid structures, such as the spleen, remain sterile when wild-type mice are treated with intestinal doses of commensal bacteria, mice without mesenteric lymph nodes lose this protection and live commensals can be cultured from the spleen. Breaking the firewall also has functional consequences. Mice without mesenteric lymph nodes develop extreme splenomegaly, lymphadenopathy and skin acanthosis during these experiments (22).
Another approach to looking at the importance of innate immunity in providing the immune mutualism with commensal intestinal microbes was to study the effect of mice deficient in both myeloid differentiation primary response gene 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-beta (TRIF) adaptor molecules, which in turn results in deficient Toll-like receptor (TLR) signaling (38). These MyD88/TRIF double deficient mice are hard to breed in normal animal vivaria, but we found that they were very stable once re-derived germ-free (18). We found that when these MyD88/TRIF deficient mice were colonised with a limited ("modified Schaedler") microbiota, containing only 8 culturable bacteria, unlike heterozygous littermates, they spontaneously developed serum IgG antibody responses to the organisms in their commensal microbiota (18). This could be reproduced with a monocolonisation, so it was not a function of particular bacterial species present.
The reason for an abnormal systemic immune response in the face of a MyD88/TRIF double lesion, is that immune phagocytes are poor at killing commensals. This was shown by persistence of commensals following intravenous injection. Moreover, when doses of commensals were gavaged into MyD88/TRIF double deficient mice culturable bacteria can be recovered from the spleen: this is not due to a barrier defect, as measurements of intestinal permeability ex vivo in Ussing chambers or the extent of serum protein loss into the intestinal lumen in vivo were normal. Indeed when we directly studied mice deficient in the Phox enzyme required to produce superoxide radicals as part of the lysosome biocidal mechanism, the same systemic immune response to the commensal microbiota was seen (18).
These abnormalities in host-intestinal microbial mutualism in the face of severe innate immune defects show us two things.
1. Innate immunity is an essential requirement for the handling of commensal organisms. It is inevitable that some of these microbes should penetrate the extremely thin epithelial layer; indeed they need to do so in order to induce host mucosal immunity as part of the mutualism process. Biocidal mechanisms of macrophages are very likely to be crucial in mopping up commensal microbes that penetrate the barrier, or in eliminating microbes that are released live from effete dendritic cells.
2. The fact that there is a systemic antibody response suggested that the innate and adaptive immune systems work as a continuum in host microbial mutualism. This point was addressed experimentally by breeding a MyD88 deficient murine strain that also carries a deletion of the J segments of the immunoglobulin heavy chain locus (JH-/-), so it cannot produce antibody of any isotype. The MyD88 lesion was chosen in these experiments as it was known to exert most of the phenotype of the MyD88/TRIF double deficient strain (18). Under germ-free conditions the MyD88, JH-/- mice bred well and matured normally, but when colonised with an altered Schaedler microbiota the offspring commonly died in the neonatal period, and those that survived to weaning had a severe growth defect indicating that specific serum anticommensal antibodies can partially compensate for defective innate immune mechanisms.
7. CONCLUSIONS
This review has concentrated on the different compartments in which antibodies to commensal intestinal microbes are induced, as a means of exploring the immune geography of host-microbial mutualism. Of course this is a (small) part of the story and mutualism at the level of the mucosal immune system is a multilayered process with innate responses by epithelial cells and an important component of effector and regulatory T cells. We commonly read that mammals must be 'tolerant' of their commensal intestinal microbes: of course semantically this is so, but in an immunological sense we would like to persuade our readers that the evidence for compartmentalisation which allows generation of a selective mucosal immune response without unnecessarily involving systemic immunity is far better than the concept that systemic immunity is in fact downregulated to these organisms. There would be a significant disadvantage of such downregulation as we would be left liable to serious sepsis from our commensals.
8. ACKNOWLEDGEMENT
This work was supported by grants from the Swiss National Science Foundation.
7. REFERENCES
1. W. B. Whitman, D. C. Coleman and W. J. Wiebe: Prokaryotes: The unseen majority. PNAS, 95(12), 6578-6583 (1998)
doi:10.1073/pnas.95.12.6578
2. R. B. Sartor: Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am J Gastroenterol, 92(12 Suppl), 5S-11S. (1997)
PMid:9395346
3. P. Rutgeerts, K. Goboes, M. Peeters, M. Hiele, F. Penninckx, R. Aerts, R. Kerremans and G. Vantrappen: Effect of faecal stream diversion on recurrence of Crohn's disease in the neoterminal ileum. Lancet, 338, 771-774 (1991)
doi:10.1016/0140-6736(91)90663-A
4. J. Hampe, A. Cuthbert, P. J. P. Croucher, M. M. Mirza, S. Mascheretti, S. Fisher, H. Frenzel, K. King, A. Hasselmeyer, A. J. Macpherson, S. Bridger, S. van Deventer, A. Forbes, S. Nikolaus, J. Lennard-Jones, U. R. Foelsch, M. Krawczak, C. Lewis, S. Schreiber and C. G. Mathew: Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet, 357, 1925-1928 (2001)
doi:10.1016/S0140-6736(00)05063-7
5. J. P. Hugot, M. Chamaillard, H. Zouali, S. Lesage, J. P. Cezard, J. Belaiche, S. Almer, C. Tysk, C. A. O'Morain, M. Gassull, V. Binder, Y. Finkel, A. Cortot, R. Modigliani, P. Laurent-Puig, C. Gower-Rousseau, J. Macry, J. F. Colombel, M. Sahbatou and G. Thomas: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature, 411(6837), 599-603. (2001)
doi:10.1038/35079107
PMid:11385576
6. Y. Ogura, D. K. Bonen, N. Inohara, D. L. Nicolae, F. F. Chen, R. Ramos, H. Britton, T. Moran, R. Karaliuskas, R. H. Duerr, J. P. Achkar, S. R. Brant, T. M. Bayless, B. S. Kirschner, S. B. Hanauer, G. Nunez and J. H. Cho: A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature, 411(6837), 603-606. (2001)
doi:10.1038/35079114
PMid:11385577
7. K. Smith, K. D. McCoy and A. J. Macpherson: Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol, 19(2), 59-69 (2007)
doi:10.1016/j.smim.2006.10.002
PMid:17118672
8. L. Pasteur: Observations relatives a la note de M. Duclaux. Comp. rend., 100, 69 (1885)
9. M. Cohendy: Experiences sur la vie sans microbes. Compt. rend., 154, 533-536 (1912)
10. M. Cohendy: Experiences sur la vie sans microbes, élevage aseptique de cobages. Compt. rend., 158, 1283-1284 (1914)
11. G. Glimstedt: Bakterienfrei Meerschweinchen. Aufzucht, Lebensfähigkeit und Wachstum, nebst Untersuchung über das lymphatische Gewebe. Acta Pathol. Microbiol. Scand. Suppl., 30, 1-295 (1936)
12. A. J. Macpherson, M. B. Geuking and K. D. McCoy: Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology, 115(2), 153-162 (2005)
doi:10.1111/j.1365-2567.2005.02159.x
PMid:15885120 PMCid:1782138
13. A. J. Macpherson and N. Harris: Interactions between commensal intestinal bacteria and the immune system. Nature Reviews Immunology, 4, 478-485 (2004)
doi:10.1038/nri1373
PMid:15173836
14. L. V. Hooper and A. J. Macpherson: Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol, 10(3), 159-169 (2010)
doi:10.1038/nri2710
PMid:20182457
15. K. D. McCoy, N. L. Harris, P. Diener, S. Hatak, B. Odermatt, L. Hangartner, B. M. Senn, B. J. Marsland, M. B. Geuking, H. Hengartner, A. J. Macpherson and R. M. Zinkernagel: Natural IgE Production in the Absence of MHC Class II Cognate Help. Immunity, 24(3), 329-339 (2006)
doi:10.1016/j.immuni.2006.01.013
PMid:16546101
16. A. J. Macpherson, D. Gatto, E. Sainsbury, G. R. Harriman, H. Hengartner and R. M. Zinkernagel: A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science, 288(5474), 2222-2226 (2000)
doi:10.1126/science.288.5474.2222
PMid:10864873
17. A. Konrad, Y. Cong, W. Duck, R. Borlaza and C. O. Elson: Tight mucosal compartmentation of the murine immune response to antigens of the enteric microbiota. Gastroenterology, 130(7), 2050-2059 (2006)
doi:10.1053/j.gastro.2006.02.055
PMid:16762628
18. E. Slack, S. Hapfelmeier, B. Stecher, Y. Velykoredko, M. Stoel, M. A. Lawson, M. B. Geuking, B. Beutler, T. F. Tedder, W. D. Hardt, P. Bercik, E. F. Verdu, K. D. McCoy and A. J. Macpherson: Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science, 325(5940), 617-620 (2009)
doi:10.1126/science.1172747
PMid:19644121
19. A. J. Macpherson and T. Uhr: Compartmentalization of the mucosal immune responses to commensal intestinal bacteria. Ann N Y Acad Sci, 1029, 36-43 (2004)
doi:10.1196/annals.1309.005
PMid:15681741
20. S. Hapfelmeier, M. A. Lawson, E. Slack, J. K. Kirundi, M. Stoel, M. Heikenwalder, J. Cahenzli, Y. Velykoredko, M. L. Balmer, K. Endt, M. B. Geuking, R. Curtiss, 3rd, K. D. McCoy and A. J. Macpherson: Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science, 328(5986), 1705-1709 (2010)
doi:10.1126/science.1188454
PMid:20576892
21. M. Rescigno, M. Urbano, B. Valzasina, M. Francolini, G. Rotta, R. Bonasio, F. Granucci, J. P. Kraehenbuhl and P. Ricciardi-Castagnoli: Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol, 2(4), 361-367. (2001)
doi:10.1038/86373
PMid:11276208
22. A. J. Macpherson and T. Uhr: Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science, 303, 1662-1665 (2004)
doi:10.1126/science.1091334
PMid:15016999
23. J. L. Coombes and F. Powrie: Dendritic cells in intestinal immune regulation. Nat Rev Immunol, 8(6), 435-446 (2008)
doi:10.1038/nri2335
PMid:18500229 PMCid:2674208
24. J. L. Coombes, K. R. Siddiqui, C. V. Arancibia-Carcamo, J. Hall, C. M. Sun, Y. Belkaid and F. Powrie: A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med, 204(8), 1757-1764 (2007)
doi:10.1084/jem.20070590
PMid:17620361 PMCid:2118683
25. C. M. Sun, J. A. Hall, R. B. Blank, N. Bouladoux, M. Oukka, J. R. Mora and Y. Belkaid: Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med, 204(8), 1775-1785 (2007)
doi:10.1084/jem.20070602
PMid:17620362 PMCid:2118682
26. B. Johansson-Lindbom, M. Svensson, O. Pabst, C. Palmqvist, G. Marquez, R. Forster and W. W. Agace: Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J Exp Med, 202(8), 1063-1073 (2005)
doi:10.1084/jem.20051100
PMid:16216890 PMCid:2213212
27. E. Jaensson, H. Uronen-Hansson, O. Pabst, B. Eksteen, J. Tian, J. L. Coombes, P. L. Berg, T. Davidsson, F. Powrie, B. Johansson-Lindbom and W. W. Agace: Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J Exp Med, 205(9), 2139-2149 (2008)
doi:10.1084/jem.20080414
PMid:18710932 PMCid:2526207
28. K. Atarashi, J. Nishimura, T. Shima, Y. Umesaki, M. Yamamoto, M. Onoue, H. Yagita, N. Ishii, R. Evans, K. Honda and K. Takeda: ATP drives lamina propria T(H)17 cell differentiation. Nature, 455(7214), 808-812 (2008)
doi:10.1038/nature07240
PMid:18716618
29. J. H. Niess, S. Brand, X. Gu, L. Landsman, S. Jung, B. A. McCormick, J. M. Vyas, M. Boes, H. L. Ploegh, J. G. Fox, D. R. Littman and H. C. Reinecker: CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science, 307(5707), 254-258 (2005)
doi:10.1126/science.1102901
PMid:15653504
30. T. Kucharzik, N. Lugering, K. Rautenberg, A. Lugering, M. A. Schmidt, R. Stoll and W. Domschke: Role of M cells in intestinal barrier function. Ann N Y Acad Sci, 915, 171-183 (2000)
doi:10.1111/j.1749-6632.2000.tb05240.x
31. M. Chieppa, M. Rescigno, A. Y. Huang and R. N. Germain: Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J Exp Med, 203(13), 2841-2852 (2006)
doi:10.1084/jem.20061884
PMid:17145958 PMCid:2118178
32. A. J. Husband and J. L. Gowans: The origin and antigen-dependent distribution of IgA-containing cells in the intestine. J. Exp. Med., 148, 1146-1160 (1978)
doi:10.1084/jem.148.5.1146
PMid:722238
33. N. F. Pierce and J. L. Gowans: Cellular kinetics of the intestinal immune response to cholera toxoid in rats. J. Exp. Med., 142, 1550-1563 (1975)
doi:10.1084/jem.142.6.1550
PMid:1238506
34. J. R. Mora, M. Iwata, B. Eksteen, S. Y. Song, T. Junt, B. Senman, K. L. Otipoby, A. Yokota, H. Takeuchi, P. Ricciardi-Castagnoli, K. Rajewsky, D. H. Adams and U. H. von Andrian: Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science, 314(5802), 1157-1160 (2006)
doi:10.1126/science.1132742
PMid:17110582
35. P. Sansonetti: Phagocytosis of bacterial pathogens: implications in the host response. Semin Immunol, 13(6), 381-390. (2001)
doi:10.1006/smim.2001.0335
PMid:11708894
36. P. J. Sansonetti: War and peace at mucosal surfaces. Nat Rev Immunol, 4(12), 953-964 (2004)
doi:10.1038/nri1499
PMid:15573130
37. M. U. Shiloh, J. D. MacMicking, S. Nicholson, J. E. Brause, S. Potter, M. Marino, F. Fang, M. Dinauer and C. Nathan: Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase. Immunity, 10(1), 29-38. (1999)
doi:10.1016/S1074-7613(00)80004-7
38. K. Hoebe, X. Du, P. Georgel, E. Janssen, K. Tabeta, S. O. Kim, J. Goode, P. Lin, N. Mann, S. Mudd, K. Crozat, S. Sovath, J. Han and B. Beutler: Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature, 424(6950), 743-748 (2003)
doi:10.1038/nature01889
PMid:12872135
39. D. K. Podolsky: Inflammatory bowel disease. N Engl J Med, 347(6), 417-429 (2002)
doi:10.1056/NEJMra020831
PMid:12167685
40. W. Strober, I. Fuss and P. Mannon: The fundamental basis of inflammatory bowel disease. J Clin Invest, 117(3), 514-521 (2007)
doi:10.1172/JCI30587
PMid:17332878 PMCid:1804356
41. H. Mashimo, D. C. Wu, D. K. Podolsky and M. C. Fishman: Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science, 274(5285), 262-265 (1996)
doi:10.1126/science.274.5285.262
PMid:8824194
42. D. Taupin and D. K. Podolsky: Trefoil factors: initiators of mucosal healing. Nat Rev Mol Cell Biol, 4(9), 721-732 (2003)
doi:10.1038/nrm1203
PMid:14506475
43. T. G. Bush, T. C. Savidge, T. C. Freeman, H. J. Cox, E. A. Campbell, L. Mucke, M. H. Johnson and M. V. Sofroniew: Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell, 93(2), 189-201 (1998)
doi:10.1016/S0092-8674(00)81571-8
44. M. Steinkamp, I. Geerling, T. Seufferlein, G. von Boyen, B. Egger, J. Grossmann, L. Ludwig, G. Adler and M. Reinshagen: Glial-derived neurotrophic factor regulates apoptosis in colonic epithelial cells. Gastroenterology, 124(7), 1748-1757 (2003)
doi:10.1016/S0016-5085(03)00404-9
45. C. M. Panwala, J. C. Jones and J. L. Viney: A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis. J Immunol, 161(10), 5733-5744 (1998)
PMid:9820555
46. L. Maggio-Price, D. Shows, K. Waggie, A. Burich, W. Zeng, S. Escobar, P. Morrissey and J. L. Viney: Helicobacter bilis infection accelerates and H. hepaticus infection delays the development of colitis in multiple drug resistance-deficient (mdr1a-/-) mice. Am J Pathol, 160(2), 739-751 (2002)
doi:10.1016/S0002-9440(10)64894-8
47. J. N. Wilk, J. Bilsborough and J. L. Viney: The mdr1a-/- mouse model of spontaneous colitis: a relevant and appropriate animal model to study inflammatory bowel disease. Immunol Res, 31(2), 151-159 (2005)
doi:10.1385/IR:31:2:151
48. M. Schwab, E. Schaeffeler, C. Marx, M. F. Fromm, B. Kaskas, J. Metzler, E. Stange, H. Herfarth, J. Schoelmerich, M. Gregor, S. Walker, I. Cascorbi, I. Roots, U. Brinkmann, U. M. Zanger and M. Eichelbaum: Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology, 124(1), 26-33 (2003)
doi:10.1053/gast.2003.50010
PMid:12512026
49. C. E. Hornquist, X. Lu, P. M. Rogers-Fani, U. Rudolph, S. Shappell, L. Birnbaumer and G. R. Harriman: G(alpha)i2-deficient mice with colitis exhibit a local increase in memory CD4+ T cells and proinflammatory Th1-type cytokines. J Immunol, 158(3), 1068-1077 (1997)
PMid:9013944
50. U. Rudolph, M. J. Finegold, S. S. Rich, G. R. Harriman, Y. Srinivasan, P. Brabet, G. Boulay, A. Bradley and L. Birnbaumer: Ulcerative colitis and adenocarcinoma of the colon in G alpha i2-deficient mice. Nat Genet, 10(2), 143-150 (1995)
doi:10.1038/ng0695-143
PMid:7663509
51. M. L. Hermiston and J. I. Gordon: Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science, 270(5239), 1203-1207 (1995)
doi:10.1126/science.270.5239.1203
PMid:7502046
52. I. Okayasu, S. Hatakeyama, M. Yamada, T. Ohkusa, Y. Inagaki and R. Nakaya: A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology, 98(3), 694-702 (1990)
PMid:1688816
53. L. A. Dieleman, B. U. Ridwan, G. S. Tennyson, K. W. Beagley, R. P. Bucy and C. O. Elson: Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology, 107(6), 1643-1652 (1994)
PMid:7958674
54. S. Kitajima, M. Morimoto, E. Sagara, C. Shimizu and Y. Ikeda: Dextran sodium sulfate-induced colitis in germ-free IQI/Jic mice. Exp Anim, 50(5), 387-395 (2001)
doi:10.1538/expanim.50.387
PMid:11769541
55. K. M. Maslowski, A. T. Vieira, A. Ng, J. Kranich, F. Sierro, D. Yu, H. C. Schilter, M. S. Rolph, F. Mackay, D. Artis, R. J. Xavier, M. M. Teixeira and C. R. Mackay: Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature, 461(7268), 1282-1286 (2009)
doi:10.1038/nature08530
PMid:19865172
56. M. F. Neurath, I. Fuss, B. L. Kelsall, E. Stuber and W. Strober: Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med, 182(5), 1281-1290 (1995)
doi:10.1084/jem.182.5.1281
PMid:7595199
57. M. Van der Sluis, B. A. De Koning, A. C. De Bruijn, A. Velcich, J. P. Meijerink, J. B. Van Goudoever, H. A. Buller, J. Dekker, I. Van Seuningen, I. B. Renes and A. W. Einerhand: Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology, 131(1), 117-129 (2006)
doi:10.1053/j.gastro.2006.04.020
PMid:16831596
58. K. S. Bergstrom, V. Kissoon-Singh, D. L. Gibson, C. Ma, M. Montero, H. P. Sham, N. Ryz, T. Huang, A. Velcich, B. B. Finlay, K. Chadee and B. A. Vallance: Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog, 6(5), e1000902 (2010)
doi:10.1371/journal.ppat.1000902
PMid:20485566 PMCid:2869315
59. A. Velcich, W. Yang, J. Heyer, A. Fragale, C. Nicholas, S. Viani, R. Kucherlapati, M. Lipkin, K. Yang and L. Augenlicht: Colorectal cancer in mice genetically deficient in the mucin Muc2. Science, 295(5560), 1726-1729 (2002)
doi:10.1126/science.1069094
PMid:11872843
60. K. M. Tytgat, F. J. Opdam, A. W. Einerhand, H. A. Buller and J. Dekker: MUC2 is the prominent colonic mucin expressed in ulcerative colitis. Gut, 38(4), 554-563 (1996)
doi:10.1136/gut.38.4.554
PMid:8707087 PMCid:1383114
61. D. K. Podolsky and K. J. Isselbacher: Glycoprotein composition of colonic mucosa. Specific alterations in ulcerative colitis. Gastroenterology, 87(5), 991-998 (1984)
PMid:6090262
62. D. K. Podolsky and K. J. Isselbacher: Composition of human colonic mucin. Selective alteration in inflammatory bowel disease. J Clin Invest, 72(1), 142-153 (1983)
doi:10.1172/JCI110952
PMid:6192143 PMCid:1129169
63. J. E. Smithson, A. Campbell, J. M. Andrews, J. D. Milton, R. Pigott and D. P. Jewell: Altered expression of mucins throughout the colon in ulcerative colitis. Gut, 40(2), 234-240 (1997)
PMid:9071938 PMCid:1027055
64. P. Alex, M. Ye, N. C. Zachos, J. Sipes, T. Nguyen, M. Suhodrev, L. Gonzales, Z. Arora, T. Zhang, M. Centola, S. E. Guggino and X. Li: Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium-induced colitis. J Immunol, 184(7), 3988-3996 (2010)
doi:10.4049/jimmunol.0901657
PMid:20181886
65. S. Sullivan, P. Alex, T. Dassopoulos, N. C. Zachos, C. Iacobuzio-Donahue, M. Donowitz, S. R. Brant, C. Cuffari, M. L. Harris, L. W. Datta, L. Conklin, Y. Chen and X. Li: Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: potential contributors to IBD-associated diarrhea. Inflamm Bowel Dis, 15(2), 261-274 (2009)
doi:10.1002/ibd.20743
PMid:18942765 PMCid:2627787
66. H. Baribault, J. Penner, R. V. Iozzo and M. Wilson-Heiner: Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice. Genes Dev, 8(24), 2964-2973 (1994)
doi:10.1101/gad.8.24.2964
67. A. Habtezion, D. M. Toivola, E. C. Butcher and M. B. Omary: Keratin-8-deficient mice develop chronic spontaneous Th2 colitis amenable to antibiotic treatment. J Cell Sci, 118(Pt 9), 1971-1980 (2005)
doi:10.1242/jcs.02316
PMid:15840656
68. G. Z. Tao, P. Strnad, Q. Zhou, A. Kamal, L. Zhang, N. D. Madani, S. Kugathasan, S. R. Brant, J. H. Cho, M. B. Omary and R. H. Duerr: Analysis of keratin polypeptides 8 and 19 variants in inflammatory bowel disease. Clin Gastroenterol Hepatol, 5(7), 857-864 (2007)
doi:10.1016/j.cgh.2007.02.017
PMid:17509943
69. K. Takeda, B. E. Clausen, T. Kaisho, T. Tsujimura, N. Terada, I. Forster and S. Akira: Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity, 10(1), 39-49 (1999)
doi:10.1016/S1074-7613(00)80005-9
70. M. Kobayashi, M. N. Kweon, H. Kuwata, R. D. Schreiber, H. Kiyono, K. Takeda and S. Akira: Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. J Clin Invest, 111(9), 1297-1308 (2003)
PMid:12727921 PMCid:154445
71. E. G. Lee, D. L. Boone, S. Chai, S. L. Libby, M. Chien, J. P. Lodolce and A. Ma: Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science, 289(5488), 2350-2354 (2000)
doi:10.1126/science.289.5488.2350
PMid:11009421
72. M. Weng, W. A. Walker and I. R. Sanderson: Butyrate regulates the expression of pathogen-triggered IL-8 in intestinal epithelia. Pediatr Res, 62(5), 542-546 (2007)
doi:10.1203/PDR.0b013e318155a422
PMid:17805211
73. W. S. Garrett, G. M. Lord, S. Punit, G. Lugo-Villarino, S. K. Mazmanian, S. Ito, J. N. Glickman and L. H. Glimcher: Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell, 131(1), 33-45 (2007)
doi:10.1016/j.cell.2007.08.017
PMid:17923086 PMCid:2169385
74. M. Vijay-Kumar, C. J. Sanders, R. T. Taylor, A. Kumar, J. D. Aitken, S. V. Sitaraman, A. S. Neish, S. Uematsu, S. Akira, I. R. Williams and A. T. Gewirtz: Deletion of TLR5 results in spontaneous colitis in mice. J Clin Invest, 117(12), 3909-3921 (2007)
PMid:18008007 PMCid:2075480
75. A. T. Gewirtz, M. Vijay-Kumar, S. R. Brant, R. H. Duerr, D. L. Nicolae and J. H. Cho: Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease. Am J Physiol Gastrointest Liver Physiol, 290(6), G1157-1163 (2006)
76. A. L. Pauleau and P. J. Murray: Role of Nod2 in the response of macrophages to toll-like receptor agonists. Mol Cell Biol, 23(21), 7531-7539 (2003)
doi:10.1128/MCB.23.21.7531-7539.2003
PMid:14560001 PMCid:207570
77. T. Watanabe, A. Kitani, P. Murray and W. Strober: NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type-1 responses. Nature Immunology, 5, 800-808 (2004)
doi:10.1038/ni1092
PMid:15220916
78. T. Watanabe, A. Kitani, P. J. Murray, Y. Wakatsuki, I. J. Fuss and W. Strober: Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis. Immunity, 25(3), 473-485 (2006)
doi:10.1016/j.immuni.2006.06.018
PMid:16949315
79. K. S. Kobayashi, M. Chamaillard, Y. Ogura, O. Henegariu, N. Inohara, G. Nunez and R. A. Flavell: Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science, 307(5710), 731-734 (2005)
doi:10.1126/science.1104911
PMid:15692051
80. T. Petnicki-Ocwieja, T. Hrncir, Y. J. Liu, A. Biswas, T. Hudcovic, H. Tlaskalova-Hogenova and K. S. Kobayashi: Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci U S A, 106(37), 15813-15818 (2009)
doi:10.1073/pnas.0907722106
PMid:19805227 PMCid:2747201
81. S. Maeda, L. C. Hsu, H. Liu, L. A. Bankston, M. Iimura, M. F. Kagnoff, L. Eckmann and M. Karin: Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing. Science, 307(5710), 734-738 (2005)
doi:10.1126/science.1103685
PMid:15692052
82. R. E. Hammer, S. D. Maika, J. A. Richardson, J. P. Tang and J. D. Taurog: Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell, 63(5), 1099-1112 (1990)
doi:10.1016/0092-8674(90)90512-D
83. H. C. Rath, H. H. Herfarth, J. S. Ikeda, W. B. Grenther, T. E. Hamm, Jr., E. Balish, J. D. Taurog, R. E. Hammer, K. H. Wilson and R. B. Sartor: Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. J Clin Invest, 98(4), 945-953 (1996)
doi:10.1172/JCI118878
PMid:8770866 PMCid:507509
84. H. C. Rath, M. Schultz, R. Freitag, L. A. Dieleman, F. Li, H. J. Linde, J. Scholmerich and R. B. Sartor: Different subsets of enteric bacteria induce and perpetuate experimental colitis in rats and mice. Infect Immun, 69(4), 2277-2285 (2001)
doi:10.1128/IAI.69.4.2277-2285.2001
PMid:11254584 PMCid:98156
85. T. R. Orchard, H. Holt, L. Bradbury, J. Hammersma, E. McNally, D. P. Jewell and B. P. Wordsworth: The prevalence, clinical features and association of HLA-B27 in sacroiliitis associated with established Crohn's disease. Aliment Pharmacol Ther, 29(2), 193-197 (2009)
doi:10.1111/j.1365-2036.2008.03868.x
86. S. Steer, H. Jones, J. Hibbert, E. Kondeatis, R. Vaughan, J. Sanderson and T. Gibson: Low back pain, sacroiliitis, and the relationship with HLA-B27 in Crohn's disease. J Rheumatol, 30(3), 518-522 (2003)
PMid:12610811
87. D. Kontoyiannis, G. Boulougouris, M. Manoloukos, M. Armaka, M. Apostolaki, T. Pizarro, A. Kotlyarov, I. Forster, R. Flavell, M. Gaestel, P. Tsichlis, F. Cominelli and G. Kollias: Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease. J Exp Med, 196(12), 1563-1574 (2002)
doi:10.1084/jem.20020281
PMid:12486099 PMCid:2196068
88. D. Kontoyiannis, M. Pasparakis, T. T. Pizarro, F. Cominelli and G. Kollias: Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity, 10(3), 387-398 (1999)
doi:10.1016/S1074-7613(00)80038-2
89. M. Watanabe, Y. Ueno, T. Yajima, S. Okamoto, T. Hayashi, M. Yamazaki, Y. Iwao, H. Ishii, S. Habu, M. Uehira, H. Nishimoto, H. Ishikawa, J. Hata and T. Hibi: Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa. J Exp Med, 187(3), 389-402 (1998)
doi:10.1084/jem.187.3.389
PMid:9449719 PMCid:2212121
90. Y. Nemoto, T. Kanai, K. Kameyama, T. Shinohara, N. Sakamoto, T. Totsuka, R. Okamoto, K. Tsuchiya, T. Nakamura, T. Sudo, S. Matsumoto and M. Watanabe: Long-lived colitogenic CD4+ memory T cells residing outside the intestine participate in the perpetuation of chronic colitis. J Immunol, 183(8), 5059-5068 (2009)
doi:10.4049/jimmunol.0803684
PMid:19786550
91. C. A. Anderson, G. Boucher, C. W. Lees, A. Franke, M. D'Amato, K. D. Taylor, J. C. Lee, P. Goyette, M. Imielinski, A. Latiano, C. Lagace, R. Scott, L. Amininejad, S. Bumpstead, L. Baidoo, R. N. Baldassano, M. Barclay, T. M. Bayless, S. Brand, C. Buning, J. F. Colombel, L. A. Denson, M. De Vos, M. Dubinsky, C. Edwards, D. Ellinghaus, R. S. Fehrmann, J. A. Floyd, T. Florin, D. Franchimont, L. Franke, M. Georges, J. Glas, N. L. Glazer, S. L. Guthery, T. Haritunians, N. K. Hayward, J. P. Hugot, G. Jobin, D. Laukens, I. Lawrance, M. Lemann, A. Levine, C. Libioulle, E. Louis, D. P. McGovern, M. Milla, G. W. Montgomery, K. I. Morley, C. Mowat, A. Ng, W. Newman, R. A. Ophoff, L. Papi, O. Palmieri, L. Peyrin-Biroulet, J. Panes, A. Phillips, N. J. Prescott, D. D. Proctor, R. Roberts, R. Russell, P. Rutgeerts, J. Sanderson, M. Sans, P. Schumm, F. Seibold, Y. Sharma, L. A. Simms, M. Seielstad, A. H. Steinhart, S. R. Targan, L. H. van den Berg, M. Vatn, H. Verspaget, T. Walters, C. Wijmenga, D. C. Wilson, H. J. Westra, R. J. Xavier, Z. Z. Zhao, C. Y. Ponsioen, V. Andersen, L. Torkvist, M. Gazouli, N. P. Anagnou, T. H. Karlsen, L. Kupcinskas, J. Sventoraityte, J. C. Mansfield, S. Kugathasan, M. S. Silverberg, J. Halfvarson, J. I. Rotter, C. G. Mathew, A. M. Griffiths, R. Gearry, T. Ahmad, S. R. Brant, M. Chamaillard, J. Satsangi, J. H. Cho, S. Schreiber, M. J. Daly, J. C. Barrett, M. Parkes, V. Annese, H. Hakonarson, G. Radford-Smith, R. H. Duerr, S. Vermeire, R. K. Weersma and J. D. Rioux: Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet, 43(3), 246-252 (2011)
doi:10.1038/ng.764
PMid:21297633
92. M. M. Shull, I. Ormsby, A. B. Kier, S. Pawlowski, R. J. Diebold, M. Yin, R. Allen, C. Sidman, G. Proetzel, D. Calvin and et al.: Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature, 359(6397), 693-699 (1992)
doi:10.1038/359693a0
PMid:1436033
93. S. J. Engle, I. Ormsby, S. Pawlowski, G. P. Boivin, J. Croft, E. Balish and T. Doetschman: Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. Cancer Res, 62(22), 6362-6366 (2002)
PMid:12438215
94. A. Di Sabatino, K. M. Pickard, D. Rampton, L. Kruidenier, L. Rovedatti, N. A. Leakey, G. R. Corazza, G. Monteleone and T. T. MacDonald: Blockade of transforming growth factor beta upregulates T-box transcription factor T-bet, and increases T helper cell type 1 cytokine and matrix metalloproteinase-3 production in the human gut mucosa. Gut, 57(5), 605-612 (2008)
doi:10.1136/gut.2007.130922
PMid:18178611
95. G. Monteleone, M. Boirivant, F. Pallone and T. T. MacDonald: TGF-beta1 and Smad7 in the regulation of IBD. Mucosal Immunol, 1 Suppl 1, S50-53 (2008)
doi:10.1038/mi.2008.55
PMid:19079231
96. L. Gorelik and R. A. Flavell: Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity, 12(2), 171-181 (2000)
doi:10.1016/S1074-7613(00)80170-3
97. L. Fahlen, S. Read, L. Gorelik, S. D. Hurst, R. L. Coffman, R. A. Flavell and F. Powrie: T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med, 201(5), 737-746 (2005)
doi:10.1084/jem.20040685
PMid:15753207 PMCid:2212836
98. K. B. Hahm, Y. H. Im, T. W. Parks, S. H. Park, S. Markowitz, H. Y. Jung, J. Green and S. J. Kim: Loss of transforming growth factor beta signalling in the intestine contributes to tissue injury in inflammatory bowel disease. Gut, 49(2), 190-198 (2001)
doi:10.1136/gut.49.2.190
PMid:11454793 PMCid:1728415
99. R. Kuhn, J. Lohler, D. Rennick, K. Rajewsky and W. Muller: Interleukin-10-deficient mice develop chronic enterocolitis. Cell, 75(2), 263-274 (1993)
doi:10.1016/0092-8674(93)80068-P
100. K. L. Madsen, J. S. Doyle, M. M. Tavernini, L. D. Jewell, R. P. Rennie and R. N. Fedorak: Antibiotic therapy attenuates colitis in interleukin 10 gene-deficient mice. Gastroenterology, 118(6), 1094-1105 (2000)
doi:10.1016/S0016-5085(00)70362-3
101. R. K. Sellon, S. Tonkonogy, M. Schultz, L. A. Dieleman, W. Grenther, E. Balish, D. M. Rennick and R. B. Sartor: Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun, 66(11), 5224-5231 (1998)
PMid:9784526 PMCid:108652
102. S. Rakoff-Nahoum, L. Hao and R. Medzhitov: Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity, 25(2), 319-329 (2006)
doi:10.1016/j.immuni.2006.06.010
PMid:16879997
103. I. Correa, M. Veny, M. Esteller, J. M. Pique, J. Yague, J. Panes and A. Salas: Defective IL-10 production in severe phenotypes of Crohn's disease. J Leukoc Biol, 85(5), 896-903 (2009)
doi:10.1189/jlb.1108698
PMid:19237638
104. S. Schreiber, T. Heinig, H. G. Thiele and A. Raedler: Immunoregulatory role of interleukin 10 in patients with inflammatory bowel disease. Gastroenterology, 108(5), 1434-1444 (1995)
doi:10.1016/0016-5085(95)90692-4
105. A. Franke, T. Balschun, T. H. Karlsen, J. Sventoraityte, S. Nikolaus, G. Mayr, F. S. Domingues, M. Albrecht, M. Nothnagel, D. Ellinghaus, C. Sina, C. M. Onnie, R. K. Weersma, P. C. Stokkers, C. Wijmenga, M. Gazouli, D. Strachan, W. L. McArdle, S. Vermeire, P. Rutgeerts, P. Rosenstiel, M. Krawczak, M. H. Vatn, C. G. Mathew and S. Schreiber: Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet, 40(11), 1319-1323 (2008)
doi:10.1038/ng.221
PMid:18836448
106. V. Andersen, A. Ernst, J. Christensen, M. Ostergaard, B. A. Jacobsen, A. Tjonneland, H. B. Krarup and U. Vogel: The polymorphism rs3024505 proximal to IL-10 is associated with risk of ulcerative colitis and Crohns disease in a Danish case-control study. BMC Med Genet, 11, 82 (2010)
doi:10.1186/1471-2350-11-82
PMid:20509889 PMCid:2891714
107. A. Franke, D. P. McGovern, J. C. Barrett, K. Wang, G. L. Radford-Smith, T. Ahmad, C. W. Lees, T. Balschun, J. Lee, R. Roberts, C. A. Anderson, J. C. Bis, S. Bumpstead, D. Ellinghaus, E. M. Festen, M. Georges, T. Green, T. Haritunians, L. Jostins, A. Latiano, C. G. Mathew, G. W. Montgomery, N. J. Prescott, S. Raychaudhuri, J. I. Rotter, P. Schumm, Y. Sharma, L. A. Simms, K. D. Taylor, D. Whiteman, C. Wijmenga, R. N. Baldassano, M. Barclay, T. M. Bayless, S. Brand, C. Buning, A. Cohen, J. F. Colombel, M. Cottone, L. Stronati, T. Denson, M. De Vos, R. D'Inca, M. Dubinsky, C. Edwards, T. Florin, D. Franchimont, R. Gearry, J. Glas, A. Van Gossum, S. L. Guthery, J. Halfvarson, H. W. Verspaget, J. P. Hugot, A. Karban, D. Laukens, I. Lawrance, M. Lemann, A. Levine, C. Libioulle, E. Louis, C. Mowat, W. Newman, J. Panes, A. Phillips, D. D. Proctor, M. Regueiro, R. Russell, P. Rutgeerts, J. Sanderson, M. Sans, F. Seibold, A. H. Steinhart, P. C. Stokkers, L. Torkvist, G. Kullak-Ublick, D. Wilson, T. Walters, S. R. Targan, S. R. Brant, J. D. Rioux, M. D'Amato, R. K. Weersma, S. Kugathasan, A. M. Griffiths, J. C. Mansfield, S. Vermeire, R. H. Duerr, M. S. Silverberg, J. Satsangi, S. Schreiber, J. H. Cho, V. Annese, H. Hakonarson, M. J. Daly and M. Parkes: Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet, 42(12), 1118-1125 (2010)
doi:10.1038/ng.717
PMid:21102463
108. E. O. Glocker, D. Kotlarz, K. Boztug, E. M. Gertz, A. A. Schaffer, F. Noyan, M. Perro, J. Diestelhorst, A. Allroth, D. Murugan, N. Hatscher, D. Pfeifer, K. W. Sykora, M. Sauer, H. Kreipe, M. Lacher, R. Nustede, C. Woellner, U. Baumann, U. Salzer, S. Koletzko, N. Shah, A. W. Segal, A. Sauerbrey, S. Buderus, S. B. Snapper, B. Grimbacher and C. Klein: Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med, 361(21), 2033-2045 (2009)
doi:10.1056/NEJMoa0907206
PMid:19890111 PMCid:2787406
109. B. Sadlack, H. Merz, H. Schorle, A. Schimpl, A. C. Feller and I. Horak: Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell, 75(2), 253-261 (1993)
doi:10.1016/0092-8674(93)80067-O
110. N. V. Contractor, H. Bassiri, T. Reya, A. Y. Park, D. C. Baumgart, M. A. Wasik, S. G. Emerson and S. R. Carding: Lymphoid hyperplasia, autoimmunity, and compromised intestinal intraepithelial lymphocyte development in colitis-free gnotobiotic IL-2-deficient mice. J Immunol, 160(1), 385-394 (1998)
PMid:9551995
111. M. Schultz, S. L. Tonkonogy, R. K. Sellon, C. Veltkamp, V. L. Godfrey, J. Kwon, W. B. Grenther, E. Balish, I. Horak and R. B. Sartor: IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation. Am J Physiol, 276(6 Pt 1), G1461-1472 (1999)
112. D. M. Willerford, J. Chen, J. A. Ferry, L. Davidson, A. Ma and F. W. Alt: Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity, 3(4), 521-530 (1995)
doi:10.1016/1074-7613(95)90180-9
113. S. Erdman, J. G. Fox, C. A. Dangler, D. Feldman and B. H. Horwitz: Typhlocolitis in NF-kappa B-deficient mice. J Immunol, 166(3), 1443-1447 (2001)
PMid:11160181
114. I. Atreya, R. Atreya and M. F. Neurath: NF-kappaB in inflammatory bowel disease. J Intern Med, 263(6), 591-596 (2008)
doi:10.1111/j.1365-2796.2008.01953.x
PMid:18479258
115. C. H. Clegg, J. T. Rulffes, H. S. Haugen, I. H. Hoggatt, A. Aruffo, S. K. Durham, A. G. Farr and D. Hollenbaugh: Thymus dysfunction and chronic inflammatory disease in gp39 transgenic mice. Int Immunol, 9(8), 1111-1122 (1997)
doi:10.1093/intimm/9.8.1111
PMid:9263008
116. O. Ludwiczek, A. Kaser and H. Tilg: Plasma levels of soluble CD40 ligand are elevated in inflammatory bowel diseases. Int J Colorectal Dis, 18(2), 142-147 (2003)
PMid:12548417
117. P. Mombaerts, E. Mizoguchi, M. J. Grusby, L. H. Glimcher, A. K. Bhan and S. Tonegawa: Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell, 75(2), 274-282 (1993)
PMid:8104709
118. A. K. Bhan, E. Mizoguchi, R. N. Smith and A. Mizoguchi: Spontaneous chronic colitis in TCR alpha-mutant mice; an experimental model of human ulcerative colitis. Int Rev Immunol, 19(1), 123-138 (2000)
doi:10.3109/08830180009048393
PMid:10723681
119. L. Dianda, A. M. Hanby, N. A. Wright, A. Sebesteny, A. C. Hayday and M. J. Owen: T cell receptor-alpha beta-deficient mice fail to develop colitis in the absence of a microbial environment. Am J Pathol, 150(1), 91-97 (1997)
PMid:9006326 PMCid:1858528
120. G. A. Hollander, S. J. Simpson, E. Mizoguchi, A. Nichogiannopoulou, J. She, J. C. Gutierrez-Ramos, A. K. Bhan, S. J. Burakoff, B. Wang and C. Terhorst: Severe colitis in mice with aberrant thymic selection. Immunity, 3(1), 27-38 (1995)
doi:10.1016/1074-7613(95)90156-6
121. C. Veltkamp, S. L. Tonkonogy, Y. P. De Jong, C. Albright, W. B. Grenther, E. Balish, C. Terhorst and R. B. Sartor: Continuous stimulation by normal luminal bacteria is essential for the development and perpetuation of colitis in Tg(epsilon26) mice. Gastroenterology, 120(4), 900-913 (2001))
doi:10.1053/gast.2001.22547
PMid:11231944
122. S. Wirtz, S. Finotto, S. Kanzler, A. W. Lohse, M. Blessing, H. A. Lehr, P. R. Galle and M. F. Neurath: Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens. J Immunol, 162(4), 1884-1888 (1999)
PMid:9973454
123. F. Powrie, M. W. Leach, S. Mauze, L. B. Caddle and R. L. Coffman: Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol, 5(11), 1461-1471 (1993)
doi:10.1093/intimm/5.11.1461
PMid:7903159
124. M. Boirivant, I. J. Fuss, A. Chu and W. Strober: Oxazolone colitis: A murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J Exp Med, 188(10), 1929-1939 (1998)
doi:10.1084/jem.188.10.1929
PMid:9815270 PMCid:2212414
125. S. B. Snapper, F. S. Rosen, E. Mizoguchi, P. Cohen, W. Khan, C. H. Liu, T. L. Hagemann, S. P. Kwan, R. Ferrini, L. Davidson, A. K. Bhan and F. W. Alt: Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Immunity, 9(1), 81-91 (1998)
doi:10.1016/S1074-7613(00)80590-7
126. D. D. Nguyen, M. H. Maillard, V. Cotta-de-Almeida, E. Mizoguchi, C. Klein, I. Fuss, C. Nagler, A. Mizoguchi, A. K. Bhan and S. B. Snapper: Lymphocyte-dependent and Th2 cytokine-associated colitis in mice deficient in Wiskott-Aldrich syndrome protein. Gastroenterology, 133(4), 1188-1197 (2007)
doi:10.1053/j.gastro.2007.07.010
PMid:17764675 PMCid:2048975
127. M. H. Maillard, V. Cotta-de-Almeida, F. Takeshima, D. D. Nguyen, P. Michetti, C. Nagler, A. K. Bhan and S. B. Snapper: The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells. J Exp Med, 204(2), 381-391 (2007)
doi:10.1084/jem.20061338
PMid:17296786 PMCid:2118715
128. S. Humblet-Baron, B. Sather, S. Anover, S. Becker-Herman, D. J. Kasprowicz, S. Khim, T. Nguyen, K. Hudkins-Loya, C. E. Alpers, S. F. Ziegler, H. Ochs, T. Torgerson, D. J. Campbell and D. J. Rawlings: Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis. J Clin Invest, 117(2), 407-418 (2007)
doi:10.1172/JCI29539
PMid:17218989 PMCid:1764857
129. D. D. Nguyen, M. A. Eston, S. Muthupalani, M. W. Mobley, N. S. Taylor, S. B. Snapper and J. B. Fox: T1792 Helicobacter is Required for Colitis in WASP-Deficient Mice and Induces Colon Cancer. Gastroenterology, 138(5), S-579-S-578 (2010)
doi:10.1016/S0016-5085(10)62670-4
130. K. H. Hsieh, M. H. Chang, C. Y. Lee and C. Y. Wang: Wiskott-Aldrich syndrome and inflammatory bowel disease. Ann Allergy, 60(5), 429-431 (1988)
PMid:3369753
131. C. Folwaczny, C. Ruelfs, J. Walther, A. Konig and B. Emmerich: Ulcerative colitis in a patient with Wiskott-Aldrich syndrome. Endoscopy, 34(10), 840-841 (2002)
doi:10.1055/s-2002-34272
PMid:12244510
132. G. Kim, O. Turovskaya, M. Levin, F. R. Byrne, J. S. Whoriskey, J. G. McCabe and M. Kronenberg: Spontaneous colitis occurrence in transgenic mice with altered B7-mediated costimulation. J Immunol, 181(8), 5278-5288 (2008)
PMid:18832683 PMCid:2673332
133. G. Q. Phan, J. C. Yang, R. M. Sherry, P. Hwu, S. L. Topalian, D. J. Schwartzentruber, N. P. Restifo, L. R. Haworth, C. A. Seipp, L. J. Freezer, K. E. Morton, S. A. Mavroukakis, P. H. Duray, S. M. Steinberg, J. P. Allison, T. A. Davis and S. A. Rosenberg: Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A, 100(14), 8372-8377 (2003)
doi:10.1073/pnas.1533209100
PMid:12826605 PMCid:166236
134. J. P. Sundberg, C. O. Elson, H. Bedigian and E. H. Birkenmeier: Spontaneous, heritable colitis in a new substrain of C3H/HeJ mice. Gastroenterology, 107(6), 1726-1735 (1994)
PMid:7958684
135. Y. Cong, S. L. Brandwein, R. P. McCabe, A. Lazenby, E. H. Birkenmeier, J. P. Sundberg and C. O. Elson: CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease. J Exp Med, 187(6), 855-864 (1998)
doi:10.1084/jem.187.6.855
PMid:9500788 PMCid:2212186
136. S. L. Brandwein, R. P. McCabe, Y. Cong, K. B. Waites, B. U. Ridwan, P. A. Dean, T. Ohkusa, E. H. Birkenmeier, J. P. Sundberg and C. O. Elson: Spontaneously colitic C3H/HeJBir mice demonstrate selective antibody reactivity to antigens of the enteric bacterial flora. J Immunol, 159(1), 44-52 (1997)
PMid:9200437
137. H. R. Gaskins, G. L. Vondrak-Juergens, B. A. McCracken and J. H. Woolsey: Specific-pathogen-free conditions enhance inflammatory bowel disease in T-cell receptor knockout, but not C3H/HeJBir mice. Lab Anim Sci, 47(6), 650-655 (1997)
PMid:9433703
138. S. Matsumoto, Y. Okabe, H. Setoyama, K. Takayama, J. Ohtsuka, H. Funahashi, A. Imaoka, Y. Okada and Y. Umesaki: Inflammatory bowel disease-like enteritis and caecitis in a senescence accelerated mouse P1/Yit strain. Gut, 43(1), 71-78 (1998)
doi:10.1136/gut.43.1.71
PMid:9771408 PMCid:1727165
139. M. M. Kosiewicz, C. C. Nast, A. Krishnan, J. Rivera-Nieves, C. A. Moskaluk, S. Matsumoto, K. Kozaiwa and F. Cominelli: Th1-type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease. J Clin Invest, 107(6), 695-702 (2001)
doi:10.1172/JCI10956
PMid:11254669 PMCid:208944
140. K. Sugawara, T. S. Olson, C. A. Moskaluk, B. K. Stevens, S. Hoang, K. Kozaiwa, F. Cominelli, K. F. Ley and M. McDuffie: Linkage to peroxisome proliferator-activated receptor-gamma in SAMP1/YitFc mice and in human Crohn's disease. Gastroenterology, 128(2), 351-360 (2005)
doi:10.1053/j.gastro.2004.11.001
PMid:15685547
Key Words: Commensal Microflora, Host-Microbial Mutualism, Innate Immunity, Adaptive Immunity, Compartmentalization, Iga, Mucosal Immune System, Germ-Free, Anti-Commensal Immunity, Review
Send correspondence to: Kathy D. McCoy, Department of Clinical Research, Room C817, Murtenstrasse 35, 3010 Bern, Switzerland, Tel: 41 31 632 0931, Fax: 41 31 632 32 97, E-mail:mccoy@dkf.unibe.ch