Immunology_Janeway

Immunology_Janeway. Fig. 12.15 Epithelial cells have a crucial role in innate defense against pathogens. TLRs are present in intracellular vesicles or on the basolateral or apical surfaces of epithelial cells, where they recognize different components of invading bacteria. Cytoplasmic NOD1 and NOD2 detect cell‑wall peptides from bacteria. TLRs and NODs activate NFκB (see Fig. 3.15), inducing epithelial cells to produce CXCL8, CXCL1 (GROα), CCL1, and CCL2, which attract neutrophils and macrophages, CCL20, which attracts dendritic cells, and IL‑1 and IL‑6 that activate macrophages. Many types of cell damage can activate inflammasome (see Section 3‑9) that activates pro‑caspase 1 and produces IL‑1 and IL‑18. Bacteria that invade the epithelial‑cell cytoplasm or escape into the cytosol from phagosomes can induce autophagy. The organisms become ubiquitinated, leading to the recruitment of adaptor proteins that attract the phagophore, forming an autophagosome. Fusion with lysosomes then leads to destruction of


Immunology_Janeway

Immunology_Janeway. autophagy. The organisms become ubiquitinated, leading to the recruitment of adaptor proteins that attract the phagophore, forming an autophagosome. Fusion with lysosomes then leads to destruction of the cargo within the autophagosome. NOD2 can also trigger autophagosome formation by binding directly to adaptor proteins, including the Crohn’s disease‑associated molecule ATGL16L1.


Immunology_Janeway

Immunology_Janeway. Typhimurium adheres to and enters M cells, which it then kills by causing apoptosis (top left). It then can infect macrophages and gut epithelial cells. TLR‑5 expressed by the epithelial basal membrane can bind salmonella flagellin, activating the NFκB pathway. After uptake by macrophages in the lamina propria, invasive Salmonella induces caspase 1 activation, promoting production of IL‑1 and IL‑8. CXCL8 is also produced by the infected macrophages, and together these mediators recruit and activate neutrophils (lower left panel). Salmonellae can also invade gut epithelial cells directly by adherence of fine threadlike protrusions on the luminal epithelial surface called fimbriae (top middle panel). The cell processes extended between epithelial cells by mononuclear phagocytes may be infected by salmonellae in the lumen and thus effectively breach the epithelial layer (top right panel). Dendritic cells in lamina propria may become infected from infected macrophages and carry them to


Immunology_Janeway

Immunology_Janeway. by salmonellae in the lumen and thus effectively breach the epithelial layer (top right panel). Dendritic cells in lamina propria may become infected from infected macrophages and carry them to the draining mesenteric lymph node to prime the adaptive immune response (lower right panel). If containment processes in the lymph node fail, Salmonella can invade beyond the intestine and its lymphoid tissues and enter the bloodstream to cause systemic infection.


Immunology_Janeway

Immunology_Janeway. Fig. 12.16 Salmonella enterica serovar Typhimurium is an important cause of food poisoning and penetrates the epithelial layer in three ways. Salmonella


Immunology_Janeway

Immunology_Janeway. If defenses fail, salmonellae can enter the bloodstream and cause a systemic infection neutrophil caspase 1 activation IL-18 CXCL8 IL-1˜Chemokines and cytokines produced by macrophages recruit neutrophils out of blood vessels and activate them Dendritic cells loaded with bacterial antigens acquired directly or from macrophages travel to the mesenteric lymph node via afferent lymphatics and provoke an adaptive immune response Salmonellae enter and kill M cells, and then infect macrophages and epithelial cells Salmonellae invade the luminal surface of epithelial cells Salmonellae enter phagocytic cells that are sampling the gut luminal contents M cell TLR-5 gut lumen these cells form a barrier that is normally impermeable to macromolecules and invaders. The constant production of new epithelial cells from stem cells in the crypts also allows the barrier to be repaired rapidly after mechanical damage or loss of cells. Nonetheless, pathogens have acquired mechanisms to gain entry through


Immunology_Janeway

Immunology_Janeway. cells from stem cells in the crypts also allows the barrier to be repaired rapidly after mechanical damage or loss of cells. Nonetheless, pathogens have acquired mechanisms to gain entry through these barriers; some entry mechanisms used by salmonella are shown in Fig. 12.16, and those used by shigella in Fig. 12.17.


Immunology_Janeway

Immunology_Janeway. Epithelial cells also bear TLRs on both their apical and basal surfaces, from which they can sense bacteria in the gut lumen and those that have penetrated across the epithelium. In addition, epithelial cells carry TLRs in intracellular vacuoles that can detect intracellular pathogens or extracellular pathogens and their products that have been internalized by endocytosis. Epithelial cells also have intracellular sensors, described in Chapter 3, and can react when microorganisms or their products enter the cytoplasm. These sensors include the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 (see Section 3-8 and Fig. 3.17). NOD1 recognizes a diaminopimelic acid-containing peptide that is found only in the cell walls of Gram-negative bacteria. NOD2 recognizes a muramyl dipeptide found in the peptidoglycans of most bacteria, and epithelial cells defective in NOD2 are less resistant to infection by intracellular bacteria. Mice lacking NOD2 also show increased


Immunology_Janeway

Immunology_Janeway. muramyl dipeptide found in the peptidoglycans of most bacteria, and epithelial cells defective in NOD2 are less resistant to infection by intracellular bacteria. Mice lacking NOD2 also show increased translocation of bacteria across the epithelium and out of Peyer’s patches. A defect in recognition of the commensal microbiota by NOD2 also seems to be important in Crohn’s disease, as up to 25% of patients carry a mutation in the NOD2 gene that renders the NOD2 protein nonfunctional.


Immunology_Janeway

Immunology_Janeway. Shigella cell-wall peptides bind and oligomerize NOD1, activating the NF˜B pathway RIPK2 I˜K I˜B NF˜B NOD1 Ligation of TLRs or NOD proteins in epithelial cells stimulates the production of cytokines, such as IL-1 and IL-6, and the production of chemokines. The chemokines include CXCL8, which is a potent neutrophil chemoattractant, and CCL2, CCL3, CCL4, and CCL5, which attract monocytes, eosinophils, and T cells out of the blood. Stimulated epithelial cells also increase their production of the chemokine CCL20, which attracts immature dendritic cells toward the epithelial surface (see Sections 12-4 and 12-7).


Immunology_Janeway

Immunology_Janeway. Epithelial cells also express members of the intracellular NOD-like receptor (NLR) family, including gNLRP3, NLRC4, and NLRP6, that can form inflammasomes (see Fig. 12.15). As described in Section 3-9, formation of an inflammasome leads to activation of caspase 1, which cleaves pro-IL-1 and pro-IL-18 to produce the active cytokines (see Fig. 3.19). Both these cytokines contribute to epithelial defense against bacterial invasion by promoting barrier integrity, but can cause tissue damage if present for long periods.


Immunology_Janeway

Immunology_Janeway. One mechanism recently recognized as important for epithelial defense against infection is autophagy, which we discussed in Section 6-6 for its relationship to antigen processing. In this process, a crescent-shaped double-membrane fragment in the cytoplasm, called the isolation membrane, or phagophore, engulfs various cytoplasmic contents to form a complete vesicle, the autophagosome, which fuses with lysosomes to degrade the contents (see Fig. 12.15). When autophagy is disrupted, bacteria cannot be contained effectively, and epithelial cells become stressed. This can lead to increased penetration of bacteria into the body and to NFκB-mediated inflammation. Autophagy is promoted by the NOD1 and NOD2 intracellular bacterial sensors. As with NOD2, mutations in the autophagy-related genes ATG16L1 and IRGM1 are associated with susceptibility to Crohn’s disease in humans.


Immunology_Janeway

Immunology_Janeway. Certain specialized populations of epithelial cells have particularly important roles in innate immune defense of the intestine. Paneth cells are found only in the small intestine, where they produce antimicrobial peptides such as RegIIIγ and defensins when exposed to IL-22 released by CD4 TH17 cells or ILC3s. They can also respond directly to microbes, as they express TLRs and NODs and they are highly autophagic. Defects in Paneth cell function lead to reduced bacterial defense and are believed to be important in susceptibility to inflammatory bowel disease in humans. Goblet cells are a further kind of specialized epithelial cell and produce mucus in response to cytokines derived from CD4 TH2 cells or ILC2s. Mucus consists of a complex mixture of highly charged glycoproteins (mucins) and forms an essential component of immune defense in all mucosal surfaces. Its density, charge, and stickiness


Immunology_Janeway

Immunology_Janeway. Fig. 12.17 Shigella flexneri infects intestinal epithelial cells to cause bacterial dysentery. Shigella flexneri binds to M cells and is translocated beneath the gut epithelium (first panel). The bacteria infect intestinal epithelial cells from their basal surface and are released into the cytoplasm (second panel). Muramyl tripeptides containing diaminopimelic acid in the cell walls of the shigellae bind to and oligomerize the protein NOD1. Oligomerized NOD1 binds the serine/threonine kinase RIPK2 and activates the NFκB pathway (see Fig. 3.17), leading to the transcription of genes for chemokines and cytokines (third panel). Activated epithelial cells release the chemokine CXCL8, which acts as a neutrophil chemoattractant (fourth panel). IκB, inhibitor of NFκB; IκK, IκB kinase.


Immunology_Janeway

Immunology_Janeway. mean that it presents a formidable barrier to invasion, by trapping microbes and other particles. At the same time, it acts as a scaffolding to retain IgA antibodies and antimicrobial peptides that have been secreted into the lumen across the epithelium. Mucus is also slippery in nature, meaning that trapped materials can then be expelled easily by normal peristaltic movements. In the intestine, there are two layers of mucus, an outer loose layer and a much denser inner layer, found mostly in the large intestine. Although bacteria can penetrate the loose layer of mucus, they are normally kept away from the surface of the epithelial cells by the inner dense layer, and defects in this structure compromise antimicrobial defense. As we have discussed, the intestinal mucosa is also rich in cells of the innate immune system that can respond rapidly to infection. These include macrophages, eosinophils, mast cells, ILCs, MAIT cells, NKT cells, and γ:δ T cells.


Immunology_Janeway

Immunology_Janeway. 12-16 Pathogens induce adaptive immune responses when innate defenses have been breached.


Immunology_Janeway

Immunology_Janeway. If pathogenic bacteria and viruses gain access to the subepithelial space, they may interact with TLRs on inflammatory cells in the underlying tissue. Together with the cascade of inflammatory mediators released by epithelial cells, this dramatically alters the environment of the mucosa and changes the behavior of local antigen-presenting cells such as dendritic cells. As described in Section 9-8, activated dendritic cells will express high levels of co-stimulatory molecules and cytokines such as IL-1, IL-6, IL-12, and IL-23, and promote development of effector T cells. Dendritic cells activated in Peyer’s patches migrate to the T-cell-dependent areas of the patch, whereas dendritic cells that encounter antigen in the lamina propria migrate to the mesenteric lymph node under control of CCR7. The effector T cells activated in these ways acquire gut-homing molecules such as α4:β7 and CCR9 due to the presence of retinoic acid, ensuring that they return to the gut wall to encounter the


Immunology_Janeway

Immunology_Janeway. CCR7. The effector T cells activated in these ways acquire gut-homing molecules such as α4:β7 and CCR9 due to the presence of retinoic acid, ensuring that they return to the gut wall to encounter the invading organisms. Similarly, IgA-producing B lymphocytes are generated in Peyer’s patches and mesenteric lymph nodes, generating plasma cells that accumulate in the lamina propria. IgA secretion into the lumen is enhanced in response to infection because pIgR expression is enhanced by TLR ligands and pro-inflammatory cytokines. In some infections, IgG antibodies can now be found in intestinal secretions, but these are derived from serum and require invading organisms to reach systemic immune tissues.


Immunology_Janeway

Immunology_Janeway. The activated myeloid cells found in the inflamed mucosa also contribute to sustaining the functions of effector T and B cells after their arrival in the mucosa. IL-1 and IL-6 produced by recently arrived monocytes are important for maintaining the survival and function of local TH17 cells. Pro-inflammatory myeloid cells also produce mediators such as IL-6, TNF-α, and nitric oxide that help drive IgA switching and secondary expansion of mucosal B cells. 12-17 Effector T-cell responses in the intestine protect the function of the epithelium.


Immunology_Janeway

Immunology_Janeway. Once activated, the effector T cells that accumulate in the intestine behave much like their counterparts elsewhere in the body, producing cytokines and generating cytolytic activity as appropriate to the pathogen. What is different is that the aim of the protective immune response in the intestine is tailored to preserving the integrity and function of the epithelial barrier. This is achieved in a number of ways, depending on the nature of the pathogen. In virus infections, CD8 cytotoxic T cells among intraepithelial lymphocytes kill infected epithelial cells (see Fig 12.14), triggering their replacement by uninfected cells derived from the rapidly dividing stem cells in the crypts. A similar process can occur during other forms of protective immune responses, with cytokines from CD4 effector T cells directly stimulating epithelial cell division. This forces the replacement of infected cells and generates a moving target for organisms that are attempting to attach to the surface of


Immunology_Janeway

Immunology_Janeway. T cells directly stimulating epithelial cell division. This forces the replacement of infected cells and generates a moving target for organisms that are attempting to attach to the surface of the epithelium. An example of a cytokine of this kind is IL-13, produced by TH2 cells (and ILC2s) during parasitic infections. In addition to its ability to stimulate antimicrobial peptide production by Paneth cells, IL-22 produced by TH17 cells contributes to defense against extracellular bacteria and fungi by enhancing the tight junctions between epithelial cells that keep the barrier intact. Mucus is crucially important in protecting the epithelial barrier, and its production by goblet cells is enhanced by CD4 T-cell-derived cytokines such as IL-13 and IL-22, as well as by products of mast cells and other innate effector cells recruited by T cells. Finally, these mediators and others can enhance the peristaltic action of the intestine and its outward secretion of fluid, washing out pathogens


Immunology_Janeway

Immunology_Janeway. and other innate effector cells recruited by T cells. Finally, these mediators and others can enhance the peristaltic action of the intestine and its outward secretion of fluid, washing out pathogens within the lumen of the intestine. Together these processes aim to generate a hostile and unstable environment for the pathogen, reducing its ability to invade and damage the epithelial barrier.


Immunology_Janeway

Immunology_Janeway. 12-18 The mucosal immune system must maintain tolerance to harmless foreign antigens.


Immunology_Janeway

Immunology_Janeway. Antigens within food and commensal bacteria normally do not induce an inflammatory immune response, despite the lack of central tolerance to them (Fig. 12.18). The mucosal immune system’s environment is inherently tolerogenic, and this is a barrier to the development of nonliving vaccines, which need to overcome local regulatory mechanisms. Food proteins are not digested completely in the intestine; significant amounts are absorbed into the body in an immunologically relevant form. The default response to oral administration of a protein antigen is the development of a phenomenon known as oral tolerance. This is a form of peripheral tolerance that renders the systemic and mucosal immune systems relatively unresponsive to the same antigen. It can be demonstrated experimentally in mice by feeding them a foreign protein such as ovalbumin (Fig. 12.19). When the animals are then challenged with the antigen by a nonmucosal route, such as injection into the skin, the immune response one


Immunology_Janeway

Immunology_Janeway. by feeding them a foreign protein such as ovalbumin (Fig. 12.19). When the animals are then challenged with the antigen by a nonmucosal route, such as injection into the skin, the immune response one would expect is blunted. This suppression of systemic immune responses is long lasting and is antigen specific: responses to other antigens are not affected. A similar suppression of subsequent immune responses is observed after the administration of proteins into the respiratory tract, giving rise to the concept of mucosal tolerance, as the usual response to such antigens is delivered via a mucosal surface. Systemic T-cell responses can also be inhibited by feeding humans protein antigens that they have not encountered previously.


Immunology_Janeway

Immunology_Janeway. Oral tolerance can impact all aspects of the peripheral immune response, including T-cell-dependent effector responses and IgE production. Effector T-cell responses in the mucosa are also downregulated in oral tolerance, although low levels of secretory IgA antibodies directed at food proteins can be found in healthy humans, but do not lead to inflammation.


Immunology_Janeway

Immunology_Janeway. Various mechanisms are likely to account for oral tolerance to protein antigens, including anergy, deletion of antigen-specific T cells, and the generation of regulatory T cells induced in the mesenteric lymph node to become gut-homing, antigen-specific FoxP3-positive Treg cells via the production of retinoic acid and TGF-β by migratory dendritic cells (see Section 12-7). Although it is known that all these events are also essential for the suppression of systemic immune responses, the mechanisms responsible for this link between the mucosal and peripheral immune system are not yet understood. At times, oral tolerance can fail, as is believed to occur in celiac disease (discussed in more detail in Section 14-17) or peanut allergies (discussed in Sections 14-10 and 14-12).


Immunology_Janeway

Immunology_Janeway. The intestinal immune system generates protective immunity against antigens that are presented during infections by pathogenic organisms. IgA antibodies are produced locally, serum IgG and IgA are made, and the appropriate effector T cells are activated in the intestine and elsewhere. When the antigen is encountered again, there is effective memory, ensuring rapid protection. Antigens from food proteins induce tolerance locally and systemically, with little or no IgA antibody production. T cells are not activated, and subsequent responses to challenge are suppressed. In the case of commensal bacteria, there may be some local IgA production, but no primary systemic antibody responses, and effector T cells are not activated. On day 7, the mice are injected with ovalbumin plus adjuvant to stimulate an effective immune response Mice are fed either ovalbumin or a control mixture


Immunology_Janeway

Immunology_Janeway. On day 7, the mice are injected with ovalbumin plus adjuvant to stimulate an effective immune response Mice are fed either ovalbumin or a control mixture Fig. 12.19 Tolerance to antigens can be experimentally generated by oral administration. Mice are fed for 2 weeks with 25 mg of either ovalbumin, the experimental protein, or a second protein as a control. Seven days later, the mice are immunized subcutaneously with ovalbumin plus an adjuvant, and after 2 weeks, the serum antibodies and T‑cell function are measured. Mice that were fed ovalbumin have a lower ovalbumin‑specific systemic immune response than those fed the control protein. Although mucosal tolerance can be used to avoid inflammatory disease in experimental animal models of type 1 diabetes mellitus, arthritis, and encephalomyelitis, clinical trials in humans have been less successful, and have been superseded by other therapies, such as monoclonal antibodies, that we will discuss in greater detail in Chapter 16.


Immunology_Janeway

Immunology_Janeway. 12-19 The normal intestine contains large quantities of bacteria that are required for health.


Immunology_Janeway

Immunology_Janeway. The surfaces of the healthy body are colonized by large numbers of microorganisms, collectively referred to as the microbiota, or microbiome, composed mostly of bacteria, but also archaea, viruses, fungi, and protozoa . The intestine is the largest source of these organisms, although all the other mucosal tissues harbor their own, distinct populations of microbes. We each harbor more than 1000 species of commensal bacteria in our intestine, and they are present in greatest numbers in the colon and lower ileum. As many of the species cannot be grown in culture, their exact numbers and identities are only now being established by high-throughput sequencing techniques. In humans, there are several major phyla of bacteria, plus the archaea—in descending order, Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Archaea. There are at least 1014 of these microorganisms that collectively weigh about 1 kg. The intestinal microbiota normally exists in a mutually beneficial, or


Immunology_Janeway

Immunology_Janeway. Proteobacteria, Actinobacteria, and Archaea. There are at least 1014 of these microorganisms that collectively weigh about 1 kg. The intestinal microbiota normally exists in a mutually beneficial, or symbiotic, relationship known as mutualism that has been established in humans over many millennia and has coevolved with vertebrates throughout their history. As a result, the populations of these microbes found in different groups of animals are distinctive and are highly adapted to their individual host species.


Immunology_Janeway

Immunology_Janeway. The microbiota has an essential role in maintaining health. Its members assist in the metabolism of dietary constituents such as cellulose, as well as degrade toxins and produce essential cofactors such as vitamin K1. Short-chain fatty acids (SCFAs), such as acetate, propionate, and especially butyrate, produced by anaerobic metabolism of dietary carbohydrates by commensal bacteria are an essential source of energy for colonic enterocytes through their entry as substrates into the tricarboxylic acid (TCA) cycle. Surgical procedures, such as ileostomy, that remove the normal fecal flow to the colon can cause a syndrome called diversion colitis, in which enterocytes starved of SCFAs undergo inflammation and necrosis. Providing SCFAs to the affected colon segment can reverse this condition. Another important property of commensal organisms is that they interfere with the ability of pathogenic bacteria to colonize and invade the gut, partly by competing for space and nutrients. They can


Immunology_Janeway

Immunology_Janeway. Another important property of commensal organisms is that they interfere with the ability of pathogenic bacteria to colonize and invade the gut, partly by competing for space and nutrients. They can also directly inhibit the pro-inflammatory signaling pathways that pathogens stimulate in epithelial cells and that are needed for invasion. Perturbations in the balance between the various species of bacteria present in the microbiota (dysbiosis) have been found to increase susceptibility to a variety of diseases (see Sections 12-21 and 12-22).


Immunology_Janeway

Immunology_Janeway. The protective role of the commensal microbiota is dramatically illustrated by the adverse effects of broad-spectrum antibiotics. These antibiotics can kill large numbers of commensal gut bacteria, thereby creating an ecological niche for bacteria that would not otherwise be able to compete successfully. One example of a bacterium that grows in the antibiotic-treated gut and can cause a severe infection is Clostridium difficile (Fig. 12.20). This organism is an increasing problem in countries where broad-spectrum antibiotic use is prevalent, as it produces toxins that cause severe diarrhea and mucosal injury. Restoring the normal microbiota by a transplant of feces from healthy individuals can be used to treat C. difficile infection.


Immunology_Janeway

Immunology_Janeway. The importance of the local defense mechanisms against commensal bacteria for health is shown by experiments in animals that lack one or more of the factors involved. For instance, mice without secretory antibodies have increased numbers of commensal bacteria that have penetrated the intestinal mucosa and have disseminated beyond its draining lymphoid tissues. The composition of the microbiota in these mice is also altered, with increased numbers of bacteria, but decreased species diversity. Similar dysbiosis has been described in mice lacking FoxP3+ regulatory T cells or eosinophils. while preventing inflammation without compromising the ability to react to invaders.


Immunology_Janeway

Immunology_Janeway. Despite their beneficial effects, commensal bacteria are a potential threat, as is shown when the integrity of the intestinal epithelium is damaged. In these circumstances, normally innocuous gut bacteria, such as nonpathogenic E. coli, can cross the mucosa, invade the bloodstream, and cause fatal systemic infection. Therefore, the immune system in the intestine has to mount some form of response to control commensal microbes (Fig. 12.21). Since inappropriate reactions may lead to chronic inflammation and damage to the intestine, the immune system must balance the recognition and response to commensal bacteria with the cost of damaging tissues from inflammation. Commensal bacteria elicit antigen-specific responses that maintain the local balance between host and microbiota and are largely confined to the intestine itself. Unlike soluble food antigens, commensal bacteria do not induce a state of systemic immune unresponsiveness, and when these organisms enter the bloodstream, they can


Immunology_Janeway

Immunology_Janeway. confined to the intestine itself. Unlike soluble food antigens, commensal bacteria do not induce a state of systemic immune unresponsiveness, and when these organisms enter the bloodstream, they can stimulate a normal primary systemic immune response.


Immunology_Janeway

Immunology_Janeway. Recognition of the microbiota by the adaptive immune system is dependent on the uptake and intracellular transport of organisms by local dendritic cells that remain in Peyer’s patches or migrate no further than the mesenteric lymph node (see Fig. 12.21), which acts to prevent wider dissemination of the microbiota. Because commensal microbes are noninvasive, dendritic cells are not fully activated and induce a finely balanced response, comprising secretory IgA antibodies that enter intestinal secretions and are directed at commensal bacteria. Up to 75% of commensal organisms living in the lumen appear to be coated by IgA (see Fig. 12.21), limiting their adherence to and penetration of the epithelium. In addition, coating of the microbiota with SIgA can alter their gene expression. Many of the large numbers of fully differentiated TH1 and


Immunology_Janeway

Immunology_Janeway. Fig. 12.20 Infection by Clostridium difficile. Treatment with antibiotics causes massive death of the commensal bacteria that normally colonize the colon. This allows pathogenic bacteria to proliferate and to occupy an ecological niche that is normally occupied by harmless commensal bacteria. Clostridium difficile is an example of a pathogen producing toxins that can cause severe bloody diarrhea in patients treated with antibiotics.


Immunology_Janeway

Immunology_Janeway. Fig. 12.21 Several local processes ensure peaceful homeostasis between host and microbiota. Commensal bacteria in the lumen gain access to the immune system via M cells. Antigens are taken up by dendritic cells in Peyer’s patches and isolated follicles under noninflammatory conditions (left panel). Presentation of these antigens generates IgA‑switched B cells that localize in the lamina propria as IgA‑producing plasma cells (right panel). IgA then binds commensal bacteria, altering their gene expression, limiting their access to the epithelium, and blocking their binding to the surface. Interference with penetration of the epithelium is assisted by the presence of thick layers of mucus, which also contain mucin glycoproteins that have antibacterial properties. In addition, stimulation of pattern recognition receptors on Paneth cells induces the production of antimicrobial peptides such as RegIIIγ and defensins (see Section 2‑4), which are also stimulated by IL‑22 derived from TH17 CD4


Immunology_Janeway

Immunology_Janeway. recognition receptors on Paneth cells induces the production of antimicrobial peptides such as RegIIIγ and defensins (see Section 2‑4), which are also stimulated by IL‑22 derived from TH17 CD4 T cells and ILC3s. IL‑22 also tightens the epithelial barrier. Phagocytic macrophages found immediately under the epithelium can ingest and kill bacteria that penetrate the surface.


Immunology_Janeway

Immunology_Janeway. TH17 cells found in healthy intestine are also directed at the microbiota. While these cells produce mediators that can assist bacterial clearance by macrophages and epithelial cells, they come with the risk of producing inflammation and collateral damage. This does not occur, because of IL-10 produced by T cells and FoxP3+ regulatory T cells present in the mucosa. TH17 and FoxP3+ regulatory T cells in the intestine can enter germinal centers in Peyer’s patches and acquire the functions of follicular helper T cells, leading to selective IgA switching.


Immunology_Janeway

Immunology_Janeway. The endotoxin present on commensal bacteria also seems unusually sensitive to neutralization by gut enzymes such as alkaline phosphatase, leading to weaker immune activation. If commensal bacteria do cross the epithelium in small numbers, their lack of virulence factors means they cannot resist uptake and killing by phagocytic cells, and they are rapidly destroyed. In contrast to what happens in other tissues, ingestion of commensal bacteria in the intestine does not lead to inflammation. If macrophages cannot respond to the inhibitory effects of IL-10, intestinal inflammation develops spontaneously. Eosinophils in the healthy intestine assist antigen-specific IgA switching by producing APRIL, IL-6, and TGF-β when exposed to commensal microbes (see Section 12-11). Thus, commensal organisms associate with the mucosal surface without invading or provoking inflammation. This symbiosis involves many innate and adaptive immune effector cells that are usually associated with chronic


Immunology_Janeway

Immunology_Janeway. associate with the mucosal surface without invading or provoking inflammation. This symbiosis involves many innate and adaptive immune effector cells that are usually associated with chronic inflammation but in the intestine create a state sometimes referred to as physiological inflammation.


Immunology_Janeway

Immunology_Janeway. 12-21 The intestinal microbiota plays a major role in shaping intestinal and systemic immune function. Commensal bacteria and their products play an essential role in normal development of the immune system. This effect is illustrated in germ-free, or gnotobiotic, mice, in which there is no colonization of the gut by microorganisms. These animals have marked reductions in the size of all lymphoid organs, low serum immunoglobulin levels, fewer mature T cells, and markedly reduced immune responses, especially TH1 and TH17 responses. Such mice are prone to make TH2-type responses such as IgE antibodies and are more susceptible Fig 12.22 Effects of the microbiota on disease and systemic immune function.


Immunology_Janeway

Immunology_Janeway. Fig 12.22 Effects of the microbiota on disease and systemic immune function. The presence and composition of the microbiota have many downstream consequences for the function of the immune system and other body tissues, some of which may be secondary to the events in the mucosa, while others may reflect the ability of products of intestinal microbes to enter the circulation. The microbiota is also known to have many effects on susceptibility to a wide range of diseases in humans and experimental animals.


Immunology_Janeway

Immunology_Janeway. to certain immunological diseases such as type 1 diabetes. In the intestine, Peyer’s patches do not develop normally and isolated lymphoid follicles are absent. Germ-free mice also have severely reduced numbers of T lymphocytes and ILCs in the lamina propria and epithelium, nearly absent IgA-secreting plasma cells, and reduced mediators of local immunity, such as antimicrobial peptides, retinoic acid, IL-7, IL-22, IL-25, IL-33, and TSLP. In contrast, invariant NKT cells (iNKTs) are more abundant in the germ-free intestine, perhaps contributing to the TH2 bias seen in germ-free animals.


Immunology_Janeway

Immunology_Janeway. The effects of the intestinal microbiota extend far beyond the intestine (Fig. 12.22). For example, several autoimmune diseases are more frequent in germ-free animals. The germ-free state greatly increases the severity of symptoms in a genetic model of type 1 diabetes. The composition of the microbiota influences susceptibility to many different immunological diseases, metabolic disorders such as obesity, cancer, cardiovascular disease, and even psychiatric disorders. The basis for these associations is unclear and few individual commensal species have been identified in disease susceptibility. However, some affected individuals have unusual compositions of the major bacterial species that normally make up the microbiota, a form of dysbiosis, as we saw in Section 12-19. In experimental models, disease susceptibility can be conferred by transferring intestinal bacteria between affected and unaffected animals, supporting the idea that the change in microbiota is a causal factor, rather


Immunology_Janeway

Immunology_Janeway. disease susceptibility can be conferred by transferring intestinal bacteria between affected and unaffected animals, supporting the idea that the change in microbiota is a causal factor, rather than being secondary to preexisting disease. This observation underlies the use of probiotics, which are particular mixtures of live bacteria and yeast that are considered beneficial. Their use may manipulate the intestinal microbiota to prevent disease and promote health, although much remains to be understood about their potential benefits.


Immunology_Janeway

Immunology_Janeway. Many different mechanisms are probably involved in the effects of the microbiota (Fig. 12.23). Ligation of TLRs and NLRs is undoubtedly important for many of the local effects on epithelial cells and myeloid cells. Flagellin present on many intestinal bacterial species can stimulate TLR-5 on mucosal CD11b-expressing dendritic cells, inducing the production of IL-6 and IL-23 and favoring TH17 and IgA responses. There are also examples of individual bacterial species that have specific effects on immune function. Colonization of mice with segmented filamentous bacteria (SFB) enhances IgA production, accumulation of IELs, and the number of intestinal effector TH17 T cells (see Fig. 12.23). Conversion of dietary tryptophan by lactobacilli into kynurenine metabolites can activate the AhR (see Section 12-14) and enhance IL-22 production by ILC3. Polysaccharide A (PSA) from Bacteroides fragilis drives the differentiation of Treg cells in a TLR-2-dependent manner. Also, several Clostridium


Immunology_Janeway

Immunology_Janeway. Section 12-14) and enhance IL-22 production by ILC3. Polysaccharide A (PSA) from Bacteroides fragilis drives the differentiation of Treg cells in a TLR-2-dependent manner. Also, several Clostridium species stimulate the preferential generation of FoxP3+ regulatory T cells in the colon, perhaps by promoting a TGF-β-rich environment and by producing SCFAs. The mechanism by which SCFAs directly alter immune cell function is currently unclear. As yet, few specific organisms have been identified to explain the effects of dysbiosis on human disease, although certain E coli species, collectively called enteroadherent Escherichia coli, have been found to be prevalent in patients with Crohn’s disease. Recent studies have also shown increased abundance of Prevotella copri in a number of patients with newly diagnosed rheumatoid arthritis, but much more work needs to be done to confirm these associations and to find if there are similar effects in other diseases.


Immunology_Janeway

Immunology_Janeway. Fig 12.23 The microbiota tune local and systemic immune responses. The microbiota has local and distant effects on immune function, although only a few individual organisms and mechanisms have been identified. Segmented filamentous bacteria (SFB) potently induce SFB‑specific TH17 cells, perhaps by inducing epithelial cells to produce serum amyloid A (SAA) protein that may act on dendritic cells. Bacterial flagellin favors TH17 and IgA responses by stimulating TLR‑5 on mucosal CD11b‑expressing dendritic cells. The microbiota is also needed for the presence of isolated lymphoid follicles and ILCs, especially ILC3 cells, but inhibits the accumulation of invariant NKT cells (iNKTs). Besides providing energy to colonic enterocytes, butyrate and other SCFAs may also act to drive the generation of FoxP3+ Tregs, although the molecular mechanism is still unclear. Clostridia also induce production of TGF‑β by epithelial cells. The polysaccharide antigen (PSA) from Bacteroides fragilis


Immunology_Janeway

Immunology_Janeway. of FoxP3+ Tregs, although the molecular mechanism is still unclear. Clostridia also induce production of TGF‑β by epithelial cells. The polysaccharide antigen (PSA) from Bacteroides fragilis stimulates the preferential generation of regulatory T cells, possibly by binding to TLR‑2 on CD4+ T cells. Unidentified members of the microbiota are needed to maintain the production of TSLP, IL‑25, IL‑33, and RA.


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Immunology_Janeway. 12-22 Full immune responses to commensal bacteria provoke intestinal disease.


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Immunology_Janeway. Elegant experiments in the 1990s led to the now generally accepted idea that potentially aggressive T cells that can respond to commensal bacteria are present in normal animals but are usually kept in check by active regulation (Fig. 12.24). If these regulatory mechanisms fail, unrestricted immune responses to commensal bacteria can lead to inflammatory bowel diseases such as Crohn’s disease. Many genes that are associated with susceptibility to Crohn’s disease in humans encode proteins that regulate innate immunity. When these regulatory processes fail, systemic immune responses are generated against antigens from commensal bacterial, such as flagellin. T-cell responses are also generated in the mucosa, leading to severe intestinal damage. IL-23 is important in this process, promoting differentiation of TH17 effector cells. IL-23 and IL-12 in concert can also induce inflammatory TH1 responses in the intestine, with some CD4 effector T cells found to produce both IFN-γ and IL-17 under


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Immunology_Janeway. of TH17 effector cells. IL-23 and IL-12 in concert can also induce inflammatory TH1 responses in the intestine, with some CD4 effector T cells found to produce both IFN-γ and IL-17 under these circumstances. These experimental results are consistent with clinical evidence for a linkage between polymorphisms in the IL-23 receptor and Crohn’s disease in humans. In all experimental models, the intestinal damage depends on the presence of commensal bacteria, can be prevented by treatment with antibiotics, and does not occur in germ-free animals.


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Immunology_Janeway. Patients with Crohn’s disease and the related disorder ulcerative colitis exhibit dysbiosis and harbor unusual populations of intestinal microbiota. However, with the exception of enteroadherent Escherichia coli mentioned above, no individual species of commensal bacteria have yet been proven to be responsible for causing the damage. There is also experimental evidence that local responses to certain pathogenic viruses or parasites such as Toxoplasma gondii may trigger bystander activation of effector T cells specific to commensal organisms and produce persistent inflammation. Summary.


Immunology_Janeway

Immunology_Janeway. The immune system in the mucosa has to distinguish between potential pathogens and harmless antigens, generating strong effector responses to pathogens but remaining unresponsive to foods and commensals. Food proteins induce an active form of immunological tolerance in the systemic and mucosal immune systems; this tolerance may be mediated by regulatory T cells producing IL-10 and/or TGF-β. Commensal bacteria are also recognized by the immune system, but this is limited to the mucosa and its draining lymphoid tissues because commensal antigens are presented to T cells by semi-mature dendritic cells that migrate from the intestinal wall to draining mesenteric lymph nodes. This results in active mucosal tolerance and the production of local IgA antibodies that restrict colonization by the microorganisms, but ‘ignorance’ of these antigens by the systemic immune system. Because commensal bacteria have many beneficial effects for the host, these immunoregulatory processes are important in


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Immunology_Janeway. but ‘ignorance’ of these antigens by the systemic immune system. Because commensal bacteria have many beneficial effects for the host, these immunoregulatory processes are important in allowing the bacteria to coexist with the immune system. When the normal regulatory processes break down, local dendritic cells become fully activated and induce differentiation of naive T cells into effector T cells in the mesenteric lymph node. This is important for protective immunity against pathogens, but when it occurs under the wrong circumstances, it can lead to inflammatory diseases such as Crohn’s disease or celiac disease. As a consequence of these competing, but interacting, needs of the immune response, the intestine normally has the appearance of physiological inflammation, which helps maintain normal function of the gut and immune system. This process is driven mostly by the need to control the intestinal microbiota without eliminating it completely or causing damaging inflammation, and


Immunology_Janeway

Immunology_Janeway. normal function of the gut and immune system. This process is driven mostly by the need to control the intestinal microbiota without eliminating it completely or causing damaging inflammation, and results in the coordinated production of IgA, activation of regulatory and effector T cells, and several innate immune responses. Abnormalities in the host response can alter the composition and behavior of the microbiota, while changes in the microbiota can also influence the development and outcome of many diseases outside the intestine.


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Immunology_Janeway. Summary to Chapter 12. The mucosal immune system is a large and complex apparatus that has a crucial role in health, not just by protecting physiologically vital organs but also by helping to regulate the tone of the entire immune system and prevent disease. The peripheral lymphoid organs focused on by most immunologists may be a recent specialization of an original template that evolved in mucosal tissues. The mucosal surfaces of the body are highly vulnerable to infection


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Immunology_Janeway. Fig. 12.24 T cells with the potential to produce inflammation in response to commensal bacteria are present in normal animals, but are controlled by regulatory T cells. Transfer of unseparated CD4+ T cells from a normal mouse into an immunodeficient mouse, such as one lacking the rag gene (rag –/–), will lead to reconstitution of the CD4+ T‑cell compartment. However if ‘naive’ CD4+ T cells (CD4+CD45RBhi) are purified and transferred, the host mice develop severe inflammation of the colon. This can be prevented by co‑transferring the CD4+CD25+ FoxP3+ T cells that were removed during the purification of the naive CD4+ T‑cell population. The effects of these regulatory T cells are blocked by neutralizing TGF‑β in vivo and are also dependent on IL‑10. The intestinal inflammation caused by naive CD4+ T cells requires the presence of the microbiota, as it is prevented in germ‑free mice, or by treatment with antibiotics. These experiments demonstrate that some CD4+ T cells in normal animals


Immunology_Janeway

Immunology_Janeway. CD4+ T cells requires the presence of the microbiota, as it is prevented in germ‑free mice, or by treatment with antibiotics. These experiments demonstrate that some CD4+ T cells in normal animals are capable of provoking inflammatory responses against the intestinal microbiota, but that these are normally held in check by regulatory T cells. Micrographs from Powrie, F., et al.: J. Exp Med. 1996, 183:2669–2674.


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Immunology_Janeway. and possess a complex array of innate and adaptive mechanisms of immunity. The adaptive immune system of the mucosa-associated lymphoid tissues differs from that of the rest of the peripheral lymphoid system in several respects: the immediate juxtaposition of mucosal epithelium and lymphoid tissue; diffuse lymphoid tissue as well as more organized lymphoid organs; specialized antigen uptake mechanisms and distinctive dendritic cells and macrophages; the predominance of activated/memory lymphocytes and distinctive innate lymphoid cells (ILCs) even in the absence of infection; the production of dimeric secretory IgA as the predominant antibody; and the downregulation of immune responses to innocuous antigens such as food antigens and commensal microorganisms. No systemic immune response can normally be detected to these antigens. In contrast, pathogenic microorganisms induce strong protective responses. The key factor in the decision between tolerance and the development of powerful


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Immunology_Janeway. can normally be detected to these antigens. In contrast, pathogenic microorganisms induce strong protective responses. The key factor in the decision between tolerance and the development of powerful adaptive immune responses is the context in which antigen is presented to T lymphocytes in the mucosal immune system. When there is no inflammation, presentation of antigen to T cells by dendritic cells induces the differentiation of regulatory T cells. By contrast, pathogenic microorganisms crossing the mucosa induce an inflammatory response in the tissues, which stimulates the maturation of antigen-presenting cells and their expression of co-stimulatory molecules, thus favoring a protective T-cell response. This decision-making process is controlled mostly by the way in which specialized dendritic cells react to their environment before migrating to present antigen to naive T cells. The mutualistic loop formed between the host immune response and the local microbiota plays a central


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Immunology_Janeway. dendritic cells react to their environment before migrating to present antigen to naive T cells. The mutualistic loop formed between the host immune response and the local microbiota plays a central role in maintaining health and in the development of disease.


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Immunology_Janeway. Questions. 12.1 Multiple Choice: Which of the following is an incorrect statement? A. Microfold cells have a folded luminal surface and possess a thick layer of mucus that allows the entry of microbes to Peyer’s patches. B. Microfold cells recognize several bacterial proteins by GP2 and release the material to the extracellular space by a process called transcytosis. C. Gut‑associated lymphoid tissues attract dendritic cells trough chemokines such as CCL20 and CCL9. D. Pathogens such as Yersinia pestis and Shigella target microfold cells to gain access to the subepithelial space. 12.2 True or False: Intraepithelial lymphocytes are mostly CD4 T cells, in contrast to the lamina propria, where CD8 T cells predominate. 12.3 Matching: Match each chemokine or chemokine receptor to its tissue homing function. A. CXCL13 i. Recruitment of lymphocytes to the colon, lactating mammary gland, and salivary glands 12.4 Multiple Choice: Which of the following is a correct statement?


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Immunology_Janeway. A. CXCL13 i. Recruitment of lymphocytes to the colon, lactating mammary gland, and salivary glands 12.4 Multiple Choice: Which of the following is a correct statement? A. CD11b+ dendritic cells stimulate ILC3s and are the main source for IL‑12 in Peyer’s patches. B. CD11b– dendritic cells require BATF3 for their development. C. Retinoic acid production by naive T cells is required for dendritic cells for the generation of Treg cells. D. CCL20 prevents entrance of dendritic cells into the epithelial layer of Peyer’s patches. 12.5 Short Answer: IgA:antigen complexes can be reexported to the gut lumen in order to enhance pathogen excretion from the organism. In contrast, the formation of IgA:antigen complexes can also enhance the uptake of luminal antigen. How can uptake of antigen be beneficial to the organism?


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Immunology_Janeway. 12.6 Short Answer: Large amounts of IgA are produced by intestinal B cells and plasma cells and secreted into the lumen as a means to keep the microbiota in check and prevent invasion from pathogens, yet most individuals with IgA deficiency are not overly susceptible to infections. Explain why this is the case. 12.7 Multiple Choice: Which of the following best describes intraepithelial lymphocytes (IELs)? A. Express CCR9 and α4β7 integrin B. Express CCR9 and αEβ7 integrin (CD103) C. Have a CD4 to CD8 T cell ratio of 3:1 D. Contain CD4+ T cells that produce IFN‑γ, IL‑17, and IL‑22 E. Consist of 90% T cells, 80% of which express CD8 as an α:α homodimer or an α:β heterodimer F. A and C G. B and E H. A, C, and D 12.8 Multiple Choice: Which of the following cell types depend on aryl hydrocarbon receptor expression for proper development? A. Type b intraepithelial lymphocyte (EIL) B. ILC1 C. B cell D. Macrophage E. ILC2


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Immunology_Janeway. A. Type b intraepithelial lymphocyte (EIL) B. ILC1 C. B cell D. Macrophage E. ILC2 F. Neutrophil 12.9 Matching: Match the human disease with the C. Antibiotic treatment that eliminates iii. Inflammatory the bulk of commensal flora allowing bowel disease a particular species to overgrow and (Crohn’s produce toxins that lead to severe disease and diarrhea and mucosal injury ulcerative colitis) D. Hyperactive immune responses to iv. Diversion colitis commensal bacteria due to defects in innate immunity genes 12.10 True or False: Lamina propria CD4+ T cells secrete large amounts of cytokines such as IFN‑γ, IL‑17, and IL‑22 only in response to pathogens and inflammatory insults. 12.11 True or False: Most Tregs in the small intestine do not express FoxP3. General references. Hooper, L.V., Littman, D.R., and Macpherson, A.J.: Interactions between the microbiota and the immune system. Science 2012, 336:1268–1273.


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Immunology_Janeway. General references. Hooper, L.V., Littman, D.R., and Macpherson, A.J.: Interactions between the microbiota and the immune system. Science 2012, 336:1268–1273. MacDonald, T.T., Monteleone, I., Fantini, M.C., and Monteleone, G.: Regulation of homeostasis and inflammation in the intestine. Gastroenterology 2011, 140: 1768–1775. Mowat, A.M.: Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 2003, 3:331–341. Society for Mucosal Immunology: Principles of Mucosal Immunology, 1st ed. New York, Garland Science, 2013. Section references. 12-1 The mucosal immune system protects the internal surfaces of the body. Brandtzaeg, P.: Function of mucosa-associated lymphoid tissue in antibody formation. Immunol. Invest. 2010, 39:303–355. Cerutti, A., Chen, K., and Chorny, A.: Immunoglobulin responses at the mucosal interface. Annu. Rev. Immunol. 2011, 29:273–293.


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Immunology_Janeway. Cerutti, A., Chen, K., and Chorny, A.: Immunoglobulin responses at the mucosal interface. Annu. Rev. Immunol. 2011, 29:273–293. Corthesy, B.: Role of secretory IgA in infection and maintenance of homeostasis. Autoimmun. Rev. 2013, 12:661–665. Fagarasan, S., Kawamoto, S., Kanagawa, O., and Suzuki, K.: Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 2010, 28:243–273. Matsunaga, T., and Rahman, A.: In search of the origin of the thymus: the thymus and GALT may be evolutionarily related. Scand. J. Immunol. 2001, 53:1–6. Naz, R.K.: Female genital tract immunity: distinct immunological challenges for vaccine development. J .Reprod. Immunol. 2012, 93:1–8. Randall, T.D.: Bronchus-associated lymphoid tissue (BALT) structure and function. Adv. Immunol. 2010, 107:187–241. Sato, S., and Kiyono, H. The mucosal immune system of the respiratory tract. Curr. Opin. Virol. 2012, 2:225–232.


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Immunology_Janeway. Sato, S., and Kiyono, H. The mucosal immune system of the respiratory tract. Curr. Opin. Virol. 2012, 2:225–232. 12-2 Cells of the mucosal immune system are located both in anatomically defined compartments and scattered throughout mucosal tissues. Baptista, A.P., Olivier, B.J., Goverse, G., Greuter, M., Knippenberg, M., Kusser, K., Domingues, R.G., Veiga-Fernandes, H., Luster, A.D., Lugering, A., et al.: Colonic patch and colonic SILT development are independent and differentially regulated events. Mucosal Immunol 2013, 6:511–521. Brandtzaeg, P., Kiyono, H., Pabst, R., and Russell, M.W.: Terminology: nomenclature of mucosa-associated lymphoid tissue. Mucosal Immunol. 2008, 1:31–37. Eberl, G., and Sawa, S.: Opening the crypt: current facts and hypotheses on the function of cryptopatches. Trends Immunol. 2010, 31:50–55.


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Immunology_Janeway. Eberl, G., and Sawa, S.: Opening the crypt: current facts and hypotheses on the function of cryptopatches. Trends Immunol. 2010, 31:50–55. Lee, J.S., Cella, M., McDonald, K.G., Garlanda, C., Kennedy, G.D., Nukaya, M., Mantovani, A., Kopan, R., Bradfield, C.A., Newberry, R.D., et al: AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 2012, 13:144–151. Macpherson, A.J., McCoy, K.D., Johansen, F.E., and Brandtzaeg, P.: The immune geography of IgA induction and function. Mucosal. Immunol. 2008, 1:11–22. Pabst, O., Herbrand, H., Worbs, T., Friedrichsen, M., Yan, S., Hoffmann, M.W., Korner, H., Bernhardt, G., Pabst, R., and Forster, R.: Cryptopatches and isolated lymphoid follicles: dynamic lymphoid tissues dispensable for the generation of intraepithelial lymphocytes. Eur. J. Immunol. 2005, 35:98–107.


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Immunology_Janeway. Randall, T.D.: Bronchus-associated lymphoid tissue (BALT) structure and function. Adv. Immunol. 2010, 107:187–241. Randall, T.D., and Mebius, R.E.: The development and function of mucosal lymphoid tissues: a balancing act with micro-organisms. Mucosal Immunol. 2014, 7: 455–466. Suzuki, K., Kawamoto, S., Maruya, M., and Fagarasan, S.: GALT: organization and dynamics leading to IgA synthesis. Adv. Immunol. 2010, 107:153–185. 12-3 The intestine has distinctive routes and mechanisms of antigen uptake. Anosova, N.G., Chabot, S., Shreedhar, V., Borawski, J.A., Dickinson, B.L., and Neutra, M.R.: Cholera toxin, E. coli heat-labile toxin, and non-toxic derivatives induce dendritic cell migration into the follicle-associated epithelium of Peyer’s patches. Mucosal Immunol. 2008, 1:59–67.


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Immunology_Janeway. Hase, K., Kawano, K., Nochi, T., Pontes, G.S., Fukuda, S., Ebisawa, M., Kadokura, K., Tobe, T., Fujimura, Y., Kawano, S., et al.: Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response. Nature 2009, 462:226–230. Jang, M.H., Kweon, M.N., Iwatani, K., Yamamoto, M., Terahara, K., Sasakawa, C., Suzuki, T., Nochi, T., Yokota, Y., Rennert, P.D., et al.: Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl Acad. Sci. USA 2004, 101:6110–6115. Lelouard, H., Fallet, M., de Bovis, B., Meresse, S., and Gorvel, J.P.: Peyer's patch dendritic cells sample antigens by extending dendrites through M cell-specific transcellular pores. Gastroenterology 2012, 142:592–601. Mabbott, N.A., Donaldson, D.S., Ohno, H., Williams, I.R., and Mahajan, A. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 2013, 6:666–677.


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Immunology_Janeway. Mabbott, N.A., Donaldson, D.S., Ohno, H., Williams, I.R., and Mahajan, A. Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol. 2013, 6:666–677. Sato, S., Kaneto, S., Shibata, N., Takahashi, Y., Okura, H., Yuki, Y., Kunisawa, J., and Kiyono, H.: Transcription factor Spi-B-dependent and -independent pathways for the development of Peyer’s patch M cells. Mucosal Immunol. 2013, 6:838–846. Salazar-Gonzalez, R.M., Niess, J.H., Zammit, D.J., Ravindran, R., Srinivasan, A., Maxwell, J.R., Stoklasek, T., Yadav, R., Williams, I.R., Gu, X., et al.: CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer’s patches. Immunity 2006, 24:623–632.


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Immunology_Janeway. Zhao, X., Sato, A., Dela Cruz, C.S., Linehan, M., Luegering, A., Kucharzik, T., Shirakawa, A.K., Marquez, G., Farber, J.M., Williams, I., et al.: CCL9 is secreted by the follicle-associated epithelium and recruits dome region Peyer’s patch CD11b+ dendritic cells. J. Immunol. 2003, 171:2797–2803. 12-4 The mucosal immune system contains large numbers of effector lymphocytes even in the absence of disease. Belkaid, Y., Bouladoux, N., and Hand, T.W.: Effector and memory T cell responses to commensal bacteria. Trends Immunol. 2013, 34:299–306. Brandtzaeg, P.: Mucosal immunity: induction, dissemination, and effector functions. Scand. J. Immunol. 2009, 70:505–515. Cao A.T., Yao S., Gong B., Elson C.O., and Cong Y.: Th17 cells upregulate polymeric Ig receptor and intestinal IgA and contribute to intestinal homeostasis. J. Immunol. 2012, 189:4666–4673. Cheroutre, H., and Lambolez, F.: Doubting the TCR coreceptor function of CD8αα. Immunity 2008, 28:149–159.


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Immunology_Janeway. Cheroutre, H., and Lambolez, F.: Doubting the TCR coreceptor function of CD8αα. Immunity 2008, 28:149–159. Cauley, L.S., and Lefrancois, L.: Guarding the perimeter: protection of the mucosa by tissue-resident memory T cells. Mucosal. Immunol. 2013, 6:14–23. Maynard, C.L., and Weaver, C.T.: Intestinal effector T cells in health and disease. Immunity 2009, 31:389–400. Sathaliyawala, T., Kubota, M., Yudanin, N., Turner, D., Camp, P., Thome, J.J., Bickham, K.L., Lerner, H., Goldstein, M., Sykes, et al: Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 2013, 38:187–197. 12-5 The circulation of lymphocytes within the mucosal immune system receptors. Agace, W.: Generation of gut-homing T cells and their localization to the small intestinal mucosa. Immunol. Lett. 2010, 128:21–23.


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Immunology_Janeway. Agace, W.: Generation of gut-homing T cells and their localization to the small intestinal mucosa. Immunol. Lett. 2010, 128:21–23. Hu, S., Yang, K., Yang, J., Li, M., and Xiong, N.: Critical roles of chemokine receptor CCR10 in regulating memory IgA responses in intestines. Proc. Natl Acad. Sci. USA 2011, 108: E1035–1044. Kim, S.V., Xiang, W.V., Kwak, C., Yang, Y., Lin, X.W., Ota, M., Sarpel, U., Rifkin, D.B., Xu, R., and Littman, D.R.: GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science 2013, 340:1456–1459. Macpherson, A.J., Geuking, M.B., Slack, E., Hapfelmeier, S., and McCoy, K.D.: The habitat, double life, citizenship, and forgetfulness of IgA. Immunol. Rev. 2012, 245:132–146. Mikhak, Z., Strassner, J.P., and Luster, A.D.: Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4. J. Exp. Med. 2013, 210:1855–1869.


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Immunology_Janeway. Mikhak, Z., Strassner, J.P., and Luster, A.D.: Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4. J. Exp. Med. 2013, 210:1855–1869. Mora, J.R., and von Andrian, U.H.: Differentiation and homing of IgA-secreting cells. Mucosal Immunol. 2008, 1:96–109. Pabst, O., and Bernhardt, G.: On the road to tolerance--generation and migration of gut regulatory T cells. Eur. J. Immunol. 2013, 43:1422–1425. 12-6 Priming of lymphocytes in one mucosal tissue may induce protective immunity at other mucosal surfaces. Agnello, D., Denimal, D., Lavaux, A., Blondeau-Germe, L., Lu, B., Gerard, N.P., Gerard, C., and Pothier, P.: Intrarectal immunization and IgA antibody-secreting cell homing to the small intestine. J. Immunol. 2013, 190:4836–4847. Brandtzaeg, P.: Induction of secretory immunity and memory at mucosal surfaces. Vaccine 2007, 25:5467–5484.


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Immunology_Janeway. Brandtzaeg, P.: Induction of secretory immunity and memory at mucosal surfaces. Vaccine 2007, 25:5467–5484. Czerkinsky, C., and Holmgren, J.: Mucosal delivery routes for optimal immunization: targeting immunity to the right tissues. Curr. Top. Microbiol. Immunol. 2012, 354:1–18. Ruane, D., Brane, L., Reis, B.S., Cheong, C., Poles, J., Do, Y., Zhu, H., Velinzon, K., Choi, J.H., Studt, N., et al.: Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract. J. Exp. Med. 2013, 210:1871–1888. 12-7 Distinct populations of dendritic cells control mucosal immune responses. Cerovic,V.,Bain,C.C.,Mowat,A.M.,and Milling,S.W.F.: Intestinal macrophages and dendritic cells: what’s the difference? Trends Immunol. 2014, 35:270–277.


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Immunology_Janeway. Cerovic,V.,Bain,C.C.,Mowat,A.M.,and Milling,S.W.F.: Intestinal macrophages and dendritic cells: what’s the difference? Trends Immunol. 2014, 35:270–277. Goto, Y., Panea, C., Nakato, G., Cebula, A., Lee, C., Diez, M.G., Laufer, T.M., Ignatowicz, L., and Ivanov, I.I.: Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 2014, 40:594-607. Guilliams, M., Lambrecht, B.N., and Hammad, H.: Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections. Mucosal Immunol. 2013, 6:464–473. Jaensson-Gyllenback, E., Kotarsky, K., Zapata, F., Persson, E.K., Gundersen, T.E., Blomhoff, R., and Agace, W.W.: Bile retinoids imprint intestinal CD103+ dendritic cells with the ability to generate gut-tropic T cells. Mucosal Immunol. 2011, 4:438–447.


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Immunology_Janeway. Matteoli, G.: Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction. Gut 2010, 59:595–604. Schlitzer, A., McGovern, N., Teo, P., Zelante, T., Atarashi, K., Low, D., Ho, A.W., See, P., Shin, A., Wasan, P.S., et al.: IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 2013, 38:970–983. Scott, C.L., Bain, C.C., Wright, P.B., Schien, D., Kotarsky, K., Persson, E.K., Luda, K., Guilliams, M., Lambrecht, B.N., Agace, W.W., et al.: CCR2+CD103-intestinal dendritic cells develop from DC-committed precursors and induce interleukin-17 production by T cells. Mucosal Immunol. 2015, 8:327–239.


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Immunology_Janeway. Travis, M.A., Reizis, B., Melton, A.C., Masteller, E., Tang, Q., Proctor, J.M., Wang, Y., Bernstein, X., Huang, X., Reichardt, L.F., et al.: Loss of integrin αVβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 2007, 449:361–365. Vicente-Suarez, I., Larange, A., Reardon, C., Matho, M., Feau, S., Chodaczek, G., Park, Y., Obata, Y., Gold, R., Wang-Zhu, Y., et al.: Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells. Mucosal Immunol. 2015, 8:141–151. Watchmaker, P.B., Lahl, K., Lee, M., Baumjohann, D., Morton, J., Kim, S.J., Zeng, R., Dent, A., Ansel, K.M., Diamond, B., et al: Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nat. Immunol. 2014, 15:98–108. 12-8 Macrophages and dendritic cells have different roles in mucosal immune responses.


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Immunology_Janeway. 12-8 Macrophages and dendritic cells have different roles in mucosal immune responses. Bain, C.C., Bravo-Blas, A., Scott, C.L., Geissmann, F., Henri, S., Malissen, B., Osborne, L.C., Artis, D., and Mowat, A.M.: Constant replenishment from circulating monocytes maintains the macrophage pool in adult intestine. Nat. Immunol. 2014, 15:929–937. Guilliams, M., Lambrecht, B.N., and Hammad, H.: Division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections. Mucosal Immunol 2013, 6:464–473. Hadis, U., Wahl, B., Schulz, O., Hardtke-Wolenski, M., Schippers, A., Wagner, N., Muller, W., Sparwasser, T., Forster, R., and Pabst, O.: Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity 2011, 34:237–246.


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Immunology_Janeway. Mortha,A., Chudnovskiy,A., Hashimoto, D., Bogunovic, M., Spencer, S.P., Belkaid, Y., and Merad, M.: Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 2014, 343:1249288. 12-9 Antigen-presenting cells in the intestinal mucosa acquire antigen by a variety of routes. Farache, J., Zigmond, E., Shakhar, G., and Jung, S.: Contributions of dendritic cells and macrophages to intestinal homeostasis and immune defense. Immunol. Cell Biol. 2013, 91:232–239. Jang, M.H., Kweon, M.N., Iwatani, K., Yamamoto, M., Terahara, K., Sasakawa, C., Suzuki, T., Nochi, T., Yokota, Y., Rennert, P.D., et al.: Intestinal villous M cells: an antigen entry site in the mucosal epithelium. Proc. Natl Acad. Sci. USA 2004, 101:6110–6115. Mazzini, E., Massimiliano, L., Penna, G., and Rescigno, M.: Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1+ macrophages to CD103+ dendritic cells. Immunity 2014, 40:248–261.


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Immunology_Janeway. McDole, J.R., Wheeler, L.W., McDonald, K.G., Wang, B., Konjufca, V., Knoop, K.A., Newberry, R.D., and Miller, M.J.: Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 2012, 483:345–349. Schulz, O., and Pabst, O.: Antigen sampling in the small intestine. Trends Immunol. 2013, 34:155–161. Yoshida, M., Claypool, S.M., Wagner, J.S., Mizoguchi, E., Mizoguchi, A., Roopenian, D.C., Lencer, W.I., and Blumberg, R.S.: Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 2004, 20:769–783. 12-10 Secretory IgA is the class of antibody associated with the mucosal immune system. Fritz, J.H., Rojas, O.L., Simard, N., McCarthy, D.D., Hapfelmeier, S., Rubino, S., Robertson, S.J., Larijani, M., Gosselin, J., Ivanov, II, et al.: Acquisition of a multi-functional IgA+ plasma cell phenotype in the gut. Nature 2012, 481:199–203.


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Immunology_Janeway. Kawamoto, S., Maruya, M., Kato, L.M., Suda, W., Atarashi, K., Doi, Y., Tsutsui, Y., Qin, H., Honda, K., Okada, T., et al: Foxp3 T cells regulate immunoglobulin A selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 2014, 41:152–165. Lin, M., Du, L., Brandtzaeg, P., and Pan-Hammarstrom, Q.: IgA subclass switch recombination in human mucosal and systemic immune compartments. Mucosal Immunol. 2014, 7:511–520. Woof, J.M., and Russell, M.W.: Structure and function relationships in IgA. Mucosal Immunol. 2011, 4:590–597. 12-11 T-independent processes can contribute to IgA production in some species Barone, F., Vossenkamper, A., Boursier, L., Su, W., Watson, A., John, S., Dunn-Walters, D.K., Fields, P., Wijetilleka, S., Edgeworth, J.D., et al: IgA-producing plasma cells originate from germinal centers that are induced by B-cell receptor engagement in humans. Gastroenterology 2011, 140:947–956.


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Immunology_Janeway. Fagarasan, S., Kawamoto, S., Kanagawa, O., and Suzuki, K.: Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 2010, 28:243–273. Lin, M., Du, L., Brandtzaeg, P., and Pan-Hammarstrom, Q.: IgA subclass switch recombination in human mucosal and systemic immune compartments. Mucosal Immunol. 2014, 7:511–520. Tezuka, H.,Abe,Y.,Asano, J., Sato,T., Liu, J., Iwata, M., and Ohteki,T.: Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction. Immunity 2011, 34:247–257. 12-12 IgA deficiency is relatively common in humans but may be compensated for by secretory IgM. Karlsson, M.R., Johansen, F.E., Kahu, H., Macpherson, A., and Brandtzaeg, P.: Hypersensitivity and oral tolerance in the absence of a secretory immune system. Allergy 2010, 65:561–570. Yel, L.: Selective IgA deficiency. J. Clin. Immunol. 2010, 30:10–16.


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Immunology_Janeway. Yel, L.: Selective IgA deficiency. J. Clin. Immunol. 2010, 30:10–16. 12-13 The intestinal lamina propria contains antigen-experienced T cells and populations of unusual innate lymphoid cells. Buonocore, S., Ahern, P.P., Uhlig, H.H., Ivanov, I.I., Littman, D.R., Maloy, K.J., and Powrie, F.: Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 2010, 464:1371–1375. Satpathy, A.T., Briseño, C.G., Lee, J.S., Ng, D., Manieri, N.A., Kc, W., Wu, X., Thomas, S.R., Lee, W.L., Turkoz, M., et al.: Notch2-dependent classical dendritic cells orchestrate intestinal immunity to attaching-and-effacing bacterial pathogens. Nat. Immunol. 2013, 14:937–948. Klose, C.S., Kiss, E.A., Schwierzeck, V., Ebert, K., Hoyler, T., d'Hargues, Y., Goppert, N., Croxford, A.L., Waisman, A., Tanriver, Y., et al: A T-bet gradient controls the fate and function of CCR6–RORγt+ innate lymphoid cells. Nature 2013, 494:261–265.


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Immunology_Janeway. Kruglov, A.A., Grivennikov, S.I., Kuprash, D.V., Winsauer, C., Prepens, S., Seleznik, G.M., Eberl, G., Littman, D.R., Heikenwalder, M., Tumanov, A.V., et al: Nonredundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis. Science 2013, 342:1243–1246. Le Bourhis, L., Dusseaux, M., Bohineust, A., Bessoles, S., Martin, E., Premel, V., Core, M., Sleurs, D., Serriari, N.E., and Treiner, E.: MAIT cells detect and efficiently lyse bacterially-infected epithelial cells. PLoS Pathog. 2013, 9:e1003681. Spits, H., and Cupedo, T.: Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 2012, 30:647–675. 12-14 The intestinal epithelium is a unique compartment of the immune system.


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Immunology_Janeway. 12-14 The intestinal epithelium is a unique compartment of the immune system. Agace, W.W., Roberts, A.I., Wu, L., Greineder, C., Ebert, E.C., and Parker, C.M.: Human intestinal lamina propria and intraepithelial lymphocytes express receptors specific for chemokines induced by inflammation. Eur. J. Immunol. 2000, 30:819–826. Cheroutre, H., Lambolez, F., and Mucida, D.: The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 2011, 11:445–456. Eberl, G., and Sawa, S.: Opening the crypt: current facts and hypotheses on the function of cryptopatches. Trends Immunol. 2010, 31:50–55. Hayday,A.,Theodoridis, E., Ramsburg, E., and Shires, J.: Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2001, 2:997–1003.


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Immunology_Janeway. Hayday,A.,Theodoridis, E., Ramsburg, E., and Shires, J.: Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2001, 2:997–1003. Jiang, W., Wang, X., Zeng, B., Liu, L., Tardivel, A., Wei, H., Han, J., MacDonald, H.R., Tschopp, J., Tian, Z., et al: Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. J. Exp. Med. 2013, 210:2465–2476. Li, Y., Innocentin, S., Withers, D.R., Roberts, N.A., Gallagher, A.R., Grigorieva, E.F., Wilhelm, C., and Veldhoen, M.: Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 2011, 147:629–640. Pobezinsky, L.A., Angelov, G.S., Tai, X., Jeurling, S., Van Laethem, F., Feigenbaum, L., Park, J.H., and Singer, A.: Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat. Immunol. 2012, 13:569–578.


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Immunology_Janeway. 12-15 Enteric pathogens cause a local inflammatory response and the development of protective immunity. Clevers, H.C., and Bevins, C.L.: Paneth cells: maestros of the small intestinal crypts. Annu. Rev. Physio. 2013, 75:289–311. Conway, K.L., Kuballa, P., Song, J.H., Patel, K.K., Castoreno, A.B., Yilmaz, O.H., Jijon, H.B., Zhang, M., Aldrich, L.N., Villablanca, E.J., et al.: Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology 2013, 145:1347–1357. Geddes, K., Rubino, S.J., Magalhaes, J.G., Streutker, C., Le Bourhis, L., Cho, J.H., Robertson, S.J., Kim, C.J., Kaul, R., Philpott, D.J., et al: Identification of an innate T helper type 17 response to intestinal bacterial pathogens. Nat. Med. 2011, 17:837–844.


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Immunology_Janeway. Lassen, K.G., Kuballa, P., Conway, K.L., Patel, K.K., Becker, C.E., Peloquin, J.M., Villablanca, E.J., Norman, J.M., Liu, T.C., Heath, R.J., et al.: Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc. Natl Acad. Sci. USA 2014, 111:7741–7746. Prescott, D., Lee, J., and Philpott, D.J.: An epithelial armamentarium to sense the microbiota. Semin. Immunol. 2013, 25:323–333. Song-Zhao, G.X., Srinivasan, N., Pott, J., Baban, D., Frankel, G., and Maloy, K.J.: Nlrp3 activation in the intestinal epithelium protects against a mucosal pathogen. Mucosal Immunol. 2014, 7:763–774. 12-16 Pathogens induce adaptive immune responses when innate defenses have been breached. Bain, C.C., and Mowat, A.M.: Macrophages in intestinal homeostasis and inflammation. Immunol. Rev. 2014: 260:102–117.


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Immunology_Janeway. Bain, C.C., and Mowat, A.M.: Macrophages in intestinal homeostasis and inflammation. Immunol. Rev. 2014: 260:102–117. Farache, J., Koren, I., Milo, I., Gurevich, I., Kim, K.W., Zigmond, E., Furtado, G.C., Lira, S.A., and Shakhar, G.: Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity 2013, 38:581–595. Persson, E.K., Scott, C.L., Mowat, A.M., and Agace, W.W.: Dendritic cell subsets in the intestinal lamina propria: Ontogeny and function. Eu. J. Immunol. 2013, 43:3098–3107. Salazar-Gonzalez, R.M., Niess, J.H., Zammit, D.J., Ravindran, R., Srinivasan, A., Maxwell, J.R., Stoklasek, T., Yadav, R., Williams, I.R., Gu, X., et al.: CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer’s patches. Immunity 2006, 24:623–632.


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Immunology_Janeway. Uematsu, S., Jang, M.H., Chevrier, N., Guo, Z., Kumagai, Y., Yamamoto, M., Kato, H., Sougawa, N., Matsui, H., Kuwata, H., et al.: Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat. Immunol. 2006, 7:868–874. 12-17 Effector T-cell responses in the intestine protect the function of the epithelium. Cliffe, L.J., Humphreys, N.E., Lane, T.E., Potten, C.S., Booth, C., and Grencis, R.K.: Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science 2005, 308:1463–1465. Kinnebrew, M.A., Buffie, C.G., Diehl, G.E., Zenewicz, L.A., Leiner, I., Hohl, T.M., Flavell, R.A., Littman, D.R., and Pamer, E.G.: Interleukin 23 production by intestinal CD103+CD11b+ dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 2012, 36:276–287.


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Immunology_Janeway. Sokol, H., Conway, K.L., Zhang, M., Choi, M., Morin, B., Cao, Z., Villablanca, E.J., Li, C., Wijmenga, C., Yun, S.H., et al: Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology 2013, 145:591–601. Sonnenberg, G.F., Fouser, L.A., and Artis, D.: Functional biology of the IL-22IL-22R pathway in regulating immunity and inflammation at barrier surfaces. Adv. Immunol. 2010, 107:1-29. Turner, J.E., Stockinger, B., and Helmby, H.: IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection. PLoS Patho. 2013, 9:e1003698. 12-18 The mucosal immune system must maintain tolerance to harmless foreign antigens.


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Immunology_Janeway. 12-18 The mucosal immune system must maintain tolerance to harmless foreign antigens. Cassani, B., Villablanca, E.J., Quintana, F.J., Love, P.E., Lacy-Hulbert, A., Blaner, W.S., Sparwasser, T., Snapper, S.B., Weiner, H.L., and Mora, J.R.: Gut-tropic T cells that express integrin α4β7 and CCR9 are required for induction of oral immune tolerance in mice. Gastroenterology 2011, 141:2109–2118. Coombes, J.L., Siddiqui, K.R., Arancibia-Carcamo, C.V., Hall, J., Sun, C.M., Belkaid, Y., and Powrie, F.: A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 2007, 204:1757–1764. Du Toit, G., Roberts, G., Sayre, P.H., Bahnson, H.T., Radulovic, S., Santos, A.F., Brough, H.A., Phippard, D., Basting, M., Feeney, M., et al.: Randomized trial of peanut consumption in infants at risk for peanut allergy. N. Engl. J. Med. 2015, 372:803–813.


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Immunology_Janeway. Huang, G., Wang, Y., and Chi, H.: Control of T cell fates and immune tolerance by p38α signaling in mucosal CD103+ dendritic cells. J. Immunol. 2013, 191:650–659. Mowat, A.M., Strobel, S., Drummond, H.E., and Ferguson, A.: Immunological responses to fed protein antigens in mice. I. Reversal of oral tolerance to ovalbumin by cyclophosphamide. Immunology 1982, 45:105–113. 12-19 The normal intestine contains large quantities of bacteria that are required for health. preventing inflammation without compromising the ability to react to invaders. Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., Liu, H., Cross, J.R., Pfeffer, K., Coffer, P.J., et al.: Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013, 504:451–455.


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Immunology_Janeway. Atarashi, K., Tanoue, T., Oshima, K., Suda, W., Nagano, Y., Nishikawa, H., Fukuda, S., Saito, T., Narushima, S., Hase, K., et al.: Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013, 500:232–236. Belkaid, Y., and Hand, T.W.: Role of the microbiota in immunity and inflammation. Cell 2014, 157:121–141. Harig, J.M., Soergel, K.H., Komorowski, R.A., and Wood, C.M.: Treatment of diversion colitis with short-chain-fatty acid irrigation. N. Engl. J. Med. 1989, 320:23–28. Hirota, K., Turner, J.E., Villa, M., Duarte, J.H., Demengeot, J., Steinmetz, O.M., and Stockinger, B.: Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses. Nat. Immunol. 2013, 14:372–379. Kato, L.M., Kawamoto, S., Maruya, M., and Fagarasan, S.: The role of the adaptive immune system in regulation of gut microbiota. Immunol. Rev. 2014, 260:67–75.


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Immunology_Janeway. Kato, L.M., Kawamoto, S., Maruya, M., and Fagarasan, S.: The role of the adaptive immune system in regulation of gut microbiota. Immunol. Rev. 2014, 260:67–75. Macia, L., Thorburn, A.N., Binge, L.C., Marino, E., Rogers, K.E., Maslowski, K.M., Vieira, A.T., Kranich, J., and Mackay, C.R.: Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol. Rev. 2012, 245:164–176. Maynard, C.L., Elson, C.O., Hatton, R.D., and Weaver, C.T.: Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012, 489:231–241. Peterson, D.A., McNulty, N.P., Guruge, J.L., and Gordon, J.I.: IgA response to symbiotic bacteria as a mediator of gut homeostasis. Cell Host Microbe 2007, 2:328–339. Round, J.L., and Mazmanian, S.K.: Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 2010, 107:12204–12209.


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Immunology_Janeway. Round, J.L., and Mazmanian, S.K.: Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 2010, 107:12204–12209. Scher, J.U., Sczesnak, A., Longman, R.S., Segata, N., Ubeda, C., Bielski, C., Rostron, T., Cerundolo, V., Pamer, E.G., Abramson, S.B., et al.: Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2013, 2:e01202. Zigmond, E., Bernshtein, B., Friedlander, G., Walker, C.R., Yona, S., Kim, K.W., Brenner, O., Krauthgamer, R., Varol, C., Müller, W., et al: Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 2014, 40:720–733. 12-21 The intestinal microbiota plays a major role in shaping intestinal and systemic immune function. & 12-22 Full immune responses to commensal bacteria provoke intestinal disease.


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Immunology_Janeway. 12-21 The intestinal microbiota plays a major role in shaping intestinal and systemic immune function. & 12-22 Full immune responses to commensal bacteria provoke intestinal disease. Adolph, T.E., Tomczak, M.F., Niederreiter, L., Ko, H.J., Bock, J., Martinez-Naves, E., Glickman, J.N., Tschurtschenthaler, M., Hartwig, J., Hosomi, S., et al.: Paneth cells as a site of origin for intestinal inflammation. Nature 2013, 503:272–276. Alexander, K.L., Targan, S.R., and Elson, C.O.: Microbiota activation and regulation of innate and adaptive immunity. Immunol. Rev. 2014, 260:206–220. Arenas-Hernández, M.M., Martínez-Laguna, Y., and Torres, A.G.: Clinical implications of enteroadherent Escherichia coli. Curr. Gastroenterol. Rep. 2012, 14:386–394. Chung, H., Pamp, S.J., Hill, J.A., Surana, N.K., Edelman, S.M., Troy, E.B., Reading, N.C., Villablanca, E.J., Wang, S., Mora, J.R., et al.: Gut immune maturation depends on colonization with a host-specific microbiota. Cell 2012, 149:1578–1593.


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Immunology_Janeway. Coccia, M., Harrison, O.J., Schiering, C., Asquith, M.J., Becher, B., Powrie, F., and Maloy, K.J. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells. J. Exp. Med. 2012, 209:1595–1609. Knights, D., Lassen, K.G., and Xavier, R.J.: Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut 2013, 62:1505–1510. Kullberg, M.C., Jankovic, D., Feng, C.G., Hue, S., Gorelick, P.L., McKenzie, B.S., Cua, D.J., Powrie, F., Cheever, A.W., Maloy, K.J., et al.: Intestinal epithelial cells: regulators of barrier function and immune homeostasis. J. Exp. Med. 2006, 203:2485–2494. Peterson, L.W., and Artis, D.: Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 2014, 14:141–153. Shale, M., Schiering, C., and Powrie, F.: CD4+ T-cell subsets in intestinal inflammation. Immunol. Rev. 2013, 252:164–182.


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Immunology_Janeway. Shale, M., Schiering, C., and Powrie, F.: CD4+ T-cell subsets in intestinal inflammation. Immunol. Rev. 2013, 252:164–182. Zelante, T., Iannitti, R.G., Cunha, C., De Luca, A., Giovannini, G., Pieraccini, G., Zecchi, R., D'Angelo, C., Massi-Benedetti, C., Fallarino, F., et al.: Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 2013, 39:372–385. Failures of Host Defense Mechanisms


Immunology_Janeway

Immunology_Janeway. Failures of Host Defense Mechanisms In the normal course of an infection, the infectious agent first triggers an innate immune response. The foreign antigens of the infectious agent, enhanced by signals from innate immune cells, then induce an adaptive immune response that ultimately clears the infection and establishes a state of protective immunity. This does not always happen, however. In this chapter we examine circumstances in which there are failures of host defense against infectious agents, whether due to immune defects in an abnormal host, as occurs in immunodeficiency, or to the evasion or subversion of immune defenses in normal hosts by pathogens. Finally, we will consider the special case in which the immune defenses of a normal host are impaired by one infectious agent that leads to more generalized susceptibility to infection, as occurs in the acquired immune deficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV).


Immunology_Janeway

Immunology_Janeway. In the first part of the chapter, we examine primary, or inherited, immunodeficiency diseases, in which host defense fails due to an inherited defect in a gene that results in the elimination or impaired function of one or more components of the immune system, leading to heightened susceptibility to infection with particular classes of pathogens. Immunodeficiency diseases caused by defects in T or Blymphocyte development, phagocyte function, and complement components have all been discovered. In the second part of the chapter, we briefly consider mechanisms by which pathogens evade or subvert specific components of the immune response to avoid elimination, socalled immune evasion. In the last part of the chapter, we consider how persistent infection by HIV leads to AIDS, an example of secondary, or acquired, immunodeficiency. The study of circumstances and mechanisms by which the immune system can fail has already contributed greatly to our understanding of host defense mechanisms


Immunology_Janeway

Immunology_Janeway. secondary, or acquired, immunodeficiency. The study of circumstances and mechanisms by which the immune system can fail has already contributed greatly to our understanding of host defense mechanisms and, in the longer term, might help to provide new methods of controlling or preventing infectious diseases, including AIDS.


Immunology_Janeway

Immunology_Janeway. immunodeficiency diseases. evasion and subversion of immune defenses. acquired immune deficiency syndrome. Immunodeficiency diseases.


Immunology_Janeway

Immunology_Janeway. Immunodeficiencies occur when one or more components of the immune system are defective; immunodeficiencies are classified as primary (inherited, or congenital) or secondary (acquired). Primary immunodeficiencies are caused by inherited mutations in any of a large number of genes that are involved in or control immune responses. Well over 150 primary immunodeficiencies have now been described that affect the development of immune cells, their function, or both. Clinical features of these disorders are therefore highly variable, although a common feature is recurrent and often overwhelming infections in very young children. In contrast, secondary immunodeficiencies are acquired as a consequence of other diseases, or are secondary to environmental factors such as starvation, or are an adverse consequence of medical intervention. Some forms of immunodeficiency principally affect immuneregulatory pathways. Defects of this type can lead to allergy, abnormal proliferation of lymphocytes,


Immunology_Janeway

Immunology_Janeway. consequence of medical intervention. Some forms of immunodeficiency principally affect immuneregulatory pathways. Defects of this type can lead to allergy, abnormal proliferation of lymphocytes, autoimmunity, and certain types of cancer, and will be discussed in other chapters. Here, we will mainly focus on those immunodeficiencies that predispose to infection.


Immunology_Janeway

Immunology_Janeway. Primary immunodeficiencies can be classified on the basis of the components of the immune system involved. However, because of the integration of many aspects of immune defense, defects in one component of the immune system can impact the function of others. Therefore, primary defects in innate immunity can lead to defects in adaptive immunity, and vice versa. Nevertheless, it is instructive to consider immune defects in the context of the major types of immunity affected, as these can lead to distinct patterns of infection and clinical disease. By examining which infectious diseases accompany a particular immunodeficiency, we gain insights into components of the immune system that are important in the response to particular agents. The inherited immunodeficiencies also reveal how interactions between different immune cell types contribute to the immune response and to the development of T and B lymphocytes. Finally, these inherited diseases can lead us to the defective gene, often


Immunology_Janeway

Immunology_Janeway. between different immune cell types contribute to the immune response and to the development of T and B lymphocytes. Finally, these inherited diseases can lead us to the defective gene, often revealing new information about the molecular basis of immune processes and providing the necessary information for diagnosis, genetic counseling, and eventually the possibility of gene therapy for cure.


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Immunology_Janeway. 13-1 A history of repeated infections suggests a diagnosis of immunodeficiency. Patients with immune deficiency are usually detected clinically by a history of recurrent infection, often by the same or similar pathogens. The type of infection is a guide to which part of the immune system is deficient. Recurrent infection by pyogenic, or pusforming, bacteria suggests a defect in antibody, complement, or phagocyte function, reflecting the role of these parts of the immune system in defense against such infections. Alternatively, a history of persistent fungal skin infection, such as cutaneous candidiasis, or recurrent viral infections suggests a defect in host defense mediated by T lymphocytes. 13-2 Primary immunodeficiency diseases are caused by inherited gene defects.


Immunology_Janeway

Immunology_Janeway. 13-2 Primary immunodeficiency diseases are caused by inherited gene defects. Before the advent of antibiotics, most individuals with inherited immune defects died in infancy or early childhood because of their susceptibility to particular classes of pathogens. Such cases were not easily identified, because many normal infants also died of infection. Most of the gene defects that cause inherited immunodeficiencies are recessive, and many are caused by mutations in genes on the X chromosome. As males have only one X chromosome, all males who inherit an X chromosome carrying a defective gene will be affected by the disease. In contrast, female carriers with one defective X chromosome are usually healthy. Gene knockout techniques in mice (see Appendix I, Section A35) have created many immunodeficient states that are adding rapidly to our knowledge of the contribution of individual proteins to normal immune function. Nevertheless, immunodeficiency diseases.


Immunology_Janeway

Immunology_Janeway. human immunodeficiency diseases remain the best source of insight into the normal pathways of defense against infectious diseases. For example, deficiencies of antibody, of complement, or of phagocytic function each increase the risk of infection by certain types of bacteria. This reflects the fact that the normal pathway of host defense against such bacteria is the binding of antibody followed by the fixation of complement, which allows the opsonized bacteria to be taken up by phagocytic cells and killed. Breaking any of the links in this chain of events causes a similar immunodeficient state.


Immunology_Janeway

Immunology_Janeway. Immunodeficiencies also teach us about the redundancy of defense mechanisms against infectious disease. By chance, the first person to be reported with a hereditary deficiency of complement (C2 deficiency) was a healthy immunologist. This teaches us that there are multiple protective immune mechanisms against infection, such that a defect in one component of immunity might be compensated for by other components. Thus, although there is abundant evidence that complement deficiency increases susceptibility to pyogenic infection, not every human with complement deficiency suffers from recurrent infections. Examples of immunodeficiency diseases are listed in Fig. 13.1. None is very common (a selective deficiency in IgA being the most frequently reported), and some are extremely rare. These diseases are described in subsequent sections, and we have grouped the diseases according to where the specific causal defect lies in the adaptive or innate immune systems.


Immunology_Janeway

Immunology_Janeway. 13-3 Defects in T-cell development can result in severe combined immunodeficiencies. The developmental pathways leading to circulating naive T cells and B cells are summarized in Fig. 13.2. Patients with defects in Tcell development are highly susceptible to a broad range of infectious agents. This demonstrates the central role of Tcell differentiation and maturation in adaptive immune responses to virtually all antigens. Because such patients exhibit neither Tcelldependent antibody responses nor cellmediated immune responses, and thus cannot develop immunological memory, they are said to suffer from severe combined immunodeficiency (SCID).


Immunology_Janeway

Immunology_Janeway. Xlinked SCID (XSCID) is the most frequent form of SCID and is caused by mutations in the gene IL2RG on the human X chromosome, which encodes the interleukin2 receptor (IL2R) common gamma chain (γc). γc is required in all receptors of the IL2 cytokine family (IL2, IL4, IL7, IL9, IL15, and IL21). Patients with XSCID thus have defects in signaling of all IL2family cytokines, and, owing to the defects in IL7 and IL15, their T cells and NK cells fail to develop normally (see Fig. 13.2). Bcell numbers, on the other hand, are normal, but due to absence of Tcell help, their function is not. XSCID patients are overwhelmingly male; in females who are carriers of the mutation, Tcell and NKcell progenitors in which Xinactivation has preserved the wildtype IL2RG allele progress through development to establish a normal mature immune repertoire. XSCID is known as the ‘bubble boy disease’ after a boy with XSCID who lived in a protective bubble for more than a decade before he died from complications


Immunology_Janeway

Immunology_Janeway. a normal mature immune repertoire. XSCID is known as the ‘bubble boy disease’ after a boy with XSCID who lived in a protective bubble for more than a decade before he died from complications of a bone marrow transplant. A clinically and immunologically indistinguishable type of SCID is associated with an inactivating mutation in the kinase Jak3 (see Section 81), which physically associates with γc and transduces signaling through γcchain cytokine receptors. This autosomal recessive mutation also impairs the development of T and NK cells, but the development of B cells is unaffected.


Immunology_Janeway

Immunology_Janeway. Other immunodeficiencies in mice have pinpointed more precisely the roles of individual cytokines and their receptors in Tcell and NKcell development. For example, mice with targeted mutations in the βc gene (IL2RB) defined a key role for IL15 as a growth factor for the development of NK cells, as well as Fig. 13.1 Human immunodeficiency syndromes. the specific gene defect, the consequence for the immune system, and the resulting disease susceptibilities are listed for some common and some rare human immunodeficiency syndromes. Severe combined immunodeficiency (SCiD) can be due to many different defects, as summarized in Fig. 13.2 and described in the text. aiD, activation-induced cytidine deaminase; atM, ataxia telangiectasiamutated protein; eBV, epstein–Barr virus; iKK, inhibitor of κ B kinase; Stat3, signal transducer and activator of transcription 3; taP, transporters associated with antigen processing; unG, uracil-Dna glycosylase.


Immunology_Janeway

Immunology_Janeway. a role for the cytokine in Tcell maturation and trafficking. Mice with targeted mutations in IL15 itself or the α chain of its receptor also have no NK cells and relatively normal Tcell development, but they show a more specific Tcell defect, primarily limited to impaired maintenance of memory CD8 T cells.


Immunology_Janeway

Immunology_Janeway. Humans with a deficiency of the IL7 receptor α chain have no T cells but normal levels of NK cells, illustrating that IL7 signaling, while essential for Tcell development, is not essential for the development of NK cells (see Fig. 13.2). Interestingly, mice with a genetargeted deficiency of the IL7R share with humans a deficiency of T cells, but also lack B cells, which is not the case in humans. This illustrates the speciesspecific role of certain cytokines, and provides a cautionary note against extrapolating findings from mice to humans. In humans and mice whose T cells show defective production of IL2 after receptor stimulation, most Tcell development itself is normal, although there is impaired development of FoxP3+ Treg cells that predisposes to immuneregulatory abnormalities and autoimmunity (see Chapter 15). The more limited effects of individual cytokine signaling defects are in contrast to the global defects in T and NKcell development in patients with XSCID.