Lecture 27: Mucosal and Cutaneous Immunity PDF

Chapter 12: Mucosal and cutaneous immunity  Lecture outline Mucosal Immunity Barrier Mucous Antimicrobial peptides Tight Junctions Mucosa Associated Lymphoid Tissue (MALT) Gut Associated Lymphoid Tissue (GALT) Bronchial Associated Lymphoid Tissu...

Chapter 12: Mucosal and cutaneous immunity  Lecture outline Mucosal Immunity Barrier Mucous Antimicrobial peptides Tight Junctions Mucosa Associated Lymphoid Tissue (MALT) Gut Associated Lymphoid Tissue (GALT) Bronchial Associated Lymphoid Tissue (BALT) Nasal Associated Lymphoid Tissue (NALT) Skin Associated Lymphoid Tissue (SALT) Mucosal immunity: Overview  Mucosal and cutaneous immunity Most human and animal pathogens gain entry to the body by penetrating through skin or mucosal surfaces. Both mucosa-associated lymphoid tissue (MALT) and skin- associated lymphoid tissues (SALT) are collection of APCs & lymphocytes under the mucosae and skin, respectively. MALT and SALT function as independent arms of the immune system and induce mucosal and cutaneous immune responses.  Mucosal and cutaneous immunity Mucosal and cutaneous immune responses are distinct from systemic immune responses & they are mounted locally where Ag is first encountered without involvement of draining lymph node. The effector cells that are generated may enter efferent lymphatics or circulation but they home specifically to mucosal or cutaneous sites to exert their effector functions. However, an accompanying systemic immune response can also be induced when Ag-bearing APCs of MALT or SALT migrate to local lymph node and activate naïve B and T cells in this location. Epithelial and Immune Function  Mucosal immunity: Overview Two types of mucosae: – Type I mucosae: occur in intestine and lung-composed of single layer of columnar epithelium. – Type 2 mucosae: Squamous epithelium where tougher tissue is required such as mouth, nose and vagina. Both types of mucosa are capable of producing mucus which is a viscous solution of polysaccharides in water. Pelaseyed, T., Bergström, J. H., Gustafsson, J. K., Ermund, A., Birchenough, G. M. H., Schütte, A., et al. (2014). The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunological Reviews, 260(1), 8–20.  Mucosal immunity: Overview Mucus also contain – Various Abs, predominantly IgA in type 1 mucosae and IgG in type II mucosae. – Antimicrobial molecules such as lysozyme (breaks down bacterial cell wall components) & lactoferrin (sequesters iron needed for bacterial growth). Mucosae are also constantly defended against pathogen assaults by immune responses mounted in MALT.  Mucosal immunity: Overview Inductive site: is a specific area in a mucosa where an Ag is encountered & a primary adaptive immune response is initiated e.g. in the gut – Peyers’s patches (PPs) in small intestine – Appendix – diffused collection of lymphocytes or follicles under gut epithelium. Effector site: is a specific area in a mucosa to which effector lymphocytes are dispatched e.g. – Exocrine glands: salivary & lacrimal glands. They produce saliva & tears that contain antimicrobial molecules & Abs.  Mucosal immunity: Overview Regions of MALT linked to type 1 mucosa are more densely populated with DCs & lymphocytes than that are underlying type II mucosae. In addition to constitutive induction sites such as PPs, individual induction sites can also arise in the gut and lungs in response to infection and injury. These new sites are considered to be patches of induced MALT (iMALT) and are a form of ‘tertiary lymphoid tissue’.  Mucosal immunity: Overview Appearance of iMALT (includes iBALT or iGALT) depends upon the same molecules involved in generating secondary lymphoid tissues during mammalian embryogenesis. In particular, lymphotoxin (LT) and IL-17, whose local production is induced by inflammation, drive the ectopic development of lymphoid follicles and lymphatic vessels. The cell types that produce LT and IL-17 include TH17 cells and lymphoid tissue inducer cell (LTi) cells. Example of MALT induction: Appearance of areas of iBALT in lungs of mice following vaccine delivery by intranasal route.  Mucosal immunity: Overview After mucosal T & B cells are activated in an inductive site, they migrate through the lymphatics & blood to various effector sites and complete their differentiation into Th effectors, CTLs & plasma cells in these locations. Thus, the defense at multiple and widely separated mucosal effector sites may occur in response to lymphocyte activation in one inductive site. Example: When Ag is captured in a PP (inductive site), and Ab response may be detected not only in the intestinal mucosa but also in the urogenital tract and in tissues as remote as the mammary glands (effector sites). This concept is referred as ‘common mucosal immune system’.  Components of the GALT Integration of many components of GALT provides effective immune defense against ingested pathogens & toxins. Basic structure: Two major sections of GALT: – Gut epithelium – Lamina propria In general, the gut epithelium is not flat but rather folded into repeated crypt (‘cave’) and villus (‘hill’) structures. The exceptions are small flat areas of the gut epithelium called ‘follicle associate epithelium’ (EAE), which contains ‘M cells’ and overlie intestinal follicles, interfollicular regions and dome regions. Lamina propria: is composed of loose connective tissue between basolateral (tissue facing) surface of the epithelium and the muscle layer.  Components of the GALT Elements of gut epithelium: Enterocytes: – comprise majority of gut epithelium. – primary function is in nutrient absorption. – Important in integrating myriad internal and external signals and coordinating immune responses in the GALT. Other epithelial cell types interspersed among enterocytes: – Enteroendocrine cells: localize in the villi, produce mucus and secrete harmone-like molecules. – Paneth cells: located at the bottom of intestinal crypts and produce antimicrobial peptides. – Goblet cells: on the sides of intestinal crypts and produce both mucus and antimicrobial molecules. Mucus provides a strong physical and antimicrobial barrier in the gut.  Components of the GALT The apical surfaces of all gut epithelial cells are protected against pathogens by several non-induced innate barriers. Any invader has to compete for nutrients & living space with commensal organisms (called microbiota/microflora). Some of these beneficial microflora secrete toxins that can seriously impede a pathogen and positively influence the underlying mucus layer.  Components of the GALT Brush border: structure formed by the folding of the exterior surfaces of gut epithelium into dense microvilli. Brush border is coated with the glycocalyx (a thick layer of glue–like molecules) which bears a negative charge and repels many pathogens. Glycocalyx also contains several types of hydrolytic enzymes that degrade microbes and macromolecules. A pathogen that succeeds in penetrating the non-induced gut innate barriers then encounters its cellular defenders. Enterocytes interact with microbiota on apical surfaces and with the innate & adaptive leukocytes present below.  Components of the GALT Enterocytes express TLRs, NLRs and RLRs that can be engaged by components of commensals under steady state conditions, or by PAPMs/DAMPs under stress conditions. The response of enterocytes to PRR engagement is usually cytokine secretion and it depends upon the nature of the PRR ligand & factors present in the microenvironment. Additional innate defense is provided by gd T cells present within or near gut epithelium and produce antimicrobial peptides (defensins & cathelicidins) that kill pathogens. NK cells and NKT cells scattered among enterocytes also mediate first line defense.  Components of the GALT Integration of many components of GALT provides effective immune defense against ingested pathogens & toxins. Fig 12.2  Elements of the lamina propria of GALT Lamina propria contains numerous macrophages & neutrophils and low numbers of NKT cells, mast cells and immature DCs. Memory ab T cells (both CD4+ and CD8+cells), memory B cells and TH17 effectors are abundant in lamina propria. Some lymphocytes are diffusely distributed in lamina propria, whereas others are organized into intestinal follicles. Intestinal follicles can occur singly or in small groups or in larger groups of 30-40, as occur in inductive sites such as PPs and appendix.  Elements of the lamina propria During a response to Ag in the lamina propria, the activation of B cells can lead to formation of a germinal center (GC). The constant attack by pathogens on the gut mucosa means that, at any given time, about 10-15% of lamina propria B cells have differentiated into plasma cells, the vast majority of which synthesize IgA. Total secretion of Abs by IgA- producing plasma cells outstrips the combined output of Abs synthesized by plasma cells in the spleen, bone marrow & lymph nodes. Plate 12.1: Germinal center in the GALT  Antigen (Ag) sampling in the gut Follicle associated epithelium (FAE): – Intestinal follicles lie under small flat sections of epithelium called ‘FAE’ which is specialized for capture of gut Ags. – Vast majority of EAE cells are enterocytes but 10-20% of EAE cells are large, odd shaped cells called ‘M’ cells (membranous or microfold cells) that are expert in Ag transcytosis. – Within the ‘dome’ region are populations of APCs that take delivery of Ag transcytosed by the M cell while ‘interfollicular regions’ contain high concentration of mature ab T cells. – Apical surface of a M cell lacks glycocalyx & thick brush border, allowing it to easily internalize Ags either by macropinocytosis, clathrin-mediated endocytosis or phagocytosis.  Follicle associated epithelium (FAE): – Ags are released by M cells into an intraepithelial pocket & are taken up by APCs (DCs & macrophages) in dome. – Dome also contains CD4+ & CD8+ ab T cells, resting B cells & Treg cells. – The intestinal follicle itself is made up of a GC containing activated B cells and follicular dendritic cells (FDCs). Fig 12.2  Antigen (Ag) sampling in the gut GALT DCs: Several DC subsets have been defined in mice. – CX3CR1 expressing DCs are found throughout the gut. – CX3CR1+ DCs can receive Ag sampled by M cells but they also directly sample gut Ag by extending ‘transepithelial dendrites’, between epithelial cells into gut lumen & routinely capture soluble food Ags, commensals and any pathogens present. – In contrast, CCR6+ DCs are present only in domes of PPs & acquire Ag solely by M-cell mediated transcytosis.  Antigen (Ag) sampling in the gut GALT DCs: continued- – Under steady state conditions, most GALT DCs function to tolerize or induce apoptosis in naïve T cells specific for food Ags & commensals or promote their differentiation to Tregs. – When inflammation is present due to injury or infection, GALT DCs mature & activate relevant Ag-specific T cells. – Mature CCR6+ DCs may migrate to draining mesenteric lymph node and mount an Ag-specific systemic immune response.  Components of NALT and BALT NALT and BALT provide immune defense against dubious substances and pathogens in inhaled air. Bacterial pneumonia is the third leading cause of mortality worldwide indicating the importance of NALT & BALT. Basic structure: – NALT: composed of nasal submucosal glands, the tonsils and the epithelial layers lining the nasopharynx (upper airway). – BALT: includes bronchial submucosal glands, epithelial layers lining the trachea, bronchi & lungs; and the follicles & diffuse collection of lymphocytes underlying the epithelium of the lower airway. – Like the gut, bronchi and lungs are covered by type I mucosae. – In contrast, a type II mucosa protects much of nasopharynx.  Basic structure of NALT and BALT Nose hairs, sweeping movements of cilia in upper respiratory tract & coughing are non-induced innate barriers in the NALT. Nasopharyngeal epithelial cells are not only coated with mucous containing sIgA, lactoferrin, lysozyme and other antimicrobial molecules but also support a normal microbiota. Under stress conditions, nasopharyngeal epithelial cells can secrete inflammatory cytokines, growth factors & chemokines that summon innate leukocytes to the site of assault. A similar defense strategy (presence of commensals & cilia in lower respiratory tract) prevails in the BALT.  Basic structure of NALT and BALT Bronchial & bronchiolar epithelial cells are good sources of IL-5, IL-6, IL-10 & TGF-b which promote isotype switching to IgA & also secrete surfactants SP-A & SP-D (collectins). In human NALT, tonsils are the most important inductive sites and they also serve as effector sites in the NALT. In the BALT, many of the inductive sites are structurally similar to those in the gut. Mucosal follicles that resemble PPs & underlie M cells are found in lamina propria underlying the bronchial epithelium.  Antigen sampling in NALT and BALT Ag uptake in the airway is easier than in the GALT as it lacks the harsh degradative enzymes & low pH of the gut. In areas lined by a single epithelial layer (type I mucosa), Ag sampling can be carried out by M cells. In the tonsils and regions of the airway covered by the stratified epithelium (type II mucosa), Ags are conveyed to inductive sites by DCs that can extend their dendrites between epithelial cells into the lumen. These DCs commence maturation and return to underlying diffuse lymphoid tissues in the lamina propria to initiate an immune response or migrate to the more distant draining lymph nodes to initiate a systemic response.  Components of NALT and BALT Read details from the text book. Fig 12.3  Next Lecture Chapter 12: Mucosal and Cutaneous immunity.