Chapter 14 Specialized Immunity - PowerPoint Presentation

1. Chapter 14 Specialized Immunity at Epithelial Barriersand in Immune Privileged Tissues

2. The collection of the immune cells and molecules serving specialized functions at a particular anatomic location is called a regional immune system

3. Regional immune systems include the mucosal immune systems, which protect the gastrointestinal, bronchopulmonary, and genitourinary mucosal barriers, and the cutaneous (skin) immune system.The immune systems at epithelial barriers share a basic anatomic organization:An outer epithelial layer that prevents microbial invasionUnderlying connective tissue (such as the dermis in the skin and the lamina propria in the gut) containing various cells types (lymphocytes, dendritic cells (DCs), macrophages, and other cells) that mediate innate immune responses and adaptive immune responses to organisms that do invade through the epithelium. local or more distant draining lymph nodes Mucosal tissues also contain unencapsulated but organized secondary lymphoid tissues , which include B and T lymphocytes, DCs, and macrophages. These collections of immune cells, often called mucosa-associated lymphoid tissue (MALT), are sites of development of some adaptive immune responses.GENERAL FEATURES OF IMMUNITY AT EPITHELIAL BARRIERS

4. IMMUNITY IN THE GASTROINTESTINAL SYSTEM

5. The gastrointestinal system, like other mucosal tissues, is composed of a tube-like structure lined by a continuous epithelial cell layer sitting on a basement membrane that serves as a physical barrier to the external environment. Underlying the epithelium is a layer of loose connective tissue called the lamina propria that contains blood vessels, lymphatic vessels, and MALTsInnate Immunity in the Gastrointestinal TractIntestinal epithelial cells lining the small and large bowel are an integral part of the gastrointestinal innate immune system, involved in responses to pathogens and antigen sampling for delivery to the adaptive immune system In the gut:Mucus-secreting goblet cells, which reside at the top of the intestinal villi; antigen-sampling M cells, found in specialized dome structures overlying lymphoid tissues; and anti-bacterial peptide–secreting Paneth cells, found at the bottom of the crypts

6. The gastrointestinal immune system

7. Innate immune protection in the gut is mediated in part by the physical and chemical barrier provided by the mucosal epithelial cells and their secretions.Epithelial cells are held together by proteins that form tight junctions, which block the movement of microbes between the cells into the lamina propria.Mucosal epithelial cells produce antimicrobial substances, including defensins. Defensins are peptides produced by various cell types in the body that exert lethal toxic effects on microbes by inserting into and causing loss of integrity of their outer phospholipid membranesIn the small bowel, the major defensins are the α-defensins, including human defensin 5 (HD5) and HD6 produced by Paneth cells. In the colon, β-defensins are produced by absorptive epithelial cells in the intestinal crypts, some constitutively and others in response to IL-1 or invasive bacteria.Several different extensively glycosylated proteins, called mucins, are secreted by goblet cells and form a viscous physical barrier that prevents microbes from contacting the epithelial lining of the gastrointestinal tract.

8. Mucins contain many different O-linked oligosaccharides and include secreted and cell surface glycoproteins. The secreted mucins, including MUC2, MUC5, and MUC6Membrane-bound mucin proteins, which combine with various glycolipids to form the glycocalyx. This is a dense macromolecular layer at the epithelial cell surfaceSeveral different environmental and immune stimuli can induce dramatic increases in mucin production. These stimuli include cytokines (IL-1, IL-4, IL-6, IL-9, IL-13, tumor necrosis factor [TNF], and type I interferons), neutrophil products (such as elastase), and microbial adhesive proteins

9. Toll-like receptors (TLRs) and cytoplasmic Nod-like receptors (NLRs) expressed by intestinal epithelial cells promote immune responses to invasive pathogens but are also regulated to limit inflammatory responses to commensal bacteria.Intestinal epithelial cells express a wide range of TLRs, including TLRs 2, 4, 5, 6, 7, and 9, with different receptors expressed in different regions of the gut. Ligation of some TLRs results in increased strength of the junctions between epithelial cells. TLR signaling also increases intestinal epithelial motility and proliferation. TLR signaling stimulates the secretion of defensins.Because inflammatory responses can impair barrier function and can lead to bacterial invasion and pathologic inflammation, control mechanisms have evolved to limit innate immune responses.In healthy individuals, dendritic cells and macrophages in the lamina propria of the gut inhibit inflammation and maintain homeostasis.

10. Innate lymphoid cells in the intestinal mucosa contribute to immune defense against bacteria and parasites, promote epithelial barrier function, and suppress responses to commensal bacteria.ILCs do not express T cell antigen receptors (TCRs), but rather respond to local cytokine cues by secreting effector cytokines, and subsets of ILCs exist that secrete cytokines typical of helper T cell subsets.Most of the ILC3s in the body are found in the gut. In response to IL-1β (an alarmin) and IL-23, ILC3s secrete IL-17 and IL-22.ILC2s play an important initial role in intestinal innate immunity against helminths. In response to the alarmin cytokine IL-33 released by stressed or damaged epithelial cells and the epithelium-derived cytokine IL-25, ILC2s secrete IL-5 and IL-13.

11. Adaptive Immunity in the Gastrointestinal TractThe major form of adaptive immunity in the gut is humoral immunity directed at microbes in the lumen, which prevents commensals and pathogens from colonizing and invading through the mucosal epithelial barrierThis function is mediated by dimeric IgA antibodies that are secreted into the lumen of the gut or, in the case of breast-feeding infants, IgA that is secreted into colostrum and mother’s milk and ingested by the infant. The dominance of IgA in mucosal secretions, especially in the gut, is because B cells activated at these sites tend to undergo class switching to IgA and IgAproducing B cells tend to home to the gut.

12. Th17 cells are the most numerous effector T cell subset in the intestinal mucosa, but Th1 and Th2 cells are also present.A major mechanism for controlling responses in the gut is the activation of regulatory T cells (Treg), and some subsets of Treg are more abundant in mucosa-associated lymphoid tissues (MALT) than in other lymphoid organsAdaptive immune responses in the gut are initiated in GALT and in mesenteric lymph nodes. These gut-associated lymphoid tissues adjacent to the mucosal epithelium are sometimes referred to as GALT, which is the gastrointestinal version of MALTDistinct from lymph nodes, GALT structures are not encapsulated. The most prominent GALT structures are Peyer’s patches.Peyer’s patches have the structure of lymphoid follicles, with germinal centers containing B lymphocytes, follicular helper T cells, follicular dendritic cells, and macrophages. Between the follicles are T cell–rich parafollicular areas, similar to lymph nodes.

13. A major pathway of antigen delivery from the lumen to the GALT is through specialized cells within the gut epithelium called microfold (M) cells. M cells are located in regions of the gut epithelium called follicle associated (or dome) epithelium. M cells express various surface molecules that bind microbial structures and mediate their uptake.The main function of M cells is transport of various substances from the lumen of the intestine across the epithelial barrier to underlying antigen-presenting cells. M cells take up luminal contents efficiently and in various ways, including phagocytosis, and fluid-phase endocytosis.Endocytic vesicles

14. The gastrointestinal immune systemMesenteric lymph nodes collect lymph-borne antigens from the small and large intestines and are sites of differentiation of effector and regulatory lymphocytes that home back to the lamina propria. There are 100 to 150 of these lymph nodes in the mesentery.

15. DCs in the intestinal mucosaDCs in the lamina propria take up and process protein antigens from transport these antigens via lymphatics to mesenteric lymph nodes. Induce the differentiation of T cells into Th1, Th2, or Th17 effector cells or into FoxP3+ Tregs.Some DCs in the gut project dendrites between epithelial cells, and sample luminal contents. These cells, identifiable by expression of the chemokine receptor CX3CR.Pass the sampled antigens to more mobile lamina propria DCs, which then migrate to mesenteric lymph nodes and activate effector T cell responses to those antigens.

16. Homing properties of intestinal lymphocytesEffector lymphocytes that are generated in the GALT and mesenteric lymph nodes are imprinted with selective integrin and chemokine receptor–dependent gut-homing properties, and they circulate from the blood back into the lamina propria of the gut.The gut-homing phenotype of IgA-producing B cells and effector T cells is imprinted by DCs through the action of retinoic acid during the process of T cell activation.Gut lymphoid tissues are exposed to dietary vitamin A, and DCs in GALT and mesenteric lymph nodes express retinaldehyde dehydrogenase (RALDH), the enzyme needed for retinoic acid synthesis from vitamin A.

17. Humoral Immunity in the Gastrointestinal TractHumoral immunity in the gut is dominated by production of secretory IgA in the GALT and transport of the antibody across the mucosal epithelium into the lumenSmaller but significant quantities of IgG and IgM are also secreted into the gut lumenAntibodies bind to microbes and toxins and neutralize them by preventing their binding to receptors on host cells. This form of humoral immunity is sometimes called secretory immunity.The dominance of IgA production by intestinal plasma cells is due in part to selective induction of IgA isotype switching in B cells in GALT and mesenteric lymph nodes.

18. IgA class switching in the gutIgA class switching in the gut occurs by both T-dependent and T-independent mechanisms.T-independent IgA class switching involves dendritic cell activation of IgM+ B cells, including B-1 cells. TLR ligand–activated dendritic cells secrete cytokines that induce IgA class switching, including BAFF, APRIL, and TGF-β. This T cell–independent pathway yields relatively low-affinity IgA antibodies to intestinal bacteria.

19. Transport of IgA across epithelial cellsSecreted IgA is transported through epithelial cells into the intestinal lumen by an Fc receptor called the poly-Ig receptor (integral membrane glycoprotein/synthesized by mucosal epithelial cells).On the apical cell surface, the poly-Ig receptor is proteolytically cleaved, its transmembrane and cytoplasmic domains are left attached to the epithelial cell, and the extracellular domain of the receptor, carrying the IgA molecule, is released into the intestinal lumen.

20. T cells are found within the gut epithelial layer, scattered throughout the lamina propria, and within Peyer’s patches and other GALT structures.In humans, most of the intraepithelial T cells are CD8+ cells. In mice, about 50% of intraepithelial lymphocytes express the γδ form of the TCRLamina propria T cells are mostly CD4+, and most have the phenotype of activated effector or memory T cells, the latter with an effector memory phenotypeTh1, Th2, and Th17 cells are found in the lamina propria of the intestine, and the commensal bacterial microflora of the gut lumen exerts profound influences on T cell phenotypes.TH17 cells appear to play a special role in maintaining mucosal epithelial barrier function because of the actions of the two signature cytokines they produce, IL-17 and IL-22.TH2 cells. Intestinal helminthic infections induce strong TH2 responses, which are effective in eliminating the worms.T Cell–Mediated Immunity in the Gastrointestinal Tract

21. Regulation of Immunity in the Gastrointestinal Tractby Regulatory T Cells and CytokinesRegulatory T cells are abundant in GALT and prevent inflammatory reactions against intestinal commensal microbes. It is estimated that the proportion of FoxP3+ Tregs among CD4+ cells is about twofold greater in the intestine than in other tissue.Both retinoic acid and TGF-β promote FoxP3 expression and inhibit the generation of Th1 and Th2 cells.Several cytokines, including TGF-β, IL-10, and IL-2, appear to play crucial roles in maintaining homeostasis in the gut immune system, and deficiencies in these cytokines or their receptors result in pathologic bowel inflammation.

22. Oral Tolerance and Oral VaccinesOral administration of antigen in the setting of concomitant stimulation of innate immunity can lead to productive adaptive immune responses, as in the use of oral viral vaccines to induce protective antibody responses to viruses. These vaccines are live attenuated microbes that may infect cells in the intestine and stimulate strong innate responses that then promote T and B cell activation.Oral tolerance is systemic adaptive immune tolerance to antigens that are ingested or otherwise administered orally and is a potential way of treating diseases in which unwanted immune responses occur, such as autoimmunity.

23. The Role of the Commensal Microbiome in Immune RegulationThe human intestinal microbiome includes all of the commensal bacteria that normally reside in the intestines as well as thousands of species of viruses, fungi, and protozoans.Commensal organisms in the intestines are required for and regulate innate immune responses in the gut, and also influence systemic innate immunity (proliferation and repair of the intestinal epithelial barrier after injury, stimulate the expression of mucins and antimicrobial molecules, short chain fatty acids from gut bacteria dampen neutrophil inflammatory responses)Intestinal commensal organisms influence local and systemic adaptive immune responses

24. Diseases Related to Immune Responses in the GutUnregulated responses to commensal organisms or to antigens in food.Inflammatory bowel disease (IBD) is a heterogeneous group of disorders characterized by chronic remitting inflammation in the small or large bowel, likely due to poorly regulated responses to commensal bacteria.Crohn’s disease, which can affect the entire thickness of the bowel wall tissue in any part of the gastrointestinal tract but most frequently involves the terminal ileum, and ulcerative colitis, which is restricted to the colonic mucosa. Symptoms include abdominal pain, vomiting, diarrhea, and weight loss.

25. Immunologic abnormalities may contribute to the development of IBD:Defects in innate immunity to gut commensalsAbnormal TH17 and TH1 responsesDefective function of regulatory T cells that cause the disease called immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX). Severe gut inflammation as well as autoimmunity in many other tissues.Polymorphisms of genes that are associated with macroautophagy and the unfolded protein response to endoplasmic reticulum stress are risk factors for IBD.

26. Celiac disease is an inflammatory disease of the small bowel mucosa caused by immune responses against ingested gluten proteins present in wheatPatients produce IgA and IgG antibodies specific for gluten as well as IgA and IgG autoantibodies specific for transglutaminase 2A.CD4+ T cell responses to gliadin are involved in disease pathogenesisIn addition to CD4+ T cell responses, CD8+ cytotoxic T lymphocyte (CTL) killing of intestinal epithelial cells may also contribute to celiac disease

27. Food allergies are caused by TH2 responses to many different food proteins and cause acute inflammatory responses locally in the gut and systemically on ingestion of these proteins.Prolonged immune responses to gastrointestinal microbes can lead to tumors arising in the gastrointestinal tract (H. pylori)

28. Mucosal Immunity in the Respiratory SystemInnate responses in the alveolus serve antimicrobial functions but are tightly controlled to prevent inflammation, which would impair gas exchange.Surfactant proteins A (SP-A) and D (SP-D), which are secreted into the alveolar spaces, are members of the collectin family.These surfactants are involved in viral neutralization and clearance of microbes from the airspaces, but they also suppress inflammatory and allergic responses in the lung.

29. SP-A inhibits TLR2 and TLR4 signaling and inflammatory cytokine expression in alveolar macrophages.SP-A also binds to TLR4 and inhibits lipopolysaccharide binding. SP-A and SP-D reduce the phagocytic activity of alveolar macrophages.Alveolar macrophages express IL-10, nitric oxide, and TGF-β and are poorly phagocytic compared with resident macrophages in other tissues, such as spleen and liver.Alveolar macrophages inhibit T cell responses as well as the antigen presentation function of CD103+ airway DCs.

30. Protective humoral immunity in the airways is dominated by secretory IgA, as in other mucosal tissues, although the amount of IgA secreted is much less than in the gastrointestinal tract.There are relatively few aggregated or isolated lymphoid follicles in the lamina propria in the lower airways compared with the gut.Secretory IgG plays an important role in the upper airwayT cell responses in the lung are initiated by DC sampling of airway antigens and presentation of these antigens to naive T cells in peribronchial and mediastinal lymph nodes.Adaptive Immunity in the Respiratory System

31. THE CUTANEOUS IMMUNE SYSTEMWithin both of these layers, a variety of different cell types and their products, comprising the cutaneous immune system, provide physical barrier and active immune defense functions against microbes.Langerhans cells express langerin (CD207)95% of T cells have a memory phenotype, 2% are intraepidermal lymphocyteshelper subset, Th1, Th2, Th17, and TregMigration of effector or memory T cells into the skin depends on CLA that binds to E-selectinT cell expression of CCR4, CCR8, and CCR10, which bind the chemokines CCL17, CCL1, and CCL27, respectively, is also required for T cell trafficking to skin.

32. forming a physical barrierProduction of Antimicrobial peptides including defensins, S100, and cathelicidins .The cytokines made by keratinocytes include TNF, IL-1, IL-6, IL-18, IL-25, and IL-33, which promote inflammation .GM-CSF which induces differentiation and activation of DCs in the epidermis.IL-10, which controls immune responses.Keratinocytes produce the chemokine CCL27, which participates in recruitment of lymphocytes expressing CCR10.Keratinocytes express most of the TLRs and NLRP3 inflammasomes that generate active IL-1 and IL-18.Keratinocytes

33. Homing properties of skin lymphocytessunlight and vitamin D appear to play an important role in T cell migration to the skin, analogous to the role of vitamin A and its metabolite retinoic acid in lymphocyte migration to the gut.Within the node,1,25(OH)2D3 enters T cells that have been activated by antigen-presenting DCs, translocates to the nucleus, and induces transcription of CCR10.

34. Diseases Related to Immune Responses in the SkinPsoriasis, a chronic inflammatory disorder of the skin characterized by red scaly plaques, is caused by dysregulated innate and T cell–mediated immune responses triggered by various environmental stimuli. IL-17 is abundant in affected skin in this phase of the disease. Anti-IL-17 antibodies are effective therapies for psoriasis, as are TNF inhibitors. IL-22, another type 3 cytokine, contributes to epithelial proliferation in psoriasisAtopic dermatitis is a chronic inflammatory disease of the skin characterized by itchy rashes, in which IgE specific for environmental antigens and cells expressing high-affinity Fc receptors for IgE (FcεRI) play a central role.

35. IMMUNE PRIVILEGED TISSUESImmune responses and associated inflammation in certain parts of the body, including brain, eye, testes, placenta, and fetus, carry a high risk of lethal organ dysfunction or reproductive failure.These tissues, which have evolved to be protected, to a variable degree, from immune responses, are called immune-privileged sites.The mechanisms underlying immune privilege vary between these tissues and are not fully understood.Some of the mechanisms are similar to mechanisms of regulation in gut and skin (discussed earlier) and mechanisms of selftolerance.

36. The avascular nature of the cornea, and the absence of lymphatics draining the anterior chamber, which limits access of the adaptive immune system to antigens in the eye. The Eye There are several soluble factors with immunosuppressive/anti-inflammatory properties in the anterior chamber, including neuropeptides (α-melanocyte–stimulating hormone, vasointestinal peptide, somatostatin), TGF-β, and indolamine 2,3-dioxygenase (IDO). Cells constitutively express Fas ligand and PD-L1, which can induce death or inactivation of T cells, respectively.Anterior chamber–associated immune deviation, may be mediated by Treg, is a phenomenon in which introduction of foreign protein antigen into the anterior of the eye actively induces systemic tolerance to that antigen.

37. The Brain. Inflammation in the brain can lead to functional derangement and death of neurons, with disastrous consequences. Anatomic features of the brain that impair initiation of adaptive immunity to antigens include an absence of conventional lymphatic drainage and a scarcity of DCs, neuropeptides.The brain is rich in resident macrophages, called microglia, The threshold for their activation, may be higher than that of macrophages in other tissues.The Testis Immune privilege in the testis serves to limit inflammation that may impair male fertility. The hormonal milieu of the testis, which is rich in androgens, has an antiinflammatory influence on macrophages. TGF-β contributes to local immune suppression.

38. Immune Privilege of the Mammalian FetusSeveral experimental observations indicate that the anatomic location of the fetus is a critical factor in the absence of rejection.The uterine decidua may be a site where immune responses are functionally inhibited.IDO catabolizes tryptophan, Tryptophan is required for proliferating cells, including lymphocytes T cell, responses to the fetus are normally blocked because decidual tryptophan levels are kept low.FasL expression by fetal trophoblast cells that promote apoptosis of activated Fas-expressing maternal lymphocytes.Trophoblast and decidua may also be resistant to complement-mediated damage activation.

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