Insights on Gastrointestinal Immunity: I mmune System of the Gut

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

4. Regional immune systems include: • mucosal immune system, which protects the gastrointestinal, bronchopulmonary, and genitourinary mucosal barriers, and • cutaneous (skin) immune system

6. IMMUNITY IN THE GASTROINTESTINAL SYSTEM

7. Perspective of the immunologist, the gastrointestinal tract has two remarkable properties: • First, the combined mucosa of the small and large bowel has a total surface area of more than 200 m2 (the size of a tennis court), made up mostly of small intestinal villi and microvilli • Second, the lumen of the gut is teeming with microbes, many of which are ingested along with food and most of which are continuously growing on the mucosal surface in healthy individuals as commensals

8. Innate Immunity in the Gastrointestinal Tract • Intestinal epithelial cells lining the small and large bowel are an integral part of the gastrointestinal innate immune system, involved in responses to pathogens, toleranceto commensal organisms, and antigen sampling for delivery to the adaptive immune system in the gut • Several different types of intestinal epithelial cells: mucus-secreting goblet cells, which reside at the top of the intestinal villi; cytokine-secreting absorptive epithelial cells; antigen sampling M cells, found in specialized dome structures overlying lymphoid tissues; and antibacterial peptide secreting Paneth cells, found at the bottom of the crypts

9. Several different extensively glycosylated proteins, called mucins, form a viscous physical barrier that prevents microbes from contacting the cells of the gastrointestinal tract • The secreted mucins, including MUC2, MUC5, and MUC6 • Several 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

10. Defensins produced by intestinal epithelial cells • 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 • In healthy individuals, lamina propria DCs and macrophages in the gut inhibit inflammation and serve to maintain homeostasis

11. Mechanism of regulation of innate immune responses in the intestinal mucosa

12. Adaptive Immunity in the Gastrointestinal Tract • The 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 barrier • This 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. • Significant quantities of IgG and IgM antibodies are also present in the gut lumen and contribute to humoral immunity in this location

13. Dominant protective cell-mediatedimmune response consists of TH17 effector cells • Suppresspotential immune responses to food antigens and commensal microbial antigens to prevent inflammatory reactions that would compromise the mucosal barrier • 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 organs

14. The gastrointestinal immune system

15. M cells in the small intestine

16. DCs in the intestinal mucosa

17. Homing properties of intestinal lymphocytes

18. Humoral Immunity in the Gastrointestinal Tract • Humoral 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 lumen • Smaller but significant quantities of IgG and IgM are also secreted into the gut lumen • Antibodies 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

19. IgA is produced in larger amounts than any other antibody isotype • 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

21. IgA class switching in the Gut

22. Transport of IgA across epithelial cells

23. T Cell–Mediated Immunity in the Gastrointestinal Tract • T cells are found within the gut epithelial layer, scattered throughout the lamina propriaand submucosa, and within Peyer’s patches and other organized collections of follicles • In humans, most of the intraepithelial T cells are CD8+ cells. In mice, about 50% of intraepithelial lymphocytes express the γδ form of the TCR • 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

24. Regulation of Immunity in the Gastrointestinal Tractby Regulatory T Cells and Cytokines • Regulatory T cells are abundant in GALT and prevent inflammatory reactions against intestinal commensal microbes • 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.

25. Oral Tolerance and Oral Vaccines • 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 • Oral 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

26. The Role of the Commensal Microbiome in Immune Regulation • The 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 regulateinnate immune responses in the gut, and also influence systemic innate immunity • Intestinal commensal organisms influence local and systemicadaptive immune responses

27. Diseases Related to Immune Responses in the Gut • 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

28. Defects in innate immunity to gut commensals • Abnormal TH17 and TH1 responses • Defective function of regulatory T cells that cause the disease called immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), • Polymorphisms of genes that are associated with macroautophagyand the unfolded protein response to endoplasmic reticulum stress are risk factors for IBD

29. Celiac disease (gluten-sensitiveenteropathy or nontropical sprue) is an inflammatory disease of the small bowel mucosa caused by immune responses against ingested gluten proteins present in wheat • Patients 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 pathogenesis

30. 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)

31. Mucosal Immunity in the Respiratory System • Innate 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

32. SP-A inhibitsTLR2 and TLR4 signaling and inflammatory cytokine expression in alveolar macrophages, and SP-A also binds to TLR4 and inhibits lipopolysaccharide binding. SP-A and SP-D reduce the phagocytic activity of alveolar macrophages • Alveolar macrophages represent the majority of free cells within the alveolar spaces. These cells are functionally distinct from macrophages in most other tissues in that they maintain an anti-inflammatory phenotype. They 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.

33. Protective humoral immunity in the airways is dominated by secretoryIgA, as in other mucosal tissues, although the amount of IgA secreted is much less than in the gastrointestinal tract • SecretoryIgG plays an important role in the upper airway • T 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

34. Mucosal Immunity in the Genitourinary System • Stratified squamous epithelium lines the vaginal mucosa and terminal male urethra, • The vaginal epithelium contains Langerhans cells, and a variety of DCs and macrophages • IgA is the dominant antibody isotype, most of the antibodies in genital secretions are IgGs

35. THE CUTANEOUS IMMUNE SYSTEM

36. Homing properties of skin lymphocytes

37. Diseases Related to Immune Responses in the Skin • Psoriasis, 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 • Atopic 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.

38. IMMUNE PRIVILEGED TISSUES • The Nobel laureate immunologist Sir Peter Medawar coined the term immune privilege in the 1940s to describe the lack of immune responses to tissue transplanted into the brain or the anterior chamber of the eye of experimental animals

39. The Eye. There are several soluble factors with immunosuppressive/anti-inflammatory properties in the aqueous humor that fills the anterior chamber, including neuropeptides (α-melanocyte–stimulating hormone, vasointestinal peptide, somatostatin), TGF-β, and indolamine 2,3-dioxygenase (IDO). Cells lining the anterior chamber, including the epithelium of the iris and the endothelium, 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

40. 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 conventionallymphatic drainage and a scarcity of DCs • The Testis. Immune privilege in the testis serves to limit inflammation that may impair male fertility. Many self antigens in the adult testis are first expressed at the time of puberty, well after the development of a competent immune system, which may include testis antigen–specific precursor T and B cells

41. Immune Privilege of the Mammalian Fetus • Several 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 • Immune responses to the fetus may be regulated by local concentrations of indolamine2,3-dioxygenase (IDO) catabolizes tryptophan and T cell responses to the fetus are normally blockedbecause decidual tryptophan levels are kept low or the levels of toxic metabolites are high • Trophoblast and decidua may also be resistantto complement-mediateddamage activation