BMS2045 5c Tolerance, Hypersensitivity & Mucosal Immunity 2024 PDF

Theme 5c Tolerance, Hypersensitivity, and Mucosal Immunity Tolerance, Hypersensitivity, and Mucosal Immunity 1 Theme 5 learning outcomes Explain the difference between central and peripheral tolerance and the different mechanisms involved in its maintenance Describe how a breakdown in tolerance can...

Theme 5c Tolerance, Hypersensitivity, and Mucosal Immunity Tolerance, Hypersensitivity, and Mucosal Immunity 1 Theme 5 learning outcomes Explain the difference between central and peripheral tolerance and the different mechanisms involved in its maintenance Describe how a breakdown in tolerance can cause autoimmune disease Distinguish between different types of hypersensitivity responses, identify the underlying mechanisms and the diseases they can cause Describe the specialised structural and cellular features of mucosa that contribute to mucosal immunity Tolerance, Hypersensitivity, and Mucosal Immunity 2 Mucosal Immunity Commensal bacteria outnumber host cells 10:1 Commensals metabolise and produce vital nutrients and protect host from true pathogens However, mucosal surfaces are principle point of entry for most pathogens (gut, skin, lung, urinary and genital tracts, eyes) Mucosal infections are main cause of death in children under 5 years of age ~80% of immune cells are located in the gut Food represents another source of antigenic diversity How does the gut immune system distinguish between pathogens and harmless antigens??? Tolerance, Hypersensitivity, and Mucosal Immunity 3 Mucosal Immunity Gut-associated lymphoid tissues (GALT) – Effector sites vs Inductive sites Maintaining the barrier requires 3 systems: 1. A physical barrier eg. mucus, epithelium 2. Innate immunity eg. DCs & macrophages 3. Adaptive immunity eg. IgA, TH17 and Tregs Effector Induction site Effector Effector Tolerance, Hypersensitivity, and Mucosal Immunity 4 (1) A Physical Barrier: The Intestinal Mucosa MUCUS MUC2 GLYCOCALYX MICROVILLI TIGHT JUNCTIONS ENTEROCYTES BASEMENT MEMBRANE The mucus provides a semi-permeable barrier made up of compacted glycoproteins (eg. MUC2) secreted by goblet cells, anti-microbial peptides (eg. beta defensins) secreted by Paneth cells and secretory IgA which is moved across the epithelial cells using ‘transcytosis’ The intestinal specialised Tolerance, epithelium (enterocytes) expresses tight junction proteins Hypersensitivity, and Mucosal 5 to maintain an intact barrier to all but the smallest molecules Immunity (2) Innate immunity: DCs, MFs and ILCs Innate Lymphoid cells All in close proximity to epithelium – attracted by MIP3a (chemokine) released by intestinal epithelial cells (enterocytes) DCs and MFs can capture Ag direct from lumen by reaching in-between enterocytes whilst maintaining the tight-junctional integrity and are highly endocytic with lots of PPRs important for clearing bacteria and apoptotic/senescent cells Mucosal DCs preferentially produce IL-10 and TGFb which are ‘tolerogenic’ (antiinflammatory) and promote differentiation of Tregs and class-switching to IgA Very sensitive to cytokine environment and can be quickly activated to produce inflammatory cytokines Tolerance, Hypersensitivity, and Mucosal Activation of DCs leads to recruitment of ILCs which secrete further cytokines 6 Immunity (3) Adaptive Immunity: Peyer‘s Patches Peyer’s patches are lymphoid aggregates found in the small intestine (not present in colon) Antigens enter via specialised epithelial cells called Microfold (M) cells via PRRs (eg TLRs) on surface, through transcytosis, DC/MFs reaching between cells or Ab/FcR transcytosis Antigens are collected by sub-epithelial network of APCs (DCs and MFs) Germinal centres of lymphoid follicles contain populations of B cells undergoing isotype switching and somatic hypermutation – main function is development of IgA+ B cells in response to infection etc Tolerance, Hypersensitivity, and Mucosal Immunity 7 (3) Adaptive Immunity: Peyer’s patches under tolerant (homeostatic) conditions Secretory IgA TLR NF-kb cells TLR-activated epithelial cells release DC TGFb PEYER’S PATCH DC/MFs capture antigens from M M cell pIgR IgA ILC3 etc IL-10, TGFb MHCII TCR CD4 CD80/86 CD28 Th2 growth factors and TGFb that ‘condition’ the DCs and ILC3 cells (≡ IgA+ Plasma Tregs) cell DCs migrate to the T cell areas of the Peyer’s patches and induce some Th2 and lots of Treg cells Treg CD4 CD4 CD4 TCR CD40L CD4 MHCII CD4 CD40 IL-10 CD4 B IL-4 IL-5 IL-13 TGFb B B B Class switch recombination and B B Somatic hypermutation IgA+ Plasma cell Activated CD4+ T cells provide help to activated B cells B cells undergo class switching to IgA and somatic hypermutation under the influence of survival factors and cytokines B cells differentiate to IgA+ plasma cells in the mucosal lymph nodes and then migrate to the lamina propria Tolerance, Hypersensitivity, and Mucosal Immunity 8 (3) Adaptive immunity: secretory IgA >75% of Ig in body is IgA – most is secreted at mucosal membranes (~ 3g/day!) J chain IgA produced as a dimer linked by the J chain from plasma B cells beneath the epithelium The polymeric IgA receptor (pIgR) on epithelial cells binds the J chain and transports IgA into the lumen Proteases cleave the pIgR leaving the ‘secretory component’ attached sIgA prevents bacterial adhesion to mucosa, aids clearance of pathogens and neutralises pathogens and toxins IgA deficiency is most common human immunodeficiency but has v. mild phenotype? IgM compensates? IgA does not fix COMPLEMENT, does not activate granulocyte degranulation, does not Hypersensitivity, and Mucosalrather than inflammatory induce full DC maturationTolerance, – activity is homeostatic 9 Immunity (3) Adaptive Immunity: dealing with pathogens Adherent/invasive bacteria Mucus Antimicrobial peptides TLR Adherent or invasive bacteria result in sustained TLR signals from the epithelium changes cytokines secreted to inflammatory ones such as IL-1, IL-6, and TNFα This fully activates the gut DCs and ILC1 cells which promote the expansion of Th17 cells (in the presence of TGFb, IL-6, IL-1β) + Th1 cells NF-kb IL-1, IL-6, IL-8, TNFa TGFβ IL-22 DC recruitment, and antimicrobial activities IL6 Th17 CD4+ CD4+ Th17 Th17 Th17 Th17 Th17 Th17 Th17 CD4+ Th2 ILC2 CD4+ Th1 Th17 cells produce high levels of IL-17 & IL-22 IL-17A - enhances neutrophil differentiation, ILC1 IL-17A Neutrophil recruitment Myofibroblast activation MMP production IL-22 - triggers antimicrobial peptide production from paneth cells and increases epithelial permeability allowing transmigration of immune cells into the lumen IgA production remains but see some switching to IgG If the infection is worms, different TLRs are activated and a more Th2-like response Tolerance, Hypersensitivity, and Mucosal develops. ILC2 cells are then involved in recruiting eosinophils etc to the site. Immunity 10 Mucosal Immunity: Summary Mucosal surfaces are the principle point of antigen entry. Because of this, 80% of immune cells reside in the gut 3 layers of protection control immune responses at mucosal surfaces: o The physical barrier – eg. mucus, anti-microbial peptides, epithelial cells o Innate immunity – eg. macrophages and DCs with tolerogenic phenotypes o Adaptive immunity – eg. Tregs and Th17 cell balance between food/commensal bacteria and pathogens – IgA dominated IgA serves to neutralise potential pathogens without triggering damaging inflammatory responses – it is transported across the epithelium via the polymeric Ig receptor Peyer’s patches are sites of B cell isotype switching to IgA - driven by immunoregulatory factors such as IL-10 and TGFb The gut has a large population of FoxP3+ Tregs which are maintained by tolerogenic DCs In the presence of pathogens, Th17 cells produce cytokines (IL-17, IL-22) to attract neutrophils and enhance epithelial barrier repair Tolerance, Hypersensitivity, and Mucosal Immunity 11 Inflammatory Bowel Disease: Multifactorial diseases A group of debilitating disorders with mostly unknown aetiologies Not considered to be autoimmune 5-20% of IBD patients have a family history of IBD Monozygotic Twin concordance rates: Crohn’s Disease ~50% Ulcerative Colitis ~20% GENETICS MHC haplotype Gene polymorphisms influencing epithelial function and innate / adaptive immunity MICROORGANISMS Altered bacterial populations Altered bacterial metabolism Increased attachment and ENVIRONMENT invasion of mucosa Western diets Smoking Medications Insufficient nutrients from environment eg. Vitamin D Tolerance, Hypersensitivity, and Mucosal Immunity 12 Inflammatory Bowel Disease Mainly affects small intestine. Th1 / Mainly affects colon. Mixed Th1 / Th2 Th17 cells, neutrophil infiltrate, cells, disruption of mucosal barrier inflammatory macrophages, only, crypt abcesses, loss of goblet granuloma formation, transmural cells, increased risk of colorectal Tolerance, Hypersensitivity, and Mucosal inflammation, IgG to bacterial antigens Immunitycarcinoma 13 Additional Reading Kuby 8th Edition Chapters 15, 16 (until Transplantation Immunology) (main text; boxes optional) and chapter 13 (until end of ‘Springing into action’ section) (main text; boxes optional) Kuby 7th Edition Chapters 15 and 16 Male, Brostoff, Roth, Roitt, 8th Edition Section 2: Chapter 12, Section 4: Chapters 4, 19, 20 (p370-373), 23-26 Immunology in the Gut Mucosa - YouTube Tolerance, Hypersensitivity, and Mucosal Immunity 14 Session outcomes/learning profiles Provide a definition of immunological tolerance Describe the mechanisms by which autoreactive T and B cells are deleted List and describe the four different mechanisms underlying peripheral tolerance of T cells Explain the three mechanisms of how peripheral tolerance of B cells is induced Explain why breakdown in tolerance leads to autoimmune disease Name the four different types of hypersensitivity and the main features of each Compare the underlying mechanism of the different types of hypersensitivity Give examples of diseases in which the different types of hypersensitivity play a role Describe the main features of the mucosal immune system Define the physical features of the intestinal mucosa and the specialised structures contained within it Explain the different mechanisms by which the gut mucosa remains tolerant of commensal bacteria and food antigens Describe the process of IgA+B cell development and secretory IgA production Compare how the mucosal immune system responds to pathogenic as opposed to commensal microbes