BMS150_PHL5-05_GutImmuneP1_Win2023_2.pdf

Barrier Immunology in the Gut Text: Kuby’s Immunology, 8th ed. BMS 150 Week 12 Chapter 13 T-helper polarization – a quick review IL-12 iCOS, CD40 interactions T-helper polarization –...

Barrier Immunology in the Gut Text: Kuby’s Immunology, 8th ed. BMS 150 Week 12 Chapter 13 T-helper polarization – a quick review IL-12 iCOS, CD40 interactions T-helper polarization – a quick review IL-12 iCOS, CD40 interactions Antibody production: Th1 & Th2 review Different cytokines secreted by the T-helper cells will induce class switching ▪ TH1 cells secrete IFN-y which stimulates class switching to IgG subtypes ▪ TGF-beta and Retinoic Acid seem to stimulate class switching to IgA IL-21 ▪ TH2 cells secrete IL-4 & IL- IL-4 5, which stimulates class switching to IgE Also secretion of large amounts to IgM Kuby Immunology (6th ed) Figure 11-19, page 271 Antibody classes: IgE review Secreted as a monomer in small quantities Functions: ▪ Binds to cells with an Fc receptor for IgE triggering degranulation of granulocytes Eosinophils, basophils, mast cells TOP: Adapted from: https://upload.wikimedia.org/wikipedia/commons/1/14/2221_Five_Classes_of_Antibodies_new.jpg BOTTOM: Kuby Immunology (6th ed) Figure 4-16, page 94 Antibody classes: IgA Predominantly found as a dimer secreted into the GI and respiratory tract mucous ▪ Also tears, saliva, breastmilk Functions: ▪ Neutralizing and aggregating pathogens ▪ Important function in developing tolerance within the mucosal immune system The antibody produced in the highest quantity in our body – up to 5 grams/day ▪ Mostly secreted across mucosa Adapted from: https://upload.wikimedia.org/wikipedia/commons/1/14/2221_Five_Classes_of_Antibodies_new.jpg Innate Lymphoid Cells - Review Major types of innate lymphoid cells (ILCs): ▪ NK cells – already discussed as a cytotoxic monitor of and responder to abnormal-looking or stressed cells ▪ “Resident” ILCs – these cells live in barrier tissues Type 1 ILCs (ILC1) → secrete cytokines such as IFN- and TNF- → “pushes” the barrier into a “Type 1” response and favours the development of Th1 cells Type 2 ILCs (ILC2) → secrete cytokines such as IL-4, IL-5, IL-9, IL-13 → “pushes” the barrier into a “Type 2” response and favours the development of Th2 cells Type 3 ILCs (ILC3) → secrete IL-17, IFN- → effective against extracellular bacteria ▪ also contribute to lymphoid tissue development at the barrier and developing gut tolerance Tight Junctions - Review Key proteins: Claudins – trans-membrane proteins that can act as channels for small molecules (paracellular) Occludin – trans-membrane protein, function not clear Junctional adhesion molecules (JAM) ▪ Trans-membrane protein that may mediate permeability to larger molecules ZO-proteins ▪ Important in tight junction formation, interact with the cytoskeleton https://commons.wikimedia.org/wiki/File:Life_cycle_and_protein_associations_of_connexins.jpg An Immunology Model of the Gut  Immune Structures in the Gut Peyer’s patches: large collections of lymphoid nodules in the ileum ▪ A few cm in length, can be palpated, most individuals have about 100 ▪ MALT that is very thick and well- developed, extends right to the submucosa ▪ Luminal surface lined by M (microfold) cells Isolated lymphoid follicles (ILFs) ▪ Found throughout the gut, MALT nodules without capsules ▪ Much smaller than Peyer’s patches ▪ Can still have M (microfold) cells at the A Peyer’s Patch luminal surface Gut Cells with Immune Functions Enterocytes: Many PRRs – these PRRs tend to be intracellular or located at the basolateral surface ▪ Studies suggest that these PRRs are “meant” to detect bacteria that have invaded the enterocyte (intracellular) or have penetrated the epithelial tight junction barrier (basolateral surface) ▪ Some PRRs are expressed at the luminal surface – more later Translocation of IgA ▪ enterocytes “grab” secreted IgA from plasma cells in the lamina propria → assemble it with the secretory component and the J-chain → and then exocytose it into the luminal layer of mucus ▪ Polymeric IgA receptor = the receptor that binds to secreted IgA at the basolateral surface of the enterocyte Gut Cells with Immune Functions IgA secretion by enterocytes IgA is secreted bound to the secretory component and the J (“joining”) chain Studies suggests that glycans on the secretory component may also have a role in binding bacteria (as well as the Fab fragment)  Gut Cells with Immune Functions Goblet Cells: All throughout the intestine, but the highest population in the colon Secrete mucous, which presents a barrier to bacterial invasion (commensal or pathogenic) Secrete anti-microbial peptides (AMPs) that prevent bacteria from getting “too close” to the epithelial lining Can transport antigen from the lumen to APCs in the lamina propria Paneth Cells (located in the crypts): Secrete large quantities of AMPs  Gut Cells with Immune Functions Microfold cells Very specialized cells present over the surface of Peyer patches and isolated lymphoid follicles (ILFs) Smooth apical surface that captures antigen Large basolateral “pocket” that intimately contacts APCs and lymphocytes Less mucous is found over sites with M-cells basement membrane is sieve-like (see next slide) and allows movement of lymphocytes/dendritic cells past it A close-up view of M-cells in the ileum Before we begin: The immunology of the barrier tissues – ESPECIALLY the GI mucosal barrier – is extremely complex and is changing as studies accumulate and study methods improve ▪ It seems like every few years “non-traditional” immunology mechanisms are proven to be physiologically and clinically relevant ▪ An example – the secretory portion of the IgA molecule is very likely able to bind to microbes, not just the Fab segments We will discuss immunology and disease models that are unlikely to change much in the future because they have been fairly well-established… but they might change The Challenges of the Gut The GI tract MUST ▪ maintain commensal bacteria and be exposed to potentially antigenic macronutrients in the diet ▪ fight off pathogenic microbes The GI tract MUST NOT (most of the time) ▪ develop an inflammatory response to potentially antigenic macronutrients or healthy commensals Although these challenges are present in all mucosal tissue, they are especially pronounced in the gut ▪ The GI tract has the best-developed barrier immune system and has developed unique “uses” for antibodies and AMPs that are unique from the systemic, internal immune system Immune Tolerance in the Gut – an Overview Immune Tolerance in the Gut Maintaining distance Mucous in the lumen impairs bacterial mobility and makes it difficult for bacteria to penetrate the epithelial barrier ▪ The mucins are glycoproteins that impair bacterial mobility ▪ This layer is very thick in the large intestine → lots and lots of goblet cells Enterocytes and Paneth cells secrete large amounts of AMPs ▪ Defensins, phospholipases, and lysozyme all can degrade bacterial cell walls or create pores in them ▪ REG3 – secreted mostly by Paneth cells, mainly toxic against gram (+)-ve bacteria but also seems to have some activity against gram (-)-ves Unique to the GI tract Immune Tolerance in the Gut Maintaining distance Secreted IgA can perform a number of functions ▪ “unshuffled” IgA – the antibody sequence has not undergone affinity maturation – is often broadly specific for a wide range of microbes Recognize a number of microbial molecular patterns and do not tend to bind specifically or with high affinity Generally inhibits microbe penetration into the mucosa Likely itself somewhat tolerogenic – reduces the likelihood of inflammation in the mucosa ▪ “shuffled”, high-affinity IgA – the antibody sequence has undergone affinity maturation due to Th-B cell interactions Can fight off pathogens that have been recognized to be pathogenic – higher affinity, more “deadly” antibody May be more likely to be related to overall inflammation in the gut (more later)  Immune Tolerance in the Gut Different methods of antigen presentation Each of the methods illustrated below may be tolerogenic or cause the development of inflammation, depending on the activation state of APC and the presence of messengers ▪ Alarmins, other cytokines ▪ DAMPs Note that IgA bound to antigen can be endocytosed and later presented by an APC If a microbe penetrates the epithelial barrier, then a pro- inflammatory response is more likely Immune Tolerance in the Gut What is a “happy”, non-inflammatory gut environment? ▪ Results from tolerance in the GI tract, because we can’t avoid the presence of “non-self” molecules in the gut ▪ “Tolerogenic” features and molecules: Very low or zero levels of molecules that together promote either Type 1 or Type 2 inflammation Low levels of signals that are associated with Th17 and ILC3 activation “Normal” levels of anti-inflammatory cytokines and regulatory Th cells Immune Tolerance in the Gut Signals that are associated with maintenance of tolerance in the gut: ▪ IL-10, retinoic acid (RA), TGF-beta Produced by many immune and non-immune cells Tend to enhance Treg and IgA production as well as inhibiting inflammation ▪ APRIL, BAFF These are pro-B cell messengers released by epithelial cells and resident APCs They enhance T-independent B cell production of IgA ▪ Low levels of Th17-type cytokines IL-23, IL-17, IL-22 Enhance production of anti-microbial proteins