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81 Cards in this Set
- Front
- Back
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What is the origin of the cells lining the mucosal surface (epithelium) of the intestine?
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Crypt of Lieberkuhn stem cells
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What cells are in the epithelium and overly the Peyer's Patches? Function?
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M cells - involved in antigen sampling and mucosal immunity
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What kind of B cells are stimulated in the Peyer's Patches?
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IgA producing, mature into plasma cells
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How does the type and frequency of epithelial cells differ from the small to the large intestine?
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Large intestine has:
- More goblet cells - M cells - Outer mucus and inner mucus layer that is thick and continuous throughout (in small intestine it is thin and discontinuous) |
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What is the intrinsic defense barrier in the GI tract?
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Epithelium - in the intestine it is a single layer of cells that are hooked together with tight junctions and gap junctions
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What are the types of extrinsic defense barriers in the GI tract?
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- Mechanical / Involuntary Reflexes
- Structural - Chemical - Microbiological |
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What are the mechanical / involuntary reflex extrinsic defense barriers in the GI tract?
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- Cough
- Gag - Peristalsis (When these are lacking, you are more prone to infection) |
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What are the structural extrinsic defense barriers in the GI tract?
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Mucus
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What are the chemical extrinsic defense barriers in the GI tract?
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- Acid
- Enzymes - Antimicrobial peptides and polypeptides |
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What are the microbiological extrinsic defense barriers in the GI tract?
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Commensal microbiota (specifically in intestines)
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What is the organization of the intestinal mucus?
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- In large intestine this barrier is continuous, in small intestine it is discontinuous
- Made of outer and inner mucus layers - Bacteria usually reside in the outer mucus layer - A lot less bacteria in the inner mucus layer where it is secreted by the Goblet Cells - IgA is also found in the inner mucus layer which is secreted by plasma cells in the lamina propria to keep it relatively sterile - Antimicrobial proteins also released into inner mucus layer |
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What is mucus made of?
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Mucins - viscoelastic gel
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What are mucins secreted by? Characteristics of secretion?
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Specialized Goblet cells
- Secretion can be continuous or regulated - 10L released / day |
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What is the function of Mucins?
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- Forms selectively permeable mucus blanket
- Mucus-commensal interactions - Bacterial exclusion - Containment of secreted antibodies and antimicrobials |
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What are the contents of mucus?
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- Mucins
- Water - Ions - Proteins - Lipids - Antibodies - Antimicrobial peptides - Bacteria |
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How do mucins interact with commensal organisms?
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- Specific binding of some commensals via adhesions allows bacteria to "graze" on mucus
- Bacteria cleave specific sugars from tips of oligosaccharides - Small subset of commensals digest mucus |
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How do mucins exclude bacteria? How do they interact?
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- Thickness and viscosity contribute to exclude bacteria
- Bacteria and LPS have been shown to induce MUC gene expression and secretion - Pathogens have developed specific mechanisms to evade the barrier (flagella, interference w/ exocytosis) |
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How do mucins function in containment of antibodies and antimicrobials?
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- IgA and other secreted antibodies bind mucus through low affinity bonds and interact with commensals and pathogens
- Cationic antimicrobial peptides may be contained via electrostatic interactions with mucins |
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Where do the secreted chemical defenses come from?
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- Mostly from epithelium
- Some inflammatory cells and bacteria also contribute |
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What are the secreted chemical defenses?
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- Acid (stomach)
- Lectins / collectins (lung surfactant proteins) - Enzymes and inhibitors - Antimicrobial peptides and proteins |
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What enzymes and inhibitors are secreted to defend against pathogens?
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- Lysozyme (muramidase, hydrolyze peptidoglycans)
- Peroxidases (MPO) - SLPI (protease inhibitor) - sPLA2 |
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How do secreted antimicrobial peptides and proteins function to protect against pathogens?
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- Direct killing by forming pores in microbial cell walls and membranes (eg, defensins (alpha, beta, and theta), cathelicidins)
- Iron sequestration (lactoferrin, lipocalin) prevents bacterial growth since they require iron (some bacteria have mechanisms to extract iron) |
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What kind of cells secrete antimicrobial peptides?
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- WBCs
- Epithelial cells lining mucosal surface |
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What is the action of the antimicrobial peptides secreted by WBCs and epithelial cells?
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- Broad-spectrum of activity
- Make holes in bacterial cell membranes |
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What is an example of a cationic antimicrobial peptide found in mammals? Characteristics?
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Defensins:
- Invariant 6-cysteine array involved in intramolecular disulfide - α-defensin (neutrophils and paneth cells) and β-defensin (mucosal epithelium) types - |
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Where are α-defensins expressed? When are they expressed?
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- Neutrophils
- Paneth cells - Expressed constitutively (always) |
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Where are β-defensins expressed? When are they expressed?
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- Mucosal epithelium
- Constitutive and inducible expression |
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What are the contents of Paneth Cell granules?
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- α-Defensins (HD5 and HD6)
- CRS peptides - Lysozyme - sPLA2 - RegIII-γ - Angiogenin-4 - α-1-Antitrypsin - TNF-α - IL17a - MMP7 - IgA |
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What are the forms of Defensin found in Paneth cells?
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- HD5
- HD6 |
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What are the serological secreted immunological defenses?
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- sIgA - predominant Ig
- IgM - IgG - IgE - IgD |
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Which is the predominant immunoglobulin in mucosal secretions?
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sIgA (secretory IgA)
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What are the components of IgA? Function?
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- Secretory component (SC) is part of pIgA (polymeric, mucosal) and transports IgA into secretions
- Alpha chain - J chain (only associated with pIgA) |
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If someone has an IgA deficiency (1 in 800), what happens?
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Usually doesn't cause significant problems because they compensating by inducing release of IgM
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What are the limitations of IgM as an immunological defense?
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- Secretory component (SC) transports IgM into secretions
- May not be transported as well as IgA because of MW restrictions in SC dependent transport |
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What are the relative levels of IgG in immunological defenses?
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- Found at same levels as IgM
- Proportion of IgA to IgG varies by site and time of collection (ie, proportion varies through menstrual cycle) |
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Where/when is IgE found?
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- Found in low concentration
- Associated with mucosal allergic responses |
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Where/when is IgD found?
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- Found in low concentration
- Found in milk and saliva |
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What are the two structures of IgA? How do they differ?
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- Serum IgA - predominantly monomeric
- Mucosal IgA - predominantly polymeric |
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How is IgA synthesized?
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Synthesized as monomer and forms pIgA (polymeric) prior to secretion
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How much IgA is secreted daily? How is it removed?
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- 4g secreted daily
- Metabolized and cleared by liver |
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How do IgA secreting plasma cells get induced to secrete IgA? Effect of IgA?
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- Bacteria at mucosal surface (commensal and pathogenic)
- Dendritic cells sample bacteria by sticking out an arm which can then present this to B cells - M cells in epithelium also sample bacteria and activate plasma cells - Plasma cells release IgA (non-inflammatory) which binds to bacteria in lumen and prevent them from gaining access to epithelium |
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What are the biological activities of IgA?
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- Inhibits adherence of bacteria to epithelium (repels attachment to mucosa)
- Mucus-trapping (traps microbes in mucus) - Virus neutralization (inhibits attachment) - Enzyme and toxin neutralization - Inhibits antigen penetration (including food) |
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How does IgA inhibit enzymes and toxins? Which ones specifically by location?
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- Saliva: inhibits enzymes from oral bacteria (neuraminidase, hyaluronidase, chondroitin sulfatase, glucosyltransferase)
- Gut: neutralizes bacterial toxins (cholera toxin, heat-labile enterotoxin, clostridial enterotoxin A) |
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What are the mechanisms by which microbes evade the action of IgA?
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- Specific IgA proteases
- Other proteases - Glycosidases - IgA binding proteins |
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What is the action of specific IgA proteases for microbial evasion of IgA?
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- Cleaves one of several prolyl-seryl or prolyl-threonyl peptide bonds in hinge region
- Cleaves off intact Fab fragments that retain binding activity - Exquisitively substrate specific, not inhibited by protease inhibitors - Causes local IgA deficiency in vivo |
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What microbes are associated with having specific IgA proteases to evade the anti-microbial action of IgA?
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Meningitis: H. influenzae, N. meningitidis, S. pneumoniae
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What is the action of other proteases for microbial evasion of IgA?
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Wide spectrum protease can cleave IgA
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What microbes are associated with having wide spectrum proteases used to evade the anti-microbial action of IgA?
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- Peridontal pathogen: Porphyromonas gingivalis
- Some intestinal Enterobacteriaceae |
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What is the action of glycosidases for microbial evasion of IgA?
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IgA is heavily glycosylated and thus subject to damage by bacterial glycosidases, which disrupt the conformation, net charge, and resistance to proteolysis
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What is the action of IgA binding proteins for microbial evasion of IgA?
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- Cell surface proteins bind IgA non-specifically (ie, Fc region)
- Lectin binding of O-linked carbohydrate in IgA hinge region |
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An elderly nursing home patient with dementia presents with fever and elevated white blood cell count. A chest x-ray suggests lobar pneumonia. Which is the MOST LIKELY mechanism of pathogenesis?
a) Decreased secretion of mucus b) IgA deficiency c) Loss of gag/cough reflex d) Disruption of the commensal microbiota secondary to poor nutrition e) Reduced stomach acid secondary to protein pump inhibitor use |
Loss of gag / cough reflex
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What is a microbiome?
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Totality of native microbes, their genetic information, and the milieu in which they interact
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What are the three major classes of bacteria in a healthy microbiota?
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- Symbionts
- Commensals - Pathobionts |
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What is the action of symbionts?
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Share mutual relationship with the host, have known health promoting factors
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What is the action of commensals?
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Permanent residents of this ecosystem and provide no benefit or detriment to the host
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What is the action of pathobionts?
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Live as commensals (providing no benefit or detriment) but have the potential to induce pathology
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What is the term for an altered microbial composition? What are the implications of this state?
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Dysbiosis - associated with diseases like IBD, auto-immunity, obesity, diabetes, asthma and allergy, colorectal carcinoma, etc
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What is the role of the mucosal surface of the GI tract? Characteristics?
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- Constantly in contact with microbes
- Primary role is to allow normal physiological function while protecting from infection - Mucosal immune system protects host from microbiota, but microbiota has a symbiotic role in host protection and host physiology |
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How does the composition of microbes in the lower GI tract (small and large intestines) compare?
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- Microbial composition changes from proximal to distal intestine, moving from domination by aerobic species to facultative and obligate anaerobes in colon
- Also as you go more distally there are increasing numbers and diversity of microbes |
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What factors shape the microbial composition?
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- Immune factors: defensins, IgA
- Non-Immune factors: O2 tension, pH, digestive enzymes, bile salts, mucus, DIET |
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How does breast milk help select for the microbial composition of the GI tract?
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- Human milk contains HMO (human milk oligosaccharides)
- HMOs are completely indigestable by humans but can be digested by Bifidobacterium - Bifidobacterium has major host benefits for infants |
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What are the main functions of the commensal intestinal microbiota?
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- Protection
- Structure - Metabolism |
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How do the commensal intestinal microbiota supply protection to the intestine?
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- Pathogen displacement
- Nutrient competition - Receptor competition - Produce anti-microbial factors (eg, bacteriocins, lactic acids) |
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What are the structural functions that the commensal intestinal microbiota provide to the intestine?
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- Barrier fortification
- Induction of IgA - Apical tightening of tight junctions - Develops immune system |
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What are the metabolic functions that the commensal intestinal microbiota provide to the intestine?
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- Control IEC diferentiation and proliferation
- Metabolize dietary carcinogens - Synthesize vitamins (eg, biotin and folate) - Ferment non-digestable dietary residue and endogenous epithelial-derived mucus - Ion absorption - Salvage of energy |
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What happens to mice that lack a mature mucosal immune system?
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- Underdevelopment of lymphatic tissues
- Delayed B cell migration in response to bacterial antigen - Reduced antibody diversity - Reduced lymphocyte responsiveness |
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What happens to mice that lack a mature mucosal immune system when they develop a normal mucosal immune system?
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- Increased lymphocyte infiltration of gut mucosa
- Germinal center formation in Peyer's patches - Induction of innate antimicrobial effector molecules - Treatment with bacterial polysaccharide from bacterial symbiont (B. fragilis) restores many immune functions |
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How do commensal microbiota prevent pathogen colonization?
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• Bacteriocin production
• SCFA production • Consumption of oxygen • Competition for nutrients • Competition for attachment sites • Induction of epithelial antimicrobials • Induction of mucus production and secretion |
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How do commensal bacteria regulate digestion?
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- Mediation of bile acid synthesis
- Lipid absorption - Amino acid metabolism - Vitamin synthesis, such as Vitamin K - SCFA production - Byproducts of commensal fermentation (metabolites) regulate the immune system |
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Which is a function of the intestinal microbiota?
a) Water absorption b) Digestion of dietary sucrose c) Displacement of bacterial pathogens d) Synthesis of vitamin C e) Production of human milk oligosaccharides |
Displacement of bacterial pathogens
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What diseases are associated with the intestinal microbiome?
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- Inflammatory Bowel Disease
- Obesity and obesity-related disease (diabetes and non-alcoholic fatty liver disease) - Cancer - Allergy / asthma |
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How is the intestinal microbiome associated with Inflammatory Bowel Disease?
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Abnormal host immune response to the colonizing bacteria in a genetically susceptible host leads to uncontrolled inflammation
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How is the intestinal microbiome associated with Obesity and obesity-related diseases (Diabetes and Non-Alcoholic Fatty Liver Disease)?
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Efficiency of bacterial fermentation and products of metabolic byproducts can contribute to obesity and its complications
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How is the intestinal microbiome associated with cancer?
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Byproducts of bacterial metabolism can promote cell growth and act as carcinogens
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How is the intestinal microbiome associated with allergies and asthma?
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- "Hygiene hypothesis" - decreased early infections lead to immune dysregulation
- "Microflora hypothesis" - dysbiosis leads to immune dysregulation - "Vanishing microbiota hypothesis" - interactions w/ certain microbes are wired into our immunoregulatory networks based on constant presence in our environment, resulting in tolerance; loss of these co-evolved microbes can result in allergic hyper-responsiveness |
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What happens in Inflammatory Bowel Disease?
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Abnormal bacterial colonization (dysbiosis) and abnormal immune function leads to abnormal host response
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What is the definition of a probiotic?
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A viable microbial food supplement which beneficially influences the health of the host
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What are the criteria for a probiotic?
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– Origin of microbe
– Stability in the GI tract (acid and bile resistant) – Viability – Adherence to human intestinal mucus/mucosa – Antimicrobial activity against pathogens |
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What are the functions of a probiotic?
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– Improves intestinal barrier function
– Stimulates mucin secretion – Stimulates antimicrobial peptide expression – Inhibits adherence and invasion of pathogens – Enhances IgA production – In epithelial cell culture, some probiotics have anti-inflammatory activity (attenuate IL-8 and TNF-α secretion, inhibit NF-κΒ pathway, prevent apoptosis) – Metabolic and neurologic effects are currently being examined |
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What can probiotics be used to treat? How?
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Treatment of immune disorders
- Restore the barrier function (prevent excess antigen transfer across skin and gut barriers) - Skew T cell immune responses to Th1 type |
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What are probiotics being studied to treat?
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- Pouchitis
- IBS: Irritable Bowel Syndrome - Cow's milk allergy - Atopic excema (in high risk neonates) - Allergy |
