Host Defense - GI and Nutritional Pathophysiology Flashcards
What causes physiologic inflammation of the GI tract?
Host resistance and tolerance to bacteria, viruses, fungi, parasites and food borne antigens
What are the two types of pathophysiologic inflammation of the GI tract
- Acute: Infection
- Chronic/recurring: Allergic disorders and chronic inflammation
What are the three types of host defense barriers?
- Immediate: existing physical and chemical barriers
- Early: Existing innate immune cells and mediators
- Late: Activation of the appropriate adaptive immune cells and mediators
What makes up the epithelial and physiologic components of the first line of host defense (immediate)?
- Epithelium: Physical barrier, ion transport
- Physiologic: pH, mucus, microbiota, lysozyme, antimicrobial peptides
*The complement system also contributes
What cells make up the second line of defense (early immunity) and what is a main function of each?
- Phagocytes → Inflammation
- Macrophages → Inflammation
- Granulocytes → anti-parasitic
- NK cells → anti-viral
What cells make up the adaptive immunity component of the host defense?
- T cells
- Helper T cells (CD4)
- Cytotoxic T cells (CD8) → anti-viral
- B cells
Name the types of helper T cells involved in host defense, the interleukin they secrete, and their main function
- Th1: IFN → inflammation
- Th2: IL4 → Anti-parasitic
- Th17: IL17 → Inflammation
What four immunoglobulins are used in host defense?
IgA; IgG; IgE; IgM
In the Immediate-Early defense, what secretions help in host defense?
- Cl- transport → diarrhea
- Antimicrobial peptides (defensins)
- Cytokines/Chemokines
How does the microbiota contribute to immediate host defense?
- Compete for resources with more virulent organisms
- Produce their own antimicrobial peptides (AMPs)
- Keep innate immune cells in an “attentive” state
What are the functions of the following barrier defense proteins?
- Lysozyme:
- Lactoferrin:
- Antimicrobial Peptides:
- Lysozyme: A hydrolase that damages bacterial cell walls
- Lactoferrin: Sequesters free iron which is essential for bacteria - also oxidizes bacterial cell walls
- Antimicrobial Peptides: Forms pores in the membrane of multiple microbes
What is epithelial shedding? How does it contribute to host defense?
Enterocytes born in the crypt migrate from the crypt toward the villus apex, dislodge, and are shed into the lumen (5-6 days)
Micro-organisms (bacteria) are trapped inside the discarded or apoptotic epithelia and excreted in the feces
What are secretagogues? Name them
Secretagogues - Bind to receptors on epithelial surface and signal changes to cAMP which activates CFTR - more mucous secretion
- VIP
- Acetylcholine
- Substance P
- Prostaglandins and Leukotrienes
- Histamine
- Serotonin
What are inhibitors to ion transport? (counteract secretagogues)
Norepinephrine
Somatostatin
How does TGF-ß lead to restitution of the epithelial barrier (repair)?
TGF-ß (transforming growth factor)
- Fibrogenic agent
- Inhibits lymphocyte proliferation
- Stimulates division, differentiation and migration of surrounding epithelial cells
How are the immediate and early defense responses linked?
Dendritic cells
What cytoplasmic and cell surface receptors are responsible for recognizing pathogens (PAMPS)?
Nod-like receptors (NLR): found in cytoplasm
Toll-like receptors (TLR): found on basolateral membrane and on dendritic cells
Mannose receptor: membrane receptor on phagocytes
What PAMPs are recognized by each of the three cell associated receptors?
- TLR: Numerous bacterial, fungal and viral structures
- NLR: Bacterial wall components (peptidoglycans)
- Mannose receptor: Bacterial cell wall carbohydrate; fungal wall glycans
What are the soluble pattern recognition receptors and what PAMPs do they recognize?
- C-reactive protein: microbial cell wall components
- Mannose-binding lectin (MBL): bacterial cell wall carbohydrates
- Complement (C3): Microbial cell walls
- IgM: Bacterial cell walls
What is the function of TLR?
Activates genes necessary for defense against the recognized bacterial, viral, or fungal organism (expression of cytokines TNF, IL-1, IL-6)
What bacteria are associated with the different levels of intestinal infection?
- Minimally invasive:
- Invasive:
- Toxigenic:
- Minimally invasive: Campylobacter; Clostridium; Candida; Cryptococcus
- Invasive: **Listeria; Enteroinvasive E. Coli; **Clostridium and Shigella are opportunists
- Toxigenic: **Enterotoxigenic E. Coli; Vibrio cholerae; ****Clostridium and Shigella are opportunists
Which receptors recognize bacteria (cell associated and soluble)?
- TLR2, 4, and 5
- Nod1, 2
- C3b and MBL
- IgM
Which receptors recognize fungi (cell associated and soluble)?
- TLR3, 4, and 5
- C3b: complement
- IgM
What 3 immune cells are involved in the early response to bacterial invasion?
Neutrophils
Dendritic Cell
Activated Macrophage
What soluble mediators are involved in the early immune response to bacterial infection?
- IL-6: proinflammatory cytokine
- TGF-ß: proinflammatory cytokine
- IL-12: Released by immature dendritic cell → activates macrophages
- TNF and IL-1: released from PMNs and mature dendritic cells → activates endothelial cells
Describe how dendritic cells recruit T-cells in bacterial infection
- Dendritic cells migrate into Peyer’s patch and present a peptide antigen with an MHC II molecule
- Presents to Naive T Cell (CD4+)
- IL-12 produced by dendritic cells → T cell differentiates into Th1 which produces IFN-γ
- IFN-γ stimulates production of IgG
What is required for T cell differentiation into Th17 cells?
Environment rich in IL-6, IL-23, and TGF-ß
What happens during the resolution phase of intestinal **bacterial **infection? (Role of Th17 cells, Th1 cells and antibodies)
- T cells migrate back to lamina of gut to fight infection
- Th1 cells produce IFN-γ which increases ion transport and increases ROS killing by macrophages
- Th17 cells interact with activated macrophages, and upon seeing pathogen again, release IL-22 and IL-17 which increase the epithelial defense barrier
- IgG and IgA plasma cells - opsonization
What causes increased immune cell trafficking to the inflamed gut?
Chemokines, C5a
What are the three complement pathways?
Alternative pathway: C3 complement binds to microbe
Classical pathway: IgM binds to microbe
Lectin pathway: Mannose binding lectin
What are three common viral pathogens and what receptors recognize them?
- Viruses: Rotavirus, Norwalk, Enteroviruses
- PRRs: TLR3, 7, 9, RIG1 (NLR), IgM
What types of T-cells are involved in the anti-viral immune response?
CD8 positive T cells interact with MHC I and viral antigen
In anti-viral immune response, how does the natural killer cell assist in T cell differentiation?
NK cells produce IL-12 which causes naive T cells to become Th1 cells
NK cells also release IFN-γ
What are three types of intestinal parasites discussed in class? Which is most dangerous and which is most symbiotic?
- Worst → best
- Trematodes > Nematodes > Cestodes (most symbiotic)
What are the granulocytes and why are they important?
Granulocytes are important for defense against helminth parasites
- Eosinophils
- Basophils
- Mast Cells
- How do granulocytes defend the host?
- How are they activated?
- What does their activation depend on?
- How do granulocytes defend the host?
- By releasing their granule contents into the extracellular space (degranulation)
- How are they activated?
- By Ag-bound IgE binding cell surface FcεRI
- What does their activation depend on?
- Depends on previous exposure to an Ag
What does granulocyte excretion include?
- Vasoactive amines → SM contraction
- Proteases → disrupts parasite tegument
- Cytoknes/Leukotrienes/Prostaglandins → Stimulate macrophages, activate endothelial cells, increase leukocyte migration
What T-cell is important in the defense against parasites?
Th2 cells secrete IL-4, IL-5 and IL-13 which induce mast cells and eosinophils against helminthic parasites
