Chapter 4 Innate Immunity (63-64) & (69-80) Flashcards
What are some of the Epithelial barriers?
1) Tight Junctions limit passage 2) Keratin blocks entrance of microbes 3) Mucus viscous secretion of mucins (glycoproteins) 4) Peristalsis
What are the two antimicrobial peptides secreted by epithelial cells?
1) Definsins 2) Cathelicidin
Definsins
Produced by epithelial cells, but also can be secreted by granule containing leukocytes (neutrophils, NK cells, CTLs); Works by disrupting microbial membranes.
Cathelicidin
Produced by neutrophils and barrier epithelial cells in skin, G.I, and respiratory tracts; release stimulated by the release of cytokines and microbial products; works against LPS
Plasmacytoid Dendritic Cells
Major source of antiviral cytokines (type I interferons), express an abundant amount of endosomal TLRs (3,7,8,9) which recognize viral nucleic acids
What role do DC cells play in adaptive immunity?
Take up antigens and transport them to lymph nodes, and present them to T lymphocytes; secrete cytokines and co-stimulators to activate T cell
Mast Cells
Present in skin and mucosal epithelium, secrete histamine, TNF, express TLRs.
Histamine
Secreted by mast cells; causes vasodilation and increased capillary permeability
What are the components of the humoral innate immune system?
complement system; collectins; pentraxins; ficolins.
The Complement System
Plasma proteins that work together to opsonize microbes, promote the recruitment of phagocytes to the site of infection ,and in some cases kill microbes
What are the three types of PRRs? Give an example of each.
1) Secreted (MBL) - works via opsonization 2) Endocytic-Macrophage Mannose Receptor 3) Signaling- TLRs
Classical pathway
Uses plasma protein C1q to detect antibodies bound to microbes. C1q bind Fc portion of antibody, which activates serine proteases (Clr and Cls) which causes a proteolytic cascade; Pentraxins can also bind C1q and initiate the classical pathway.
Alternate Pathway
The phylogentically older pathway. triggered when C3 binds to microbial surface structure. Is not self reactive, because cells have the inhibitor for C3
Lectin Pathway
Triggered by MBL; recognizes terminal mannose residues on microbial glycoproteins; Process MBL binds pathogen, MASP1 and MASp2 activate proteolytic cascade.
C3 convertase Complex
1st - Cleaves C3 producing C3a and C3b, C3b attaches to microbial surface where the complement pathway was activated; C3b functions as an opsonin, C3a promotes inflammation by acting as a chemoattractant for neutrophils,;C3b binds other complement proteins to form a protease C5 convertase that cleaves C5; C5a acts as a chemoattractant, while C5 b remains attached to a microbial cell. C5b initiates the formation of a pore in concert with (C6, C7, C8, C9) called the MAC membrane attack complex. This causes lysis.
Pentraxins
Phylogenetically old group of structurally homologous pentameric proteins; includes CRP, Serum amyloid p (SAP) and long pentraxin (PTX3); all activate the classical pathway after C1q binds
CRP and SAP
Two pentraxins; CRP uses phosphorylcholine as a PAMP, while SAP uses phosphatidylethanolamene as a PAMP; ligands become exposed on apoptotic cells; synthesized by the liver; are upregulated by IL-6 and IL-1 secretion by phagocytes; Both acute reactive proteins.
What are the soluble effectors of innate immune system
MBL, Pulmonary Surfactant proteins (SP-A and SP-D); act as opsonins
What are the three ways that the innate immune system fights against infection?
inducing inflammation, inducing viral defense, stimulating adaptive immunity.
What are the major inflammatory cytokines?
TNF, IL-1, IL-6
TNF
Causes inflammation and thrombosis of tumor blood vessels; membrane protein in macrophages; membrane protein can be cleaved by metalloproteinase to form the free floating triangular TNF molecules
TNF-RI, TNF-RII, CD40
TNF receptors. TNF binding on plasma membranes of cells leads to the recruitment of proteins cal TRAFs
TRAFs
Tumor Necrosis Factor Associated Factors; TRAFs activate transcription factors (NF-kB and AP-1); Cytokine binding to TNF-RI recruits adaptor protein that activates cascade and triggers apoptosis.
Septic Shock
Mediated by TNF when bacteria enter the blood stream
IL-1
Produced by mononuclear phagocytes, neutrophils, epithelial cells, keratinocytes, and endothelial cells; IL-1B the most secreted form (Most biologically active)
IL-1 ß production
Requires two signals: 1) 1st activation of gene transcription to produce Pro-IL-1B, 2) 2nd activation of inflammasome to proteolytically cleave the precursor to generate IL-B. IL-B transctiption induced by TLR, NLR both activate NF-kB
IL-6
Induces synthesis of other proinflammatory mediators in the liver; stimulates neutrophil production in the bone marrow; promotes differentiation of IL-17 producing helper T cells; is synthesized by mononuclear phagocytes, vascular endothelial cells; and other cells in response to PAMPs and in response to IL-1 and TNF.
IL-12
Secreted by DCs and macrophages; Stimulates IFN gamma production by NK and T cells; enhances NK cell and CTL-mediated cytotoxicity; promotes differentiation of TH1 cells; produced in response to TLR and other PRRs; produced in response to IFN gamma produced by NK cells or Tcells (Positive feedback loop!)
Integrin
transmembrane receptors that are the bridges for cell-cell and cell-extracellular communication
Where do TNF, IL-1, and IL-6 produced at inflammatory sites migrate to? What do they do there?
Enter the blood, migrate to bone marrow, and enhance the production of neutrophils. Also help increase responsive cells to sites of infection.
What two cytokines act on the brain in the immune response? Where specifically do they act? How?
TNF and IL-1. Act on the hypothalamus to produce fever (endogenous pyrogenes). Cause fever by increasing synthesis of prostaglandins in hypothalmic cells.
What cytokines cause production of acute phase reactants in the body from the liver? What are the acute-phase reactants?
IL-1 and IL-6; produce acute phase reactants CRP and SAP (both pentraxins); Also produces fibrogen for tissue repair
What are the systemic effects of TNF?
Inhibits myocardial contractility, vascular muscle tone, decrease blood pressure can cause shock; Causes intravascular thrombosis;
Cachexia
Wasting of muscle and fat cells
Septic Shock
Caused by LPS release by g (-) endotoxin/ cause by lipoteichoic acid released from g (+) bacteria; characterized by vascular collapse, disseminated intravascular coagulation and metabolic disturbance.
What four cytokines are key indicators of inflammation in infection and inflammation in auto immune diseases?
TNF, IL-1, IL-6, IL-12
What is the major way that the innate immune system deals with viral infection?
By inducing the expression of type I interferons; they inhibit viral replication
What cellular receptors induce Type I interferon gene expression?
RLRs, TLRs 3,4,7,8,9
How do type I interferons cause neighboring cells to confer resistance?
Type I interferons secrete autocrinely and paracrinely, cause transcription of genes that “Prep” other cells for war
What effects do type I interferons have on lymph nodes?
Cause retention of lymphocytes in lymph nodes, maximizes the opportunity for encounter w/microbial antigens; CD69 forms complex with sphingosine 1-phosphate receptor (S1PR1); S1PR1 binding cause retention of lymphocytes.
What effects do type I interferons have on NK cells, CD8+ CTLs and Th1 helper T cells?
Increase cytotoxicity of NK cells, CD8+ CTLs; Promote differentiation of naive T cells to the subset of helper T cells
How do Type I interferons improve the cytotoxic nature of CD8+ CTLs?
Type I interferons up-regulate expression of class I MHC molecules; increase the probability that virally infected cells will be recognized and killed by CD8+ CTLs
