Chapter 4 Innate Immunity (63-64) & (69-80)

Question 1

What are some of the Epithelial barriers?

Answer 1

1) Tight Junctions limit passage 2) Keratin blocks entrance of microbes 3) Mucus viscous secretion of mucins (glycoproteins) 4) Peristalsis

Question 2

What are the two antimicrobial peptides secreted by epithelial cells?

Answer 2

1) Definsins 2) Cathelicidin

Question 3

Definsins

Answer 3

Produced by epithelial cells, but also can be secreted by granule containing leukocytes (neutrophils, NK cells, CTLs); Works by disrupting microbial membranes.

Question 4

Cathelicidin

Answer 4

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

Question 5

Plasmacytoid Dendritic Cells

Answer 5

Major source of antiviral cytokines (type I interferons), express an abundant amount of endosomal TLRs (3,7,8,9) which recognize viral nucleic acids

Question 6

What role do DC cells play in adaptive immunity?

Answer 6

Take up antigens and transport them to lymph nodes, and present them to T lymphocytes; secrete cytokines and co-stimulators to activate T cell

Question 7

Mast Cells

Answer 7

Present in skin and mucosal epithelium, secrete histamine, TNF, express TLRs.

Question 8

Histamine

Answer 8

Secreted by mast cells; causes vasodilation and increased capillary permeability

Question 9

What are the components of the humoral innate immune system?

Answer 9

complement system; collectins; pentraxins; ficolins.

Question 10

The Complement System

Answer 10

Plasma proteins that work together to opsonize microbes, promote the recruitment of phagocytes to the site of infection ,and in some cases kill microbes

Question 11

What are the three types of PRRs? Give an example of each.

Answer 11

1) Secreted (MBL) - works via opsonization 2) Endocytic-Macrophage Mannose Receptor 3) Signaling- TLRs

Question 12

Classical pathway

Answer 12

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.

Question 13

Alternate Pathway

Answer 13

The phylogentically older pathway. triggered when C3 binds to microbial surface structure. Is not self reactive, because cells have the inhibitor for C3

Question 14

Lectin Pathway

Answer 14

Triggered by MBL; recognizes terminal mannose residues on microbial glycoproteins; Process MBL binds pathogen, MASP1 and MASp2 activate proteolytic cascade.

Question 15

C3 convertase Complex

Answer 15

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.

Question 16

Pentraxins

Answer 16

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

Question 17

CRP and SAP

Answer 17

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.

Question 18

What are the soluble effectors of innate immune system

Answer 18

MBL, Pulmonary Surfactant proteins (SP-A and SP-D); act as opsonins

Question 19

What are the three ways that the innate immune system fights against infection?

Answer 19

inducing inflammation, inducing viral defense, stimulating adaptive immunity.

Question 20

What are the major inflammatory cytokines?

Answer 20

TNF, IL-1, IL-6

Question 21

TNF

Answer 21

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

Question 22

TNF-RI, TNF-RII, CD40

Answer 22

TNF receptors. TNF binding on plasma membranes of cells leads to the recruitment of proteins cal TRAFs

Question 23

TRAFs

Answer 23

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.

Question 24

Septic Shock

Answer 24

Mediated by TNF when bacteria enter the blood stream

Question 25

IL-1

Answer 25

Produced by mononuclear phagocytes, neutrophils, epithelial cells, keratinocytes, and endothelial cells; IL-1B the most secreted form (Most biologically active)

Question 26

IL-1 ß production

Answer 26

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

Question 27

IL-6

Answer 27

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.

Question 28

IL-12

Answer 28

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!)

Question 29

Integrin

Answer 29

transmembrane receptors that are the bridges for cell-cell and cell-extracellular communication

Question 30

Where do TNF, IL-1, and IL-6 produced at inflammatory sites migrate to? What do they do there?

Answer 30

Enter the blood, migrate to bone marrow, and enhance the production of neutrophils. Also help increase responsive cells to sites of infection.

Question 31

What two cytokines act on the brain in the immune response? Where specifically do they act? How?

Answer 31

TNF and IL-1. Act on the hypothalamus to produce fever (endogenous pyrogenes). Cause fever by increasing synthesis of prostaglandins in hypothalmic cells.

Question 32

What cytokines cause production of acute phase reactants in the body from the liver? What are the acute-phase reactants?

Answer 32

IL-1 and IL-6; produce acute phase reactants CRP and SAP (both pentraxins); Also produces fibrogen for tissue repair

Question 33

What are the systemic effects of TNF?

Answer 33

Inhibits myocardial contractility, vascular muscle tone, decrease blood pressure can cause shock; Causes intravascular thrombosis;

Question 34

Cachexia

Answer 34

Wasting of muscle and fat cells

Question 35

Septic Shock

Answer 35

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.

Question 36

What four cytokines are key indicators of inflammation in infection and inflammation in auto immune diseases?

Answer 36

TNF, IL-1, IL-6, IL-12

Question 37

What is the major way that the innate immune system deals with viral infection?

Answer 37

By inducing the expression of type I interferons; they inhibit viral replication

Question 38

What cellular receptors induce Type I interferon gene expression?

Answer 38

RLRs, TLRs 3,4,7,8,9

Question 39

How do type I interferons cause neighboring cells to confer resistance?

Answer 39

Type I interferons secrete autocrinely and paracrinely, cause transcription of genes that “Prep” other cells for war

Question 40

What effects do type I interferons have on lymph nodes?

Answer 40

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.

Question 41

What effects do type I interferons have on NK cells, CD8+ CTLs and Th1 helper T cells?

Answer 41

Increase cytotoxicity of NK cells, CD8+ CTLs; Promote differentiation of naive T cells to the subset of helper T cells

Question 42

How do Type I interferons improve the cytotoxic nature of CD8+ CTLs?

Answer 42

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