Innate Immunity I, Ii, Iii

Front 1

What are the 2 phases of innate immune response?

Back 1

1) Immediate Response - already present; cells and proteins involved are in the sites of pathogen entry

2) Induced Response - Proteins produced during immediate response recruit help. S

Front 2

What is the function (2) of the complement system?

Back 2

1) Enhance immune cell function by stimulating phagocytosis
2) Induce inflammation

Front 3

What is complement fixation?

Back 3

The attachment of part of complement to bacterium (eg., C3b -bacteria complex)

Front 4

What happens to activate C3, the most important component of the complement system?

Back 4

C3 usually exists as inactivated protein. It must be cleaved to become activated.

Convertase converts it from inactive --> active form.

C3 --> C3a and C3b

C3a: activating - recruits phagocytes
C3b: binds the pathogen

Front 5

What can the C3b become after its thioester bond is uncovered?

Back 5

Nucleophilic attack yields either

a) water-soluble C3b (if water is nucleophile)

b) C3b capable of binding pathogen surfaces

Front 6

What are the three pathways that activate C3?

Back 6

1) Immediate innate: Alternative
2) Induced innate: Lectin
3) Induced Innate Adaptive: Classical

Front 7

What is C3 convertase?

Back 7

Catalyzes the proteolytic cleavage of C3 into C3a and C3b.

Front 8

From most important to most minor, what does C3 activation do?

Back 8

1) Recruits inflammatory cells
2) Opsonization of pathogens, facilitating uptake and killing by phagocytes
3) Perforation of pathogen cell membranes

Front 9

How does C3 activation via the alternative pathway proceed?

Back 9

1) Water attacks C3 to expose thioester site -->i(for inactive)C3

2) <b>Factor B</b> binds iC3

3) <b>Factor D</b> binds iC3B and cleaves factor B --> iC3Bb + Ba (B goes to Ba and Bb). Bb is a protease.

4) <b>iC3Bb is the C3-convertase </b> that cleaves another C3 to C3a and C3b.

Front 10

What are the two C3-convertases?

Back 10

1) iC3Bb
2) C3b (cleaved) bound to Bb (C3bBb)

Front 11

How is C3b different from iC3Bb? What is the implication of this?

Back 11

Because it was never nucleophilically attacked by water, it isn't water soluble, so it remains bound to pathogen surface.

Implication is amplification of C3b deposition on pathogen surface

Front 12

What is properdin?

Back 12

It binds with C3bBb and stabilizes it to enhance its activity --> More C3 is cleaved.

Front 13

What is factor H and I?

Back 13

They counter Properdin.

Factor H makes C3b susceptible to cleavage by Factor I.

Net result in inactivation. Ensures complement system doesn't attack host tissue.

Front 14

What kind of regulation of C3b deposition on host cell surfaces is there?

Back 14

Decay accelerating factor (DAF) and Membrane Co-factor protein (MCP) destabilize C3bBb.

Front 15

What is opsonization?

Back 15

The process by which a pathogen is marked for phagocytosis by a phagocyte.

Front 16

How does C3b participate in opsonization?

Back 16

CR1 is a receptor for C3b.

CR1-C3b/pathogen interaction facilitates pathogen uptake (opsonization). ie., When C3b is bound to a bacterium, macrophages can eat it more effectively.

Front 17

What is another part of the complement system that acts similarly to C3?

Back 17

C5. It gets cleaved to C5a and C5b.

C5a is an anaphylotoxin, andC5b recruits downstream proteins to form a pore that can cytotoxic activity.

Front 18

What does C3a and C5a do?

Back 18

They bind cellular receptors to induce inflmmatory response or anaphylaxis.

Can induce muscle cell contraction.

Induce degranulation of mast cells and basophils.

Front 19

What do serpins and &alpha;-macroglobulin do (generally?)

Back 19

host proteins block action of microbial proteases

Front 20

What are defensins?

Back 20

Small polypeptides with anti-microbial activity.

Front 21

What are the 2 groups of defensins and where are they found?

Back 21

&alpha; : made by Panneth cells (intestinal crypt)

&beta; : made by neutrophils and epithelial cells

Front 22

What are three types of macrophage receptor that recognize pathogens?

Back 22

1) Complement receptors (CR1)

2) Pattern-recognition receptors

3) Toll-like receptors (TLR) - recognize components of microorganisms

Front 23

What are the purposes of the 2 domains of Toll Like Receptor (TLR) on the macrophage?

Back 23

1) Recognition
2) Signaling

Front 24

What does TLR signaling induce?

Back 24

Production of inflammatory cytokines

Front 25

Where do TLRs interact with microbial components (Extra or intracellular)?

Back 25

BOTH

Front 26

Which TLR is a key component in response to gram-negative bacteria? How?

Back 26

TLR4.

Doesn't actually bind LPS. It binds CD14 that binds LPS. CD14/TLR4 forms a complex that induces downstream signaling cascade.

Front 27

What are major cytokines and cytokine-related proteins that TLR signaling induces?

Back 27

MyD88 (adaptor protein), IRAK4, IKK, NF-&kappa;B

Front 28

What is NF-&kappa;B?

Back 28

A transcription factor that induces expression of multiple pro-inflammatory cytokines

Front 29

What is MyD88?

Back 29

An adaptor/scaffold/linker protein that bridges signaling components IRAK4, IKK, NF-κB

Front 30

What two signaling pathways does TLR4 activate?

Back 30

Response to bacteria AND viruses

Front 31

Inflammation is mediated by what aspect of immune system?

Back 31

Innate

Front 32

Which cytokines mediate fever?

Back 32

IL-1, IL-6, TNFa

Front 33

Which cytokine causes shock? How?

Back 33

TNF&alpha; : usually it promotes increase in clotting and vascular leakage (changes in permeability to increase blood flow to infected region, helps neutrophils get in, but when activated systemically it causes systemic edema which causes collapsed blood vessels and eventually wasting.

Stems from the fact that locally, TNFa is a very good thing, but systemically it causes major problems.

Front 34

What's the role of IL-6?

Back 34

Fever, induction of acute phase protein production by hepatocytes

Front 35

What's the role of IL-1&beta;?

Back 35

Locally: Activates vascular endothelium, activates lymphocytes, local tissue destruction, increase access of effector cells

Globally: Fever, production of IL-6

Front 36

What's the role of CXCL8?

Back 36

Chemotactic factor that attracts neutrophils and basophils to infection site

Front 37

What's the role of IL-12?

Back 37

Activates NK cells

Front 38

Which cytokines attract neutrophils?

Back 38

IL8/CXC8

Front 39

What do selectins do?

Back 39

They're stimulated by TNFa/leukotriences. They're adhesion molecules that allow cells to stick

Front 40

What are the 4 types of adhesion molecules?

Back 40

1) Selectin
2) Adressin
3) Integrin
4) Members of Ig gene superfamily (like ICAM)

Front 41

Selectin interacts with _________

Back 41

adressin

Front 42

Integrin interacts with _____

Back 42

Members of Ig gene superfamily (like ICAM)

Front 43

What is the loose binding interaction that allows neutrophils to roll along endothelium?

Back 43

Selectin and S-Le

Front 44

What is the tighter binding interaction that stops the neutrophil that's rolling and allows it to diapedese?

Back 44

LFA (integrin) which is activated by IL-8 and LFA (which is increased by TNFa)

Front 45

How do neutrophils kill?

Back 45

Using granules with toxic contents

Front 46

What is the respiratory burst?

Back 46

A way of killing that neutrophils use. Enzymatic reactions involve superoxide and hydrogen peroxide. The "power" for microbial attack comes from transient increase in oxygen consumption.

Front 47

When does chronic granulomatous disease occur?

Back 47

For individuals lacking NADPH oxidase, unable to clear infection by respiratory burst so they're contained in localized nodules/granules.

Front 48

What are the three enzymes involved in the respiratory burst?

Back 48

NADPH oxidase; superoxide dismutase; catalase

Front 49

How does fever affect response to pathogens?

Back 49

1) Increased temperature decreases rate of pathogen replication
2) Allows human cells to be resistant to TNFa
3) Increase antigen processing and presentating (degradation of proteins to peptides and association with MHC proteins)

Front 50

Acute-phase proteins : defn

Back 50

a class of proteins whose plasma concentrations increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the acute-phase reaction (also called acute-phase response).

Front 51

What are 3 acute phase proteins?

Back 51

C-reactive protein; mannose binding protein; fibrinogen

Front 52

What are the two effects of the acute phase proteins?

Back 52

Complement activation, opsonization

Front 53

What cytokines are responsible for acute phase proteins?

Back 53

IL6

Front 54

Classical C3 Convertase :

Back 54

C4b and C2a form a C3 convertase:

Front 55

How does C-reactive protein activate the classical complement pathway?

Back 55

C1 (multiunit complex) binds to C-reactive protein on pathogen surface.

C1 cleaves C4 and C2. C4b-C2a (the classical convertase) is formed

Front 56

How does mannose binding lectin cause activation of C3 convertase?

Back 56

MBP is associated with MASP2 which cleaves C4 and C2 --> C4bC2a.

Front 57

what is
a) classical c3 convertase
b) alternative c3 convertase

Back 57

a) C4bC2a
b) C3bBb

Front 58

What are the three main functions of Type I interferons?

Back 58

a) Induce resistance to viral replication in all cells
b) Increase expression of ligands for receptors on NK cells (that tell NK cells to kill)
c) Activate NK cells to kill virus-infected cells.

Front 59

Primary function of NK cells

Back 59

kill virally infected cells

Front 60

What do NK cells produce that activates T cells?

Back 60

NK cells produce IFNg which activates adaptive (T cell) immunity

Front 61

How are NK cells activated or inhibited?

Back 61

Bottom line is that it's the balance of ligands that determine whether NK kills or lets them be.

Viral infection or cellular stress induces expression of ligands (MIC proteins) for NKG2D.

Health cells just express ligands that interact with inhibitory receptors.