A2: Innate Immunity

Question 1

How does the innate immune system distinguish self from nonself?

Answer 1

By recognition of motifs that are shared by microbes but not present on host cells, including pathogen-associated molecular patterns (PAMPs)

Question 2

Are the pattern recognition receptors of the innate immune system clonally distributed or non-clonally distributed?

Answer 2

They are non-clonally distributed (identical receptors are expressed on all cells of a particular type; differs from adaptive immune system)

Question 3

What are the 3 main reasons why the innate immune system does not react against self?

Answer 3

1. Receptors of innate immunity are specific for microbial structures and damaged cells
2. Pattern recognition receptors are in cellular compartments such as endosomes so healthy cells are excluded
3. Normal cells express regulatory molecules that prevent innate immune reactions

Question 4

What are the major receptors on innate immune cells (macrophages, dendritic cells, etc) that recognize PAMPs and DAMPs?

Answer 4

Toll-like receptors

NOD-like receptors

Question 5

Which Toll-like receptors are present on the cell surface and which are present in endosomes?

Answer 5

Cell surface = 1,2,4,5,6

Endosomes = 3,7,8,9

Question 6

What is the significance of the location of the TLR when compared to cell surface and endosomes?

Answer 6

Cell surface TLRs recognize bacterial and parasitic glycolipids
Endosomal TLRs recognize viral DNA and RNA products

Question 7

What TLRs recognize bacterial lipopeptides? Which recognize lipopolysaccharide (LPS)? Which recognize bacterial flagella?

Answer 7

TLR 1 and 2 recognize lipopeptides (and TLR 6)
TLR 4 is specific for bacterial LPS
TLR 5 recognizes bacterial flagella

Question 8

What TLRs recognize viral single stranded and double stranded RNAs? What recognizes unmethylated CpG DNA?

Answer 8

All of these are endosomal; TLR 3,7,8 recognize ss and dsRNA; TLR9 recognizes unmethylated CpG DNA

Question 9

What are the two outcomes of TLR engagement?

Answer 9

1. NF-kB activation which promotes expression of various cytokines and 2. interferon regulatory factors (which produce antiviral cytokines and type I interferons)

Question 10

What are the 3 most important NOD-like receptors, and what do they do?

Answer 10

NOD 1 and 2 recognize bacterial peptidolgycans and activate NF-kB.
NLRP-3 enhances production of IL-1B via the inflammasome

Question 11

What 3 components make up the inflammasome, and what is the goal of the inflammasome?

Answer 11

NLRP-3 (sensor)
Adaptor protein
Caspase-1
Goal of which is to make biologically active IL-1B

Question 12

What causes the inflammation of gout?

Answer 12

Deposition of urate crystals causes inflammation via inflammasome and IL-1B production

Question 13

What 3 components make the epithelial barrier a protection against microbes?

Answer 13

1. Physical barrier to infection
2. Locally produces antibiotics called defensins
3. Intraepithelial lymphocytes kill microbes

Question 14

What two chains make up the intraepithelial lymphocytes?

Answer 14

gamma and delta chains (compared with alpha and beta chains of the majority of T lymphocytes)

Question 15

What are the 2 main types of circulating phagocytes?

Answer 15

Monocytes and neutrophils

Question 16

Which cytokines stimulate the production of neutrophils?

Answer 16

Colony-stimulating factors

Question 17

What are two phagocytic receptors that are on the cell surface of macrophages?

Answer 17

Mannose receptors and scavenger receptors

Question 18

What are the 2 ways that macrophages are activated?

Answer 18

Classical Activation: Innate immune signals from TLRs and IFN-gamma allows macrophages to destroy microbes
Alternative Activation: IL-4 and IL-13 induce macrophages to begin tissue repair and terminate inflammation

Question 19

What is the main goal of dendritic cells?

Answer 19

Initiate inflammation and stimulate adaptive immune responses

Question 20

What activates mast cells?

Answer 20

Microbial products binding to TLRs or via antibody-dependent mechanism

Question 21

What do mast cells do?

Answer 21

Release histamine to cause vasodilation.

Synthesize and secrete prostaglandins and cytokines (eg TNF) to stimulate inflammation

Question 22

What is the difference between an innate lymphoid cell and true lymphocytes?

Answer 22

Innate lymphoid cell do not express T cell antigen receptors (TCRs)

Question 23

What is the main role of natural killer cells?

Answer 23

Recognize infected cells and kill them and secrete IFN-gamma

Question 24

What is the interplay between natural killer cells and macrophages?

Answer 24

Activated NK cells secrete IFN-gamma which activates macrophages.
Activated macrophages produce IL-12 after ingesting microbes which activates NK cells

Question 25

What 3 cytokines activate natural killer cells?

Answer 25

IL-15 (important in maturation of NK cells) type I interferons IL-12 (Type I IFN and IL-12 important to enhance killing by NK cells)

Question 26

What cells are the principal mediators of antibody-dependent cellular cytotoxicity, and how does it occur?

Answer 26

Natural killer cells. Occurs via CD16 receptor on NK cells that recognizes IgG antibodies on cells.

Question 27

What are the 2 main activating receptors of NK cells?

Answer 27

``` NKG2D: recognizes MHC class I proteins CD16: recognizes IgG antibodies and kills via antibody-dependent cellular cytotoxicity ```

Question 28

How do the activating receptors of NK cells work?

Answer 28

Activating receptors have ITAMs on their cytoplasmic tails. ITAMs that are phosphorylated promote tyrosine kinases. Tyrosine kinases lead to cytotoxic granule exocytosis and production of IFN-gamma.

Question 29

What are the two main inhibitory receptors for NK cells?

Answer 29

Killer cell immunoglobulin-like receptors (KIRs), CD94+NKG2.

Question 30

How do inhibitory receptors of NK cells work?

Answer 30

Contain ITIMs which when they bind to class I MHC become phosphorylated. ITIMs then promote tyrosine phosphatases which inactivates tyrosine residues and prevents ITAMs action

Question 31

What are the types of T cells that are present in the epithelial?

Answer 31

the gamma/delta subtypes of T cells

Question 32

What are the 3 pathways of activation for the complement protein system?

Answer 32

Classical pathway: antibodies that bind to microbes activate complement system (adaptive) Alternative pathway: proteins are activated directly from microbial surfaces (innate) Lectin pathway: Activated when mannose-binding lectin binds to mannose residues on microbes (innate)

Question 33

What is the first step of the complement pathway? What are subsequent steps?

Answer 33

C3 is cleaved to make C3a and C3b. C3b goes on to activate more of the complement system.

Question 34

What are the 3 roles of the complement system?

Answer 34

1. Opsonization (via C3b) 2. Inflammation (via C5a and C3a) 3. Cell lysis (via membrane attack complex)

Question 35

What are 3 key functions of TNF and IL-1?

Answer 35

1. Main chemoattractant (activates endothelium) 2. Activate liver to produce acute-phase proteins 3. Induce fever via action at hypothalamus

Question 36

What are the 3 steps to leukocyte migration? What molecules mediate each step?

Answer 36

1. Leukocyte rolling (selectins) 2. Leukocyte adhesion (integrins) 3. Leukocyte chemotaxis (chemoattractants)

Question 37

What is a key enzyme that is involved in oxidative burst, and what disease results if it is deficient?

Answer 37

Phagocyte oxidase converts molecular oxygen to superoxide anion and free radicals. This is key in destroying microbes via phagocytosis. Deficit in this enzyme results in chronic granulomatous disease

Question 38

What are the key molecules that act as antivirals, and what is the main cell that releases these molecules?

Answer 38

Type I interferons (interferon-alpha and interferon-beta). Mainly released by a dendritic cell called a plasmacytoid dendritic cell when activated by TLRs that recognize viral nucleic acids

Question 39

Why are adjuvants sometimes administered along with vaccines?

Answer 39

Vaccines administer the antigen without the actual microbe, so the adaptive immune system may need microbial products in order to provide the microbe-dependent secondary signals

Question 40

What two signals are needed in order to properly induce activation of the adaptive immune response?

Answer 40

Costimulators: expressed by dendritic cells when activated by microbes or IFN-gamma produced by NK cells). IL-12, IL-1, and IL-6: secreted by dendritic cells and macrophages stimulate differentiation of naive T cells into effector cells

Question 41

What other signal does a B cell need when its antibody binds to an antigen in order to become active?

Answer 41

C3d. C3d is a product of C3b proteolysis that binds to the microbe. B cells recognize the antigen and the C3d molecule and induce proliferation of that B cell.