lec 4- transition from innate to adaptive immunity

Question 1

how are neutrophils recruited from blood to tissue?

Answer 1

by complementary pairs of adhesion molecules

Question 2

what are selectins?

Answer 2

adhesion molecules expressed on neutrophils and endothelial cells that bind to a specific carbohydrate group on glycoproteins (addressins)

Question 3

what do selectins do?

Answer 3

mediate rolling adhesion on endothelial cells

Question 4

what are the three steps to neutrophil recruitment?

Answer 4

1. selectins on endothelial cells bind to s-Le carbohydrate on the neutrophils, which slows down the neutrophils as they flow through the blood
2. rolling adhesion converts to tight binding by LFA-1 on neutrophils interacting with ICAM-1 on endothelial cells
3. the chemokine CXCL8 binds to a chemokine receptor on a neutrophil, causing a cascade allowing neutrophil to alter the endothelial membrane and migrate to the site of injury by following the chemokines gradient

-(neutrophils also secrete more CXCL8 to increase recruitment of neutrophils)

Question 5

does selectin expression increase during inflammation?

Answer 5

yes

Question 6

are neutrophils the first effector cells recruited to the site of infection?

Answer 6

yes

Question 7

what do neutrophils do?

Answer 7

-engulf pathogens to kill them with toxins but do not present antigens
-short lived

Question 8

are neutrophils preloaded with enzymes because they have diverse materials of which they can consume?

Answer 8

yes

Question 9

what are the steps of a neutrophil from engulfment to apoptosis?

Answer 9

1. neutrophil engulfs bacteria
2. endosome fuses with granules
3. pH rises and antimicrobial response (respiratory burst) occurs which kills the bacteria
4. fusion with lysosome to reduce pH, bacterium degraded
5. neutrophil dies by apoptosis and is phagocytosed by macrophage

Question 10

what is the respiratory burst that neutrophils are dependent on?

Answer 10

the rapid release of reactive oxygen species done by an enzyme called NADPH which converts oxygen into superoxides

Question 11

what are people that are defective in NADPH?

Answer 11

immunodeficient, cant clear bacteria

Question 12

what is NETosis?

Answer 12

-it is when the neutrophils nucleus swells and bursts and extrudes toxic cellular contents that are stuck to sticky chromatin which continue to capture and kill microbes and prevent dissemination

(AKA the release of NETs)

Question 13

even though inflammation is localized, can effects occur throughout the body in response to cytokines?

Answer 13

yes

Question 14

what are pyrogens?

Answer 14

cytokines and other molecules that produce fever, negatively impacts most pathogens

Question 15

what are acute phase proteins?

Answer 15

proteins in the liver that respond to a pathogen threat by identifying it, eliminating it, causing the inflammatory response and coagulation

Question 16

what is the acute phase response?

Answer 16

the increase in concentration of over 30 liver proteins

Question 17

what is the role of IL-6?

Answer 17

acts on hepatocytes to induce the synthesis of acute phase proteins

Question 18

what is CRP and what does it do?

Answer 18

a pentraxins of five identical subunits that upon binding a variety of pathogen, it acts as an opsonin triggering the classical pathway of complement fixation in the absence of antibody

Question 19

what does serum amyloid A protein do?

Answer 19

-associates with HDL
-interacts with various cell surface receptors on macrophages to stimulate the production of inflammatory cytokines

Question 20

what initiates the MBL-lectin pathway of complement activation?

Answer 20

mannose-binding lectin (MBL)

Question 21

what is MBL?

Answer 21

-an acute phase protein that binds to mannose containing carbohydrates on pathogens
-circulates in serum in association with HDL

Question 22

explain the 2 steps that lead to CRP and MBL opsonizing bacteria for phagocytosis?

Answer 22

-bacteria induces macrophages to make IL-6, which causes the synthesis of acute phase proteins
-CRP and MBL are made and opsonize bacteria for phagocytosis

Question 23

can CRP and MBL each activate the complete complement pathway leading to a membrane attack complex formation?

Answer 23

yes

Question 24

what associating with MBL is activated when MBL binds to carbohydrates on pathogens?

Answer 24

MASP-1 and MASP-2

Question 25

what else does MBL facilitate the uptake of?

Answer 25

the uptake of bacteria by blood monocytes, they lack mannose receptors but can bind to MBL

Question 26

what classical C3 convertase does the MBL and classical pathway generate?

Answer 26

C4bC2a, while alternate has C3bBb

Question 27

explain the 5 steps to the MBL lectin pathway:

Answer 27

1. MBL binds to pathogen surface, activating the MASP-1 and MASP-2 2. MASP-2 cleaves C4 into C4a and C4b, C4b attaches to the microbial surface 3. MASP-2 cleaves C2 into C2a and C2b 4. C2a binds to surface C4b and forms the classical C3 convertase C4bC2a 5. C4bC2a cleaves C3 and cleaves it into C3a and C3b, C3b attaches to microbial surface

Question 28

what can activate the classical pathway?

Answer 28

IgM, IgG and CRP

Question 29

how does CRP activate the classical pathway?

Answer 29

C1 binds to CRP (which is bound to phosphorylcholine) causing the activation

Question 30

does C1 have a similar structure to MBL?

Answer 30

yes

Question 31

what is C1 made of?

Answer 31

-C1r and C1s, which are homologous to MASP-1 and MASP-2 -C1q serves as a binding site

Question 32

explain the steps of the classical pathway?

Answer 32

1. C1 binds to CRP (which is attached to phosphorylcholine) on the microbial surface 2. C1 cleaves C4 into C4a and C4b, C4b attaches to the microbial surface 3. C1 cleaves C2 into C2a and C2b 4. C2a binds to C4b to form C4bC2a (the classical C3 convertase) 5. C4bC2a cleaves C3 into C3a and C3b, C3b attaches to microbial surface

Question 33

what are ILCs (innate lymphoid cells)?

Answer 33

-cells developed from a common lymphoid precursor -5 types that all secrete cytokines to stimulate the activation of innate effector immune cells

Question 34

what is the most well studied ILC?

Answer 34

NK cells

Question 35

what do ILC1, 2, and 3 do?

Answer 35

found in tissues (unlike NK cells) and respond to different categories of pathogen

Question 36

what do Lti (lymphoid tissue inducer) cells do?

Answer 36

facilitate development of secondary lymphoid tissue

Question 37

do innate lymphoid tissues circulate?

Answer 37

no, they are resident and secrete cytokines

Question 38

what do NK cells do?

Answer 38

-kill viral infected cells

Question 39

what are the 3 needs that regulate NK cells?

Answer 39

1. NK cells can only discharge granules if in direct contact with another cell 2. multiple different interactions between NK cells and target cell receptors are needed 3. the default interaction of an Nk cell is inhibition which must be overcome by activating receptors

Question 40

what are the steps for how type 1 interferon induce the proliferation of NK cells and their differentiation into cytotoxic cells?

Answer 40

1. IFNa and IFNB (type 1 interferons) reach an NK cell 2. induce proliferation 3. induce differentiation into cytotoxic cells 4. effector NK cells kill viral infected cells by apoptosis

Question 41

what happens if a NK cells reaches a healthy cell? what happens if it reaches a viral infected cells?

Answer 41

-it moves on -it binds tightly

Question 42

how do macrophages and NK cells create a feedback loop?

Answer 42

1. macrophages infected by viral infections secrete cytokines that recruit NK cells (like IL-12) 2. NK cells and macrophage conjugate, the synapse delivers IL-15, with which IL-12 activates the NK cells 3. NK cells proliferate and differentiate into effector NK cells secreting type II interferon IFN-y 4. IFN-y binds to its receptors on the macrophage, causing an increase in phagocytosis and cytokines secretion of the macrophage

Question 43

what happens between dendritic and NK cells when in normal condition, NK cell level is high, and NK cell level is low?

Answer 43

-activation, proliferation and differentiation of NK cells is driven by dendritic cells = death of infected cells -high number of NK cells kills dendritic cells = viral infections terminated, adaptive immune response not needed -low number of Nk cells, causes NK cells to signal dendritic cells to mature = initiate an adaptive immune response when innate fails