Assignment #14-w/o review objective s

Question 1

What are the physical and chemical barrier to microbial penetration (Review from assignment #1)

Answer 1

Physical: Mucus and Skin
Chemical: Lysozyme, lactoferrin, spermine, acid pH

Question 2

What microbes lie outside the cell?

Answer 2

extracellular bacteria, viruses prior to entry into the cell and when released from cells and parasites (Depends on stage of life cycle)

Question 3

what are the cells of the innate immunity, systems and molecules and properties? (Review )

Answer 3

Monocytes/Macrophages, Neutrophils, NK cells, Mast cells, Basophils, Dendritic
Systems and Molecules: Complement, cytokines, defense molecules (armamentarium)

No lag time, no memory, no exquisite specificity

Question 4

How does tissue damage lead to production of C5a and bradykinin?

Answer 4

Activates intrinsic coagulation pathway which in particular activates Factor XII, which converts the zymogen pre-kallikrein to active kallikrein.
Kallikrein cleaves C5 to C5a + C5b
Kallikrein cleaves kininogen to kininoge(a) & bradykinin

Question 5

How does tissue damage lead to production of activation of neutrophils?

Answer 5

C5a is chemotatic for neutrophils, which must be recruited into the tissues to phagocytose microbes.

Kallikrein activates the neutrophils

Question 6

C5a leads to mast cell degranulation and histamine release. What is the role of histamine in an immune response?

Answer 6

Histamine bindings to vascular endothelial cells increases not only the vascular permeability, but also causes translocation of P-selectins rom the cytosol to the endothelial cell surface.

Question 7

What is the effect of bradykinin on vascular permeability?

Answer 7

direct effect of increasing vascular permeability greatly (more than histamine)

Question 8

Spontaneously generated C3b (tickover) binds to microbial surfaces. This is the initiating step for activation of the alternative pathway (AP) of complement. Review the steps in AP complement activation, the products generated and the role of each product in immune response to bacterial infection

Answer 8

C3b binds factor B; factor B cleaved by factor D; C3bBb is C3 convertase (AP)
C3 convertase —> C3a and C3b; C3a —> mast cells –> histamine
C3b –> C3bBbC3b, the C5 convertase (CP) –> cleaves C5 –> C5a + C5b
C3b–> opsonin for phagocytes
C5b –> initiates MAC –> osmotic lysis of microbes

Question 9

Phagocytosis by tissue macrophages and release of inflammatory mediators (cytokines, chemokines) is critical for activation of the vascular endothelium as a preparatory step for leukocyte entry into the site of infection. Review this process

Answer 9

Direction recognition (PRR) with PAMPs on microbes–> NFkB –> pro-IL-1 and pro-IL-18
DAMPS –> NALP3 inflammasome –> procaspase 1 to caspase —> IL-1 and IL-18
review the rest of this process which is already in the assignment 2 brainscape

Question 10

Activated phagocytes secrete what to allow cell entry?

Answer 10

matrix metalloproteinases (allow entry of circulating leukocytes into tissue)

Question 11

Activated vascular endothelium express what ?

Answer 11

De novo P-selection (histamine translocation from cytosol), E selection (IL-1 and TNF). Each binds molecules of Leukocytes

De novo VCAM-1, ICAM-1 and upregulates ICAM-2 (TNF and IL-1). Counter molecules on circulating leukocytes are VLA-4 (CD49d-CD29) (VCAM1), LFA-1 (CD11a-CD18) and LFA-1 (ICAM1 and ICAM2).

Endothelial cells also secrete MCP-1/CCL2 and IL-8/CXCL8

Question 12

Activated endothelium leads to what?

Answer 12

leads to cell rolling, firm adhesion and leukocyte margination

Question 13

What effect does matrix metalloproteinases have on transmigration of leukocytes?

Answer 13

degrade basement membrane and matrix

Question 14

What is diapedesis?

Answer 14

recruited cells squeeze in-between endothelial cells

Question 15

what interaction is required to pull cells through the tissues?

Answer 15

PECAM-PECAM

Question 16

Once the cells are pulled through the tissues what effect does neutrophils and monocytes have on the microbes?

Answer 16

Neutrophils –> enter and phagocytose microbes
Monocytes –> differentiate to macrophages which secrete inflammatory mediators, chemokines and cytokines after phagocytosis.
Response is now amplified

Question 17

Dendritic cells link innate and adaptive immunity, what is the role of dendritic cells in linking the two systems?

Answer 17

Immature dendritic cells endocytose microbe and mature as they transport microbe to secondary lymphoid tissue; Process antigen --> MHC class II 
Microbes transport directly to the secondary lymphoid tissue.

Question 18

The innate immune system plays a critical role in the recruitment of the adaptive immune system. Now, the products of the adaptive immunity activation help the innnate immune system. Explain how IgG, IgM, TNF and IFNgamma help

Answer 18

IgM- microbe complexes bind to C1 of classical complement pathway and triggers its activation
IgG binds to microbe –> binds to FcgammaR on phagocytes. Opsonin-mediated phagocytosis
TNF: activation of iNOS and enhances NADPH oxidase activity
IFNgamma: role in iNOS activation, enhances NADPH oxidase activity and enhances MHC class II expression on APCs

Question 19

Describe the process that down regulates the immune response

Answer 19

Th1 and Th2 cytokines: reciprocal down regulation
IgG antibodies bind to FcgammaR on B cells and Plasma cells
Tissue Inhibitors of matrix proteases inactive matrix metalloproteinases
Apoptosis of many activated cells
PD1 interaction with PDL-1 or PD-L2 delivers negative signal to T cell via PD1
Triggering CD200R by soluble or cell bound CD200 turns off T cells

Question 20

Activation of Kallikrein, consequences?

Answer 20

(i) Cleaves C5–> C5a and C5b
(ii) Activates neutrophils
(iii) Releases bradykinin from kininogen