Inflammation, Apoptosis, Response to Danger Signals

Question 1

SNS Model

Answer 1

Lymphocytes each express a receptor for a specific foreign antigen: how self-nonself is distinguished

there are cells that help this recognition (Th)
there are stimulator cells (APCs)

Question 2

INS model

Answer 2

APCs have SNS discrimination as well: use evolutionary developed receptors called PRRs to recognize ancient antigens (PAMPs)

APC activation leads to expression of co-stimulatory signals, processing of bacterial antigens, T-cell presentation

Question 3

Danger Theory

Answer 3

Immune system detects “danger” signals from injured cells, rather than by recognition of nonself antigens

danger signals are generated by toxins, pathogens, mechanical damage, injured cells signals

Question 4

Potential Danger Signals (i-v)

Answer 4

Infectious pathogens
Products of injured/necrotic/stressed cells
Immunostimulatory molecules (heparine sulfate)
Inflammatory cytokines (IFN-alpha/IFN-beta, TNF-alpha)
ruptured vessels or chemotaxis of b

Question 5

Necrosis

Answer 5

a passive, catabolic cell death in response to external toxic factors

Question 6

Necrosis is a “ “

Answer 6

dirty form of cell death characterized by swelling, rupture of cell membrane (cell lyse) which may cause inflammation or harm other neighboring cells

Question 7

a protein released during necrosis

Answer 7

HMGBI

released when cells are damaged. the receptor for HMGBI is RAGE

HMGBI activates transcription factor NF-kB

Question 8

Rage

Answer 8

the receptor for High Mobility Group Box 1 proteins released during necrosis

Question 9

Uric Acid

Answer 9

activates NF-kB

Question 10

HSPs

Answer 10

heat shock proteins, another danger signal: induces inflammatory cytokines TNF-alpha and IL-1(beta)

Question 11

Acute inflammatory response

Step 1

Answer 11

Detection of Danger/Damage signal

inflammatory process begins with clotting
detection of pathogens or cellular debris by PRRs

We would expect M1s, mast cells etc

Question 12

Acute inflammatory response

Step 2

Answer 12

Leukocyte Recruitment and Elimination of Stimuli

Signaling through PRR induces release of inflammatory mediators which act on blood vessels to promote the recruitment of leukocytes and exudation of plasma into damaged tissue

Question 13

Acute inflammatory response

Step 3

Answer 13

Resolution

elimination of microorganisms and necrotic tissue, leukocyte recruitment ceases and apoptotic neutrophils are phagocytized by macs

M2s at this stage clean all debris using scavenger receptors another type of PRRs

Question 14

Acute inflammatory response

Step 4

Answer 14

wound repair

tissue repair+remodeling involves development of new blood vessels (Angiogenesis) resurfacing of the wound (re-epithelialization) and collagen deposition

macs stimulate fibroblasts by releasing TGF-beta

Question 15

Inflammation in Atherosclerosis

5 general steps

Answer 15

1) monocytes are recruited via activated endothelia –> differentiate into MO

2) MO pick up microbes/debris via PRR
3) MO employ ROI, NO+ inflammatory molecules
4) tissue inflammation and damage occur
5) MO accumulate lipids and become foam cells

Question 16

Apoptosis versus Necrosis

Answer 16

necrosis = "dirty" cell death, swelling/lysis/inflammation
apoptosis = "clean" cell death, minimized damage to environment

Question 17

apoptotic cells are handled how compared to necrotic ones?

Answer 17

they’re removed without tissue inflammation

apoptosis produces no danger signals
HMGB1 proteins are released

apoptosis can render APCs into tolerant state

anti-inflammatory cytokines may play a role

Question 18

Apoptotic triggers

Answer 18

hypoxia
temperature change
damaged DNA 
cytokine starvation
death receptor stimulation

Question 19

Apoptotic regulators

Answer 19

death domain factors
cytochrome C 
p53
bcl-2 family
myc/oncogenes

Question 20

Apoptotic executioners

Answer 20

caspases

Question 21

Intrinsic pathway/extrinsic pathway

Answer 21

intrinsic = mitochondrial pathway
extrinsic = death receptor initiated SPECIFICALLY FAS-L

Question 22

Death receptor, the most important one for us

Answer 22

Fas-L

all cells express Fas but only lymphocytes express Fas-L

Question 23

Caspases

Answer 23

cysteine proteases that directly/indirectly orchestrate the morphological changes that occur during apoptosis

they exist as latent precursors

when activated, they initiate apoptosis by destroying key components of the cellular infrastructure

Question 24

The intrinsic mitochondrial pathway has 3 main triggers, and 4 downstream regulators, and at least one executioner

Answer 24

trigger: calcium+free radicals
regulators cytochrome C
executioner: caspase 3

Question 25

the Extrinsic Apoptotic Pathway

Answer 25

Fas-L——Fas induced —> death domain signals–>caspase 8