Lecture 9: Innate Immunity Flashcards
What is the anatomic barrier?
Prevents the entry and colonization of many microbes
- Skin: Sebum produces low pH to inhibit microbial growth
- Mucous membrane: trap organisms in mucus and propel them out of body
What is inflammation?
Complex reaction as a result from any sort of injury
- Normal conditions: protective
- Pathological conditions: inflammation is chronic
What are the signs for inlammation
Swelling
Redness
Heat
Pain
Due to mast cells producing prostaglandins, leukotrienes, and histamine
What are the steps for an acute inflammatory response? What cells are involved?
Step 1: Injury and microbes enter
Step 2: Microbes activate sentinel cells
-Mast Cells
-Macrophages
-Dendritic Cells
Step 3: Sentinel cells secrete inflammatory mediators
Step 4: Increased vascular permeability allows fluid and proteins enter tissues
Step 5: Complement, Abs, and anti-microbial proteins kill microbes
Step 6: Leukocytes enter tissue and kill microbes
What are side effects to inflammation?
Pain: due to inflammatory mediators stimulating nerves
Body Reactions: chill, fever, muscle ache
How does fever occur?
Infection triggers production of pyrogenic cytokines:
TNF, IL-1, IL-6 in macrophages
How do innate immune cells recognize non-self cells?
Innate cells look for PAMPs
- unique to pathogens
- cannot be altered
- no structural similarity to self Ags
How do Toll-Like receptors work?
Step 1: Recognize microbes by forming pairs with microbes
(via PAMPs)
Step 2: Activate transcription factors
- NFkB: promotes various cytokines and adhesion molecules (MOST IMPORTANT)
- TRIF and MyD 88: Adaptor proteins
- IRF (interferon): signalling for virus
What does the pairing of TLR 1/2 or TLR 2/6 recognize?
Tuberulosis
What does TLR 3 recognize?
Certain viruses
What does TLR 4 recognize?
Bacteria in GI tract
e.g. E. coli
What does TLR 5 recognize?
Bacteria with flagella
What does TLR 7-9 recognize?
Certain viruses
Which TLRs recognize extracellular pathogens?
TLR 1, 2, 4, 5, 6
Which TLRs recognize intracellular pathogens?
TL 3, 7, 8, 9
Which TLRs recognize bacteria?
TLR 1, 2, 4, 5, 9
Which TLRs recognize viruses?
TLR 3, 7, 8, 9
Which TLRs recognize fungi?
TLR 2, 6
What deficiencies in TLR can cause recurring infections?
MyD88 and IRAK-4 deficiency
What do NOD-like receptors do?
When activated by PAMPs, inflammasomes containing NLR will trigger activation of NFkB and pro-caspase 1.
Caspase 1 will activated IL-1B and IL-18, potent pro-inflammatory cytokines
Anti IL-1B and IL-18 therapy is used for what disease?
Gout
What are DAMPs?
Damage associated molecular patterns from dead or dying self cells
- example: necrosis
- recognized by macrophages
What are the downstream effects of DAMPs?
NFkB is activated
Stimulate production of TNF alpha and IL-1
What diseases come from DAMPs?
Plays role in autoimmune disorders
-Diabetes I, MS, Lupus, Rheumatoid arthritis
What are the steps of a PRR triggered response in phagocytes?
Step 1: fMET is a prokaryote constituent recognized by immune system
Step 2: Phagocytes bind to pathogen using fMET
Step 3: Initiate phagocytosis
What do macrophages produce in response to PAMPs and DAMPs?
1) Cytokines and chemokines
2) ROI
3) NO
4) Prostaglandins
5) Cationic proteins and polypeptides
What the functions of macrophages?
1) Activated by PAMPs and DAMPs
2) Chemotaxis and Tissue Inflammation
3) Phagocytosis, Scavenger function, Tissue repair
4) Effector function
5) Antigen presentation to T cells
6) Immunomodulation
How do mast cells react to PAMPs and DAMPs?
Express receptors for PAMPs and DAMPs
-can amplify or suppress response
Where do mast cells tend to reside?
- Sites exposed to external environment (skin)
- Close to blood vessels (regulate vascular permeability)
How do mast cells modulate behavior of nearby cells?
1) Release of inflammatory chemicals
2) Increased permeability of neutrophils and monocytes
3) Diapedesis: blood enters
4) Chemotaxis
5) Phagocytosis
What activates mast cells?
- IgE and Ag
- PAMPs
- Cytokines and chemokines
- C3a and C5a complement
- Temp and pressure
- cell to cell contact
What do effector molecules do mast cells release?
Early (Seconds):
Histamine
Proteases
TNF
Later (Minutes) :
Prostaglandins
Leukotrienes
Latest (hours):
Cytokines: IL-4 and TNF
What are cytokines?
Small proteins that mediate inflammation, immunity, and hematopoiesis
- can work short range and long range
- both pro and anti inflammatory
What are the two important anti-inflammatory cytokines?
IL-10 and TGF-B
What are the steps in classical complement pathway
Step 1: Create C3 convertase (C4bC2a)
Step 2: Create C5 convertase (C4bC2aC3b)
Step 3: Create MAC complex to lyse cell
What inflammatory cytokines are important for the acute phase of inflammation?
IL-6
IL-1
TNF alpha
What acute phase proteins can you measure for a diagnosis of inflammation?
C reactive proteins
Serum amyloid A
Mannose Binding protein
alpha 1 acid glycoprotein
Where do neutrophils and monocytes enter infected sites of injury?
Enter through post-capillary venules
In lungs, liver, and kidney, they enter via capillaries
How do neutrophils enter tissue?
Leukocyte Extravasation
Step 1: Inflammatory signals (TNF alpha and IL-1) from mast cells are activated
Step 2: Endothelial cells to activate PAF, P-selectin, and E-selectin on surface
Step 3: Leukocytes rolls on endothelial cells until PAF receptor binds with PAF (low affinity)
Step 4: I-CAM on endothelial cells stop leukocytes from rolling and to firmly adhere (high affinity)
Step 5: Leukocyte migrates between endothelial cells to tissue. Follow IL-8 to inflammatory site
What activates M1 macrophages (classical)?
Induced By:
IFN-gamma cytokines
Microbial products binding to TLR
Produces:
ROS, NO, IL-1, IL-12, IL-23
Result:
Promote inflammation
What activates M2 macrophages (alternative)?
Induced by:
IL-4 and IL-13
Produces:
IL-10 and TGF-B
Result:
Anti-inflammatory effects
How do PRR (patter recognition receptors) play a role in phagocytosis
After microbe binds to PRR, microbe undergoes phagocytosis. Lysosome will fuse with phagosome and kill microbe via ROS and NO.
How do lysosomes kill microbes?
- Oxygen consumption is increased
- Superoxide anion is produced
- Superoxide quickly converted to Hydrogen Peroxide
- H2O2 kills microbes
- H2O2 is broken down by catalase
- Resulting hydroxyl radicals react with organic molecules
Is inflammation efficient against intracellular pathogens?
ABSOLUTELY NOT
How is the anti-viral innate immune response mediated?
Type I Interferons alpha and beta
-block viral replication
Natural Killer Cells
How do NK cells work?
1) NK cells recognize infected cells and kill them through apoptosis
- Via perforins and granzymes
2) NK cells release IFN-gamma to activate macrophages
3) Macrophages kill phagocytized microbes
What are NK activating and inhibiting receptors?
Activating:
Killer Cell Immunoglobulin-like receptors
e.g. MICA and MICB
-triggers tyrosine kinases
Inhibitory
Class I MHC and Protein Tyrosine Phosphatases
If the binding between KIR and MHC I is strong, host cell will be spared
How do cells of innate immunity regulate and adaptive immune response?
Signals needed for lymphocyte activation
1) Recognition of microbial antigen by T cell
2) Signal from APC (dendritic or macrophage)
3) Cytokines
