Lecture 4: Innate Immunity Flashcards
The defense mechanisms that respond first to pathogens and dead cells is referred to as what?
Innate immune system.
What are the other two names for innate immunity?
Natural immunity
Native immunity
In general; what is the role of the innate immune system?
The innate immune system is our first response to pathogens that [prevents, controls and eliminates] infections.
It gets ride of damaged cells via phagocytosis and starts the process to repair damaged tissue.
It also signals the adaptive immune system to respond to intracellular or extracellular pathogens.
Tell me about inflammation.
Inflammation results from injury or the invasion of a pathogen. It serves to protect us, however it can also damage tissue.
Normally, any damage caused by inflammation is repaired when the inflammation subsites. However, if the infection or damaged-tissue remains, the inflammation can be chronic.q
What occurs during inflammation?
The blood vessels will become permeable to plasma proteins and immune cells, allowing them to leave the blood go to the site of injury. WBC (leukocytes) attack and release mediators which continue inflammation.
It is these inflammatory mediators that stimulate nerves and cause pain.
The body will then react: chills, fever, muscle aches.
What happens when tissue is damaged due to extracellular pathogens?
- Damaged tissue will attract mast cells, which release histamine into the blood stream.
- Histamine will cause the vessels to dilate and become leaky; allowing compliment proteins to leave the vessels and attract phagocytes.
- Blood flow to the area increases, producing, warmth, redness and swelling. This increase in blood flow is also accompanied by phagocytes.
- WBC (leukocytes), particularly phagocytes will move from vessel–> infected area and attack.
- At the same time, they release mediators which stimulate nerves and cause pain.
- If severe infection; body will react with chills, fever and muscle aches.
- Histamne and compliment signaling stop and phagocytes are no longer sent to the area.
- Growth factors from WBCs and platelets heal the would
Can inflammation protect us against intracellular pathogens?
No. Inflammation is only sufficient enough to attack extracellular pathogens.
What controls the innate immune response to intracellular pathogens: like viruses?
1, Type 1 interferons- blocks viral replication
2. NK cells- kills the virus-infected cells
How does the innate immune system recognize self vs non-self cells?
PRR (pattern recognition receptors) on cells of the innate immune system recognize PAMPs (pathogen assx molecular patterns), which are displayed on non-self cells.
They are unique to classes of pathogens and needed for the pathogen to survive. Thus, they aren’t hidden well.
Do PAMPs have any structural similarity to self antigens?
No.
What are PRR?
PRR (pattern recognition receptors) are located on innate immune system cells that detect PAMPS located on non-self cells.
They are germ-line encoded, meaning that they are found in gamete producing cells; thus, their diversity is limited between people.
Binding of PAMP and DAMP ligands to PRRs will induce intracellular signaling in _________ and lead to their _______.
Phagocytes
Activation
Toll-like receptors (TLR) are a type of _________.
Pattern recognition receptor (PRR)
TRL description
TRL are located on the cell surface (respond to extracellular microbes) and in endosome, responding to pathogens that have been ingested. They recognize PAMPS and activate inflammation.
Endosomal TLRs will only respond to nucleic acids.
What TLRs recognize extracellular pathogens?
TLR 1, 2, 4, 5, 6
Thus, they’re located on the plasma membrane
What TLRs recognize intracellular pathogens?
TLR 3, 7, 8, 9
Thus, they’re located in endosomes.
What is the PRR that recognized glycans with a TERMINAL mannose?
Mannose receptor.
In humans, there are no glycans with a terminal mannose.
TLR1: TLR2 heterdimer
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
- Lipopeptides, GPI
- Monocytes, dendritic cells, eosinophils, basophils and mast cells
- Plasma membrane
TLR2: TLR6 heteodimers
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
- Lipoteichoic acid and zymosan
- Monocytes, dendritic cells, eosinophils, basophils and mast cells
- Plasma membrane
TLR 3
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
- dsRNA
- NK cells
- Endosomes
TLR4: TLR4 Homodimer
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
- Lipopolysaccharide
- Macrophages, dendritic cells, eosinphils, mast cells
- Plasma membrane
TLR 5
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
- Flagellin
- Intestinal epithelium
- Plasma membrane
TLR 7
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
- ssRNA
- Plasmacytoid dendritic cells, NK cells, eosinophils, B cells
- Endosomes
TLR 8
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
- ssRNA
- NK cells
- Endosomes
TLR 9
- Recognizes what ligands?
- What cells carry these receptors?
- Where are they located?
- Unemethylated guanine-rich DNA
- Plasmacytoid dendritic cells, B cells, eosinophils, basophils
- Endosomes
TLR 10 homodimer and heterodimer with TLR1: TLR2
- Unknown
- Plasmacytoid dendritic cells, B cells, eosinophils, basophils
- Unkown
For TLR to initiate a response, what must occur?
signaling.
TLR 1, 2, 5, 7, 8, 9 undergo what kind of signaling?
MyD88-dependent signaling.
Activates transcription factors [NF-kB] and [IRF] (interferon regulatory factor) via Use [MyD88 adaptor protein].
Thus, they under MyD88-dependent signaling.
TLR3 undergoes what kind of signaling?
TRIF dependent signaling.
Activates transcription factors [NF-kB] and [IRF] via TRIF
TLR 4 undergoes what kind of signaling?
MyD88/TRIF dependent signaling.
Activates transcription factors [NF-kB] and [IRF] via MyD88 and TRIF.
What TLR recognize bacteria?
TLR 1, 2, 4, 5, 9`
What TLR recognizes viruses?
TLR 3, 7, 8, 9
What TLR recognizes fungi?
TLR 2, 6
Activation of transcription factors [NF-kB] and [IRF] via TRL cause what to happen?
Increases the transcription of genes that promote inflammation.
- Influence the adaptive response of the immune system and call T-cell to initiate cell-mediated immunity (via IL12)
- Kill bacteria
- Injure tissue, causing host cells to die and even septic shock.
What controls the T-cell immune response?
IL-12
Mechanism of TLR-4 Receptor
- On the surface of a macrophage, [TLR4, MD2, CD14 and LPS] assemble.
- MyD88 binds and activates [IRAK-4], which will phosphorylate [TRAF6], which then phosphorylated and activates [IKK].
- IKK phosphorylated [IkB], causing it to degrade and releases NFk-B into the nucleus.
- NFk-B activates transcription of genes for inflammatory cytokines, which are made in the cytoplasm and secreted via the ER.
What is
- LPS
- LBP
- CD14
- MD2
- lipopolysaccharide
- LPS binding protein in the blood
- receptor for LPS
- MD2 LPS binding protein that makes a bridge:
CD14-LPS-MD2-TLR4
What are DAMPS?
Damage assx molecular patterns
DAMPS are released by tissues undergoing necrosis (cell death via EXTRACELLULAR FACTORS).
Send alarms to activate immune cells, which will then cause inflammation
What are examples of DAMP signals sends?
- HMGB1 (high mobility group box 1), which binds to its receptor RAGE.
- Uric acid
- HSPs
These will all activate [NF-kB]
What are NOD-like receptors (NLRs)
NLRs (nucleotide oligomerization domain)- like receptors are intracellular, scaffolding proteins use [NF-kB and MAPK] signaling pathways to activate inflammatory caspases.
They respond to PAMPs and DAMPs by forming a signaling complex called the inflammasome. Inflammassomes then activate caspase-1, which produces IL-1B and IL-18, which are inflammatory agents.
Where are secreted forms of IL-1B and IL-18 made?
Inflammasome
Scavenger receptors are a family of what?
Scavenger receptors are another type of pattern recognition receptors (PRR) that uptake oxidized lipoproteins.
What are the 3 types of scavenger receptors?
- Scavenger receptor class A type I
- Scavenger receptor class A type II
- MARCO- macrophage receptor with collagenous structure.
What is the structure of scavenger receptors?
Trimeric complex of type II transmembrane polypeptides. They have 3 distinct extracellular structural domains
- cysteine-rich domain (absent in SR-A-II)
- collagen-like domain
- alpha-helical coiled domain (absent in MARCO)
What PRRs are expressed on macrophage and help with recognition and phagocytosis of microorganisms?
SR-A and CD-36 (a type of scavenger receptor)
What are some receptors for carbohydrates?
Lectin family of PRR.
Lectin receptors of PRR
Belong to the ______ lectin family.
Have domains that recognize ______, ______, ______
Bind what kind of lectins?
Role:
These receptors belong to the C-type lectin family because they bind carbs. They have domains that recognize carbs such as
[microbial mannose, N-acetylglucosamine and B-glucans].
The lectins that bind to lectin receptors can be soluble and found in the blood or ECF or they can be integral membrane proteins found on macrophages and DCs.
Role:
Phagocytosis
Secrete cytokines to promote the adaptive immune response.
What is soluble mannose-binding lectin (MBL)
a protein that is involved in complement activation via the lectin pathway.
What are the three components of innate immunity?
- Physical barriers
- Phagocytes- fixed and free macrophages, neutrophils, eosinophils and monocytes
- Immunological surveillance (NK cells; destroy abnormal cells)
Epithelial barriers will make anti-microbial substances like ______, ______ and ______ that will kill pathogens.
Produce anti-microbial substances, such as defensins and cathelicidins, and lymphocytes to kill pathogens.