Innate Immunity Flashcards
Key Concepts associated with innate immunity (6)
- Always on/present
- Activated rapidly
- Non-specific
- Non-adaptive- same on each encounter
- No clonal expansion
- No memory cells are generated
Name the Physical barriers of innate immunity (6)
Skin Mucosal surfaces Mucociliary escalator Normal flora Fever Eyes
Characteristics of skin that makes it an effective barrier to pathogens (7)
- Intact barrier
- Sloughing
- Keratinized cells
- pH 4 due to sebum
- Killing of microbes by locally produced Abx (defensins, cathelicidins)
- Killing of microbes and infected cells by intraepithelial lymphocytes
- Langerhans cells - if get through intraepithelial
Characteristics of Mucosal surfaces that make it a physical barrier to pathogens
- Covered in mucous
- Mucous contains lactoferrin and lysozyme (breaks down peptidoglycan)
Characteristics of Mucociliary escalator that make it a physical barrier to pathogens
Takes things you breathed in (in trachea, upper respiratory tract for example), cilia move it up and then you can swallow it and cough it out or go to acidic stomach
Characteristics of Normal flora that make it a physical barrier to pathogens
Prevents binding of pathogens and secrete bacteriocins (toxins against other bacteria)
Characteristics of Fever that make it a physical barrier to pathogens
Retards pathogen growth
Characteristics of Eyes that make it a physical barrier
- blinking
- tears have lysozyme
List enzymes and secretions that are part of the innate immune response and how they protect us from pathogens (4).
- Lysozyme
- Iron-sequestering proteins- transferrin and lactoferrin
- Antimicrobial peptides/antibiotics (defensins and cathelicidins)
- Complement
How do lysozymes protect from pathogens?
- Breaks down peptidoglycan (major component of bacterial cell membranes)
- Present in tears, mucus, and saliva
How do iron sequestering proteins protect us from pathogens?
Can bind free iron to create a lack of iron in the blood —> induced hypoferremia
- hide iron from bacteria (many bacteria need iron to survive)
Describe the location of the two iron-sequestering proteins
- Transferrin in blood
- Lactoferrin in mucosal secretions
Name two examples of Antimicrobial peptides/antibiotics
Defensins and cathelicidins
Antimicrobial peptides/Abx are found in _______
Skin, mucosal secretions, and granules within the phagocytes
Name the two innate complement pathways.
Alternative pathway
Lectin pathway
Complement consists of _______ serum proteins
> 30
Name the cells that have an important function in their innate immune response.
Phagocytes:
- Neutrophils
- Macrophages
Mechanisms used by the phagocytes to protect the body from pathogens.
Phagocytes (neutrophils and macrophages)- kill via oxidative burst
- Increased acidity of the vacuole (phagosome) by pumping in H+
- Phagocyte membrane zips up around the microbe
- Fusion of the lysosome with the phagosome —> phagolysosome
- Release of lytic enzymes and ROS and nitrogen molecules (oxidative burst) within the phagolysosome
Neutrophils:
1) Pathogen specific or non-specific?
2) Where are they found?
3) Short or long lived?
4) What do they do?
1) Non-specific
2) Blood
3) Short-lived
4) Phagocytosis (Best!)
Macrophages:
1) Pathogen specific or non-specific?
2) Where are they found?
3) Short or long lived?
4) What do they do?
1) Non-specific
2) Tissue
3) Short-lived (1-3 days)
4) Phagocytosis and repair and antigen presentation
Name the categories of receptors in the innate immune response.
Toll-like receptors (TLR) Nucleotide-binding oligomerization domain proteins (NOD)- PRRs Pentraxins- PRRs Collectins- PRRs Ficolins- PRRs
TLRs - give examples
Plasma membrane:
TLR1:TLR2- bacterial lipopeptides
TLR2- bacterial peptidoglycan
TLR4- LPS
TLR5- bacterial flagellum
TLR2:TLR6- bacterial lipopeptides
Endosome:
TLR3- dsRNA
TLR7- ssRNA
TLR8- ssRNA
TLR9- CpG DNA
Describe TLRs
Different TLRs recognize and bind different PAMPs
Some are on the surface of the cell, some are inside the cell
TLR engagement results in activation of the cell
Describe NODs
Nucleotide-binding oligomerization domain proteins (NOD)
Detect microbial PAMPs of pathogens that gain entry inside the cell
Give examples of NODs.
NOD-1: ubiquitous in tissues
- recognize peptidoglycan from Gram-negative bacteria
NOD-2: limited to myeloid cells
- recognize a different peptidoglycan motif
Describe Pentraxins
Pentraxins are Plasma proteins.
These PRRs recognize a variety of bacterial, fungal, and viral PAMPs
Once bound to the pathogen, they can activate the classical complement pathway
They are produced during the acute phase response- a systemic inflammatory response
Give examples of Pentraxins.
C-reactive protein: used as a measure of infection
Describe Collectins.
Collections are soluble PRRs.
- Lectins: proteins with a carbohydrate binding domain
- Common targets such as MANNOSE and FUCOSE are not found in high concentrations on mammalian cells
Give some examples of Collectins.
- MBL (Mannose binding lectin): which when bound to mannose on a pathogen, can activate the lectin complement pathway
- Surfactants A and D are found in alveoli and act as opsonins (something that attaches to pathogen) for alveolar macrophages
Describe Ficolins.
Ficolins are soluble PRRs.
- Ficolins have a similar “celery stalk” structure as MBL
- bind N-acetylglucosamine (in peptidoglycan) or lipoteichoic acid (in gram positive bacteria)
- when bound to a pathogen, it can also activate the lectin complement pathway
List the steps of Extravasation.
Rolling
Activation of Integrins
Stable Adhesion
Transendothelial Migration
Describe Rolling
1) Tissue macrophages detect pathogens or injury —> cytokines secreted
2) Cytokines cause an upregulation of adhesion molecules on the local vascular EC’s
3) Leukocytes (neutrophils/monocytes) drift toward the vessel wall (margination)
4) Rolling of leukocytes is caused by low affinity binding and release of the cells with the newly unregulated adhesion molecules
Activation of Integrins
The repetitive binding/detaching actions between leukocytes and EC’s results in conformational change of the adhesion molecules on the leukocytes
Once the conformation change has occurred, the leukocytes can bind with greater strength to the adhesion molecules on the vascular EC’s
Stable Adhesion
Conformational change of vascular adhesion molecules allows for stable binding and arrest of the cells
Transendothelial Migration
Now that the leukocyte has stopped moving, it undergoes changes to allow it to pass between the vascular EC’s
The cell flattens out along the endothelial surface, then squeezes between the EC’s into the tissues
What receptors are associated with Rolling?
Selectin ligand on the leukocyte binds to the selectin receptor on the EC surface
What receptors are associated with Integrin activation by Chemokines?
Proteoglycan bound to a Chemokine on the EC surface binds to the Chemokine receptor on the leukocyte which activates the integrin ligand on the EC surface
What receptors are associated with stable adhesion?
The Selectins disassociate
The integrins bind the integrin ligands in high-affinity state
Proteoglycan-Chemokine stays bound
Steps of Inflammation. (5)
Vasodilation Phagocyte migration Increased phagocytosis Cytokine production Plasmin remodeling and repair
Describe Vasodilation as a part of inflammation
Chemokines and cytokines cause vasodilation which allows plasma, cells, and molecules to enter the tissues
Describe phagocyte migration as a part of inflammation
Extravasation of neutrophils within 30-60 minutes
Extravasation of monocytes in 4-6 hours
Describe phagocytosis as a part of Inflammation
Macrophages, DCs, and recruited leukocytes increase their phagocytic activity
Describe cytokine production as a part of Inflammation.
Pro-inflammatory cytokines (IL-1, IL-6, and TNF-alpha) are produced by the activated tissue macrophages —> upregulation of adhesion molecules on vascular ECs
Name the cytokines associated with inflammation.
IL-1
IL-6
TNF-alpha
Define inflammation.
VD and increased vascular permeability occur as a result of cytokines, kinins, and histamine released by cells at the site of infection (recognized when PRR binds PAMP) or due to tissue injury
What is the acute phase response?
Systemic response that results from the cytokines entering the bloodstream and reaching distant sites
Describe 3 features of the Acute phase response
1) Fever
2) Hematopoiesis to replace the monocytes, neutrophils and complement proteins that have left the circulation
3) Sequestration of iron into the liver- induced hypoferremia
Inflammation timeline with cells:
- PRRs
- Macrophages
- Mast cells
- Cytokines
- PMNs
- Monocytes
- Tissue injury or pathogen recognition (PRR binds PAMP)
- Macrophages are activated and secrete pro-Inflammatory cytokines (IL-1,IL-6,TNF-alpha)
- Mast cells release histamine
- Cytokines and histamine act on vascular EC’s resulting in VD
- leakage of plasma fluid and proteins into tissue (tumor)
- Extravasation of neutrophils in about 30 mins
- Extravasation of monocytes —> macrophages (in about 4 hours) —> more cytokines
- Pathogens are phagocytosed and killed!!
- Repair
Describe bystander tissue damage
Result of inflammation
External release of enzymes by PMNs and macrophages can cause tissue damage to nearby tissues
Granule contents can also stimulate nerves, leading to pain (dolor)
Describe cytokines and processes involved in the Acute phase response
IL-1, IL-6, and TNF fo to he hypothalamus to “reset” body temperature = fever
IL-1 and IL-6 go to the liver to increase production of acute phase proteins (CRP, MBL, PTX3, SAP)
IL-1, IL-6, and TNF go to the bone marrow to increase Hematopoiesis (to replace neutrophils)
List 2 clinical findings seen with the Acute Phase Response.
Fever Induced Hypoferremia (for bacterial infections)
Clinical Correlation: Mutations in Nod2 has been correlated with an increase in the susceptibility of _______
Crohn’s disease
Acute Phase Proteins:
Pentraxins
Bind Cla and activate the Classical complement pathway
Acute Phase Proteins:
Pentraxins- Serum Amyloid Protein
SAP binds to components on bacterial cell walls
Acute Phase Proteins:
Pentraxins- Pentraxin 3
PTX3 binds various molecules on bacteria, fungi and viruses
Acute Phase Proteins:
Collectins
Contains lectin (a protein that binds carbohydrate)
Acute Phase Proteins:
Collectins- Mannose Binding Lectin
MBL binds mannose sugars on bacterial and yeast surfaces, activating lectin pathway
Acute Phase Proteins:
Collectins- Surfactant Proteins A and D
SP-A and SP-D: found in alveoli
Acute Phase Proteins:
Ficolins
Similar structure to MBL
Bind N-acetylglucosamine of bacterial cell walls and lipoteichoic acid of Gram + cell walls
Can activate the Lectin pathway
Acute Phase Proteins:
Pentraxins- C-reactive protein
CRP binds to components on bacterial and fungal cell walls and is a bio marker of inflammation, can increase 1000 fold during infection
What bactericidal enzyme is found in saliva?
Lysozyme
T/F: The mucosal layer is not as effective as a barrier as the skin.
True
PAMP
Pathogen-associated molecular patterns
Common motifs/patterns present on pathogens recognized by cells
PRR
Pattern recognition receptors
For innate cells, these receptors are not specific to an antigen
Bind PRR’s
What are the different types of innate immunity? (3)
1) Phagocytosis/opsonization
2) Production of Antimicrobial peptides, toxic ROS, and Nitrogen species
3) Physical barriers
What is the role of inflammation? (3)
1) Deliver immune cells and effector molecules (ex. Complement) to the site of the infection or injury
- macrophages secrete cytokines and complement proteins.
- cytokines: chemical trail for neutrophils and monocytes to follow
2) Remove or limit the spread of the injurious agent
3) Repair tissue and clean up damage
