Lecture 4 - Overview of the Immune Response Flashcards
What is an immune response?
Reaction to:
- components of microbes
- other foreign molecules
- ‘danger’
What are the four principles of the immune response?
1/ Recognition
2/ Effector response
3/ Regulation
4/ Memory
What are the requirements of the immune response?
- no harm to host
- rapid
- present at birth
- appropriate for pathogen
In general, how does the immune system recognise ‘self’ from ‘non-self’?
Molecular differences
‘Non-self’ will have molecules on the surface that distinguish it from ‘self’
What is the difference between PAMPs and Antigens?
Which receptors detect each?
PAMPs: pathogen associated molecular patterns
- common to all pathogens
- PRRs
Antigen:
- unique to a particular organism
- Antibodies / Antigen receptors
Assess the innate immune system in the following criteria:
- specificity
- diversity
- memory
- response time
- magnitude of response
- cells
- chemical barriers
- soluble proteins
- specific to PAMPs
- limited diversity
- no memory
- rapid response
- no change in magnitude
- Macrophages, NK cells
- Antimicrobial molecules
- Cytokines, complement
Assess the adaptive immune system in the following criteria:
- specificity
- diversity
- memory
- response time
- magnitude of response
- cells
- chemical barriers
- soluble proteins
- specific to antigens
- huge amount of diversity
- memory
- slow response time
- magnitude increases with exposure
- Lymphocytes
- IgA (antibodies)
- cytokines
What are the two pathways of development for the cells on the immune system?
Myeloid progenitor: • neutrophils • eosinophils • basophils • macrophages
Lymphoid progenitor:
• T lymphocytes
• B lymphocytes
• NK cells
What factors determine the fate of the progenitor cells?
Bone marrow stromal cells
CSFs: colony stimulation factors
What are the different types of PRRs?
TLR: toll-like receptors
NOD: nucleotide binding oligomerisataion domain
RIG: Retinoic acid inducible gene
Collectins: proteins that bind CHOs
What are DAMPs?
Danger associated molecular patterns
What does TLR-2 bind?
Components of the bacterial cell wall:
- peptidoglycan
What does TLR-4 bind?
LPS
What does TLR-5 bind?
Flagellin
What does TLR-9 bind?
CpG-DNA
What do NLRs bind?
Peptidoglycan on G- cells
DAMPs
What are some examples of DAMPs?
Free fatty acids
Stress metabolites
What happens when TLRs and NODs are engaged?
Expression of different cell surface receptors
- Cytokine production
- Defensin production
What happens when Mannose receptors are engaged?
Phagocytosis
What is ligation of RIGs associated with?
Anti-viral immunity
What are the constitutive factors that mediate innate IS?
- Complement proteins
- C reactive protein
- Mannose binding lectin
- Lysozyme
What does lysozyme do?
Disrupts the cell wall (peptidoglycan)
What does C reactive protein do?
Binds to the capsule –> phagocytosis
What are defensins?
Proteins that kill phagocytosed bacteria by putting holes in the cell wall
What is mannose binding lectin?
It is a protein on the cell that binds to mannose on the invader, triggering the complement cascade
How may the complement cascade be activated?
Classical pathway: antibody binds to invader
Mannose binding lectin pathway: MBL binds to mannose on microbe
Alternate pathway: binding directly to the pathogen
What are the effector responses of the complement cascade?
Opsonisation: coating, ready for phagocytosis
MAC: pore-formation in the cell wall of the bacterium
Chemotaxis: recruitment of inflammatory cells
What are the induced soluble factors that mediate immunity?
Cytokines
Chemokines
What are cytokines?
Secreted proteins that warn neighbouring cells that there is an invader present
What are chemokines?
Secreted protein that attract cells to the site of infection
What is the receptor of a B cell?
Antibody
What is the receptor of a T cell?
T cell receptor
What is the structure of antibody?
Fab: variable region
Fc: constant region
Two light chains
Two heavy chains
What is the structure of a T cell receptor?
Constant and variable region
Alpha and beta chain
What can antibodies bind?
Molecules associated with extracellular pathogens
What can T cell receptors bind?
Peptides associated with intracellular antigens
Describe the location of innate leucocytes of the innate immune system
Blood –> infected tissue
Describe how neutrophils migrate from blood to tissues
- Chemotactic gradient, cytokines making endothelium leaky
- Congestion, margination, rolling, adhesion of neutrophils in the endothelium
- Diapedesis
- Neutrophils follow the chemokine gradient to the invader
Describe the locations of the elements of the adaptive immune system
Circulate in blood
Secondary lymphoid tissue (interact here with APCs)
Migrate to infected tissue
How is it possible that pathogens present at peripheral sites can interact with circulating lymphoctes?
The lymphatic system
APCs are the relay mechanism
Describe the generalised flow of lymph
- Infected tissue
- Afferent lymphatic vessel
- Lymph node
- Efferent lymphatic vessel
- Thoracic duct
- Venous system
- Back to infected tissue
Where do naive lymphocytes come into contact with pathogens?
In secondary lymphoid organs
What are some secondary lymphoid organs?
Spleen
Lymph nodes
Peyer’s patches
Adenoids
What are some primary lymphoid tissues?
Bone marrow
Thymus
Describe blood flow through lymph nodes
Artery in through hilum
- Lymphocytes move through HEV into Paracortex and cortex
3a. B cells: B cell zone, follicle
3b. T cells: Paracortex - Encounter lymph that has come in through the afferent lymphatic
- Activated lyphocytes exit via vein
- Vein leaves via hilum
Describe how lymphoctes move from circulation into the lymph node
Where does this occur?
This occurs at the HEV: (high endothelial vessels)
- Rolling and weak adhesion to endothelium
- Strong adhesion to endothelium
- Emigration into lymph node
What is different about migration of neutrophils into infected tissue, and migration of lymphocytes into the lymph node
Same process, different selective molecules
Where do T cells hang out in the lymph node?
Paracortex
Where do B cells hang out in the lymph node?
B cell zone, follicle
What determines where the lymphocytes will migrate to, once in the lymph node?
Chemokines
How are T cells activated?
(Adhesion)
- Antigen presented to their TCR on MHC of APC
- Costimulation
- Cytokines
Which MHC molecules interact with which T cell?
CD4+ cells: MHC II
CD8+ cells: MHC I
How does peptide come to be on MHC I?
- Peptide produced within a cell
- Peptide broken down by proteasome
- Peptide delivered into ER through TAP complexes
- Peptide loaded onto MHC I
- MHC I transported to the cell surface
How does peptide come to be on MHC II?
- Bacterium taken into the cell by endocytosis, broken down
- MHC II with invariant chain gets delivered to phagolysosome
- Peptide displaces invariant chain
- MHC II + peptide delivered to the cell surface
Describe costimulation of APCs and CD4+ cells
CD80, CD86 interact with CD28
Describe Signal 3 of CD4+ cell activation
Specific cytokines (depending on the PAMP-PRR interaction), controlling the differentiation of CD4+ cells.
TGF-B skews Th cells towards…
Treg
IL-6 skews Th cells towards…
Th17
Tfh
IL-12 skews Th cells towards…
Th1
IL-4, IL-33 skews Th cells towards…
Th2
What is the role of Treg?
Downregulates immune function
What is the role of Th17?
Neutrophil recruitment
What is the role of Th1?
Inflammation
What is the role of Th2?
Parasite immunity
Allergy
What is the role of Tfh?
B cell proliferation and differentiation
What is the result of PRR-PAMP binding?
Signal transduction Gene transcription: • chemokines and cytokines • defensins • cell surface receptor expression
Compare the lifespan of macrophages and neutrophils
Macrobphages: long lived
Neutrophils: short lived
Where are macrophages found?
Compare this with neutrophils
In places where infection is likely: • respiratory tract • digestive tract • connective tissues • liver • spleen
Neutrophils: in the blood
Describe what happens when Macrophages and Neutrophils phagocytose pathogens?
Upregulation of killing mechanisms
Release of cytokines and chemokines
How do neutrophils and phagocytes recognise pathogens?
What happens next?
- PRR
- FcR
- C3bR
After binding, there is rearrangement of the actin cytoskeleton, extension of pseudopods –> phagocytosis
How do phagocytes kill pathogens once they have engulfed them?
Granules fuse with the phagosome: • ROS • hydrolases • defensins • lysozyme
Describe how larger invaders such as nematodes are killed
Too big to engulf –> extracellular killing
- Macrophages + Neutrophils + Eosinophils gather
- Exocytosis of granules
- Extracellular killing of the pathogen
Describe the response to virus infection
- Invasion
- PRR - PAMP (weird genome elements)
- IFN-a and IFN-B production
- Induction of NKs
Describe the mechanism of action of NKs
- Stimulated by IFN
- Recognise virally infected cells, because there is reduced MHC I expression
3.
How do NKs recognise virally infected cells?
Viruses in cells downregulate the expression of MHC I so that they can avoid detection by CTLs.
NKs recognise the fewer MHC I
What is really important about DCs?
They link the innate and the adaptive immune responses
Describe the mechanism of action of DCs
- PAMP-PRR
- Pathogen antigen presented on MHC
- Expression of costimulatory molecules
- Migration to lymph node
- Activation of T and B lymphocytes
