Innate immunity Flashcards
Tell me the roles of the immune system
- Defence (of host) against threat of disease by pathogenic infectious organisms (pathogen)
- IS complexity due to range of organisms encountered – evolved to deal with many challenges
- IS protects against tumours (some)
- Vaccines offer exciting new hopes for infections and cancer therapy
- Chronic immune responses can cause disease, for example sepsis, autoimmunity, Type-2 Diabetes
Cells of the immune system stem from the hematopoietic stem cell tell me the two lineage of the cells and what cells are produced via these two routes?
The immune system has many specialized cell types, all which work together to fight
infection and disease. This infographic introduces the cellular players of the immune
system and illustrates how they are activated against pathogens.
All immune cells are derived from a common progenitor known as what?
Tell me about this cell?
All immune cells are derived from a common progenitor known as the hematopoietic stem cell (HSC).
The HSC develops into two progenitor types: lymphoid and myeloid.
Most lymphoid cells contribute to adaptive immunity
while most myeloid cells contribute to innate immunity.
Tell me the properties of innate immunity?
What does this branch into and what are these branches involved in?
Tell me the properties of adaptive immunity?
What does this branch into and what are these branches involved in?
Adaptive vs innate immunity
Lecture 1 LO
- Describe the importance of innate immunity in our defence against pathogens
- Describe the different roles of innate immune cells and proteins
- Give examples of immune defence mechanisms that are used in the innate immune response and inflammation
- (Phagocytosis, complement system, toll like receptors, neutrophil recruitment)
Whats the two step process of the immune system?
The immune system: infection of the human body by pathogenic microorganisms such as bacteria, viruses, parasites or fungi triggers the immune response. It occurs in a two-step process: innate (1st) and adaptive immunity (2nd)
Innate immunity is the immediate response to infection, tell me about the 3 things its involved in and how it carries them out?
- Awareness – detection of pathogens to signal their presence
- Immediate response – resident tissue cells/factors and the recruitment of cells from the blood – chemical signals generated
- Signals sent to the acquired response for provision of immunity-long lasting - the desired response of vaccination
Tell me about the nonspecific host defences
What is inflammation?
A complex biological response to harmful stimuli like pathogens or injury
Tell me about edema and extravasation linking with inflammation?
What is each of these?
- Fluids can leak from the blood vessels and collect in the tissues (edema)
- Leukocytes will also begin to exit from blood vessels to investigate the local tissue in a process known as extravasation
What are the signs of inflammation?
When a foreign body such as a pin penetrates the skin, what is the response that is generated?
Innate vs adaptive immune system diagram
Which of the following are unique characteristics or components of the innate―but not adaptive―immune system? (Select all that apply.)
a. immune “memory”
b. natural killer cells
c. phagocytosis
d. specificity
C
Tell me about the discovery of Toll like receptors?
The discovery of the TLR
- Immune response has to start with sensing ‘danger’ Medzhitov and Janeway (1997)
Several approaches failed to find receptors that bound pathogens.
- 1985: Christiane Nusslein-Volhard identified Toll genes (Toll = cool, weird) Drosophila melangaster important gene in embryogenesis in establishing the dorsal-ventral axis
- 1996: Jules Hoffman finds that Toll has a role in the fly’s immunity to fungal infection-
- 1997: year later they reasoned that genes related to Toll exist in vertebrates
Give an example of a pathogen recognition receptor (PRR) and a pathogen associated molecular pattern (PAMP) and how they work together to produce a response.
Tell me about the responses
- Example: TLR4 (PRR): LPS from bacteria (PAMP)
- Recognition of PAMP initiates various innate responses:
- Chemokines/cytokines to recruit cells
- Phagocytosis of pathogens
- Lysis of pathogens by antimicrobial peptides
Tell me about some of the roles of interferons and cytokines
Toll-like receptors trigger an intracellular signalling cascade
Tell me the steps to TLR signalling
- MyD88 – Myeloid differentiation primary response gene (88) a universal TIR adaptor (except TLR3) MyD88 interacts via a TIR domain
- MyD88 promotes association of IRAK1 & 4 kinases (interleukin-1 receptor-associated kinase)
- IRAK4 phosphorylates IRAK1 creating a docking site for TRAF6 (TNF-receptor-associated factor 6)
- TRAF-6-IRAK1 dimer complex dissociates
- Complexes with TAK1 (+other proteins) (TGF-beta activated kinase 1) causing kinase activation
- TAK1 is pivotal as it activates both NFkappaB and Map kinase pathways
- Increased transcription of target genes
- TAK1 activates IKK which phosphorylates IkappaB causing activation of NFkappaB
When LPS binds to TLR4, tell me the onset effects?
TLR activation in macrophages results in what?
oxidative burst (phagocytosis) and inflammatory cytokine/ chemokine release
TLR activation in dendritic cells results in what?
TLR activation in dendritic cells results in maturation, antigen presentation, and cytokine production- bridge to adaptive immunity
TLRs on the cell surface and endosomes for defence against a wide range of pathogens
(Choose all that apply) When pathogenic bacteria interact with the immune system,
a) immune cells release cytokines that induce inflammation.
b) recognition of antigens by B cells activates the innate immune system.
c) Toll-like receptors recognize components of the bacterial cell wall, which induces the innate immune system.
d) None of the above.
a and c
Tell the difference/ similarity between antigens and PAMPs
Antigens and PAMPs. PAMPs- molecular patterns produced from pathogens. In a way they are antigens, as these can initiate immune response. PAMPs is used to identify a protein derived from a pathogen. Where an antigen is a protein which can stimulate a B or T cell
What are the following cells of the immune system involved with?
NK cell
Dendritic cell
Macrophage
Neutrophil
Cytokines can interact with cells in close and distant proximities, what are the words used to describe this?
Endocine= distant
paracrine= close to
Tell me about the roles of interferons?
- first line of defense in the non-specific immune system
Tell me the overall steps to JAK-STAT signalling?
What does the combination of JAKs and STATs determine?
The type of immune response
Tell me about JAKs?
- The sites they have
- What binds to them
- What effects it results in
- Jak – Janus kinase – Janus Roman God of doorways having two faces
- Jaks have two functional sites, a binding site to associate with the cytokine R and a catalytic site, when activated, has tyrosine kinase activity – (also termed Just another kinase)
- Jaks bind receptor and tyrosine phosphorylation creates a binding site for the SH2 domain of Stats, firstly on the receptor and then on the Stat itself– this leads to dissociation & dimerisation
Tell me about STATs
- What it is
- What it binds
- What it promotes
- Stat – Signal transducer and activator or transcription- is a transcription factor (TF)
- that binds DNA sequence-specifically and
- promotes transcription from GAS element in response to cytokine stimulation
- Stats may operate with other TFs
What are the local effects that cytokines induce?
What are the systemic effects thay cytokines induce?
cytokines induce local and systemic effects
Tell me some cytokines that activated macrophages secrete?
- IL-1beta
- TNF-alpha
- IL-6
- CXCL8
- IL-12
Tell me the role of the cytokine IL-1beta
what systemic effects does it have?
(systemic effects are the bottom box)
Tell me what the cytokine TNF-alpha activates
Tell me about its systemic effects
Tell me what the cytokine IL-6 activates
Tell me about its systemic effects
Tell me what the cytokine CXCL8 activates?
Tell me what the cytokine IL-12 activates
What determines what cytokine is released?
Type of pathogen depends the type of cytokine release in order to get the most appropriate immune response for that pathogen
What is the role of the interferon?
- Fever
- Anti-viral
- Neutrophil recruitment
- Don’t know
2
Which immune cells are needed to attack viruses?
cytotoxic T cells (particularly good for recognising virus cells), NK cells (can detect these cells without the need for recognising antigens), dendritic cells, macrophages
Cytokines combinations can determine the type of immune response generated
Complement activation
Whats the complement system?
The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen’s cell membrane
It is part of the innate immune system which is not adaptable and does not change during an individual’s lifetime
The complement system can, however, be recruited and brought into action by antibodies generated by the adaptive immune system.
Some facts about the complement system
- Haemolysis of red blood cells mediated by antibody involves complement – Ehrlich
- Complement has roles in innate & acquired immunity
- Complement is not only activated by antibody but also by components of innate immunity
The mammalian complement system is activates by 3 pathways, what are these?
- Classic activation pathway
- Mannose-binding lectin activation pathway
- Alternative activation pathway
What are the three mammalian complement systems activated by and what do these go on to activate?
- under the bold heading shows what they are activated by and then what that goes on to activate
- Biochemical cascade that helps clear bacteria
- All pathways merge at the key event, the proteolytic activation of the central C3 to c3b
- C3b can bind to cells (like on bacteria)
- All form together to form a pore in the bacterial membrane which destroys the membrane structure and leads to the lysis of the bacteria (binding of C3b directly destroys bacteria)
- C3–> C5 explanation on compliment system: c3b binds to membrane and recruits other proteins of compliment system including C5. They form complexes with enzymatic functions. C3b and C5 forms a complex which allows binding of other components of the compliment system. This complex looks similar to a pore and is known as the membrane attack complex. Pol-c9 is a complex of C5-8.
When covalent binding to micro-organisms occurs, what can this cause?
- phagocytosis
- lytic pathway
Tell me some of the key roles that the compliment plays in the defence against pathogens
- Production of opsonin’s
- Production of anaphylatoxins
- Direct killing of organisms
- Enhancing antigen specific immune responses
- Maintaining homeostasis
What are some of the basic functions of the complement system?
- Lysis of cells, bacteria and viruses
- Opsonisation which promotes phagocytosis of antigen
- Binding to specific complement receptors triggering cell activation
- Immune complex clearance
Tell me about C3a
C3a is an anaphylatoxin (Anaphylatoxins, or complement peptides, are fragments (C3a, C4a and C5a) that are produced as part of the activation of the complement system) and is a breakdown product of C3
Break down product of C3 is C3a and C3b. C3a is released into the blood and activates granulocytes and helps attract towards site of infection
Name a polymorphonuclear leucocyte (PMN)
Tell me about it
Neutrophil
- Short lived cell
- First line of defence – recruited to infection (IL-8, C5a)-chemokine
- Detect and phagocytose pathogens
- Effector mechanisms to kill pathogens (lysosomal killing mechanisms)
Tell me the immune response that occurs in your body when a pathogen enters a wound?
- When pathogens enter a wound, macrophages release cytokines, chemokines, and lipid mediators to relay chemical signals to leukocytes, like neutrophils
- These neutrophils bind to specific receptors found on endothelial cells and adhere to them
- Mast cells also bind to pathogens and release mediators to increase vascular permeability
- The endothelial cells become more permeable to allow neutrophils to squeeze through into the infection site, a process known as extravasation
- Finally, neutrophils engage in phagocytosis to eliminate the foreign matter
What are the steps to Leukocyte extravasation?
What is leukocyte extravasation?
The movement of white blood cells (WBC) from the circulatory system to a site of inflammation is known as leukocyte extravasation
Tell me the interactions that occur during leukocyte extravasation?
- Released immune chemokines initiate expression of selectins on endothelial surfaces which have high affinity for Sialyl Lewis X glycan epitopes
- This interaction facilitates endothelial adhesion and leukocyte movement towards the site of inflammation
- For lymphocytes (a subtype of WBC), the selectin and glycan are found on opposite surfaces for the same interaction
What are the stages of neutrophil migration?
- Tethering and rolling
- arrest
- extravasation
What occurs in the tethering and rolling stages of neutrophil migration?
What occurs in the arrest stage of neutrophil migration?
What happens in the extravasation stage of neutrophil migration?
Tell me about the differences in function between
- chemokines
- cytokines
- interferons
- Chemokines= proteins that help to recruit cells to site of infection. Can activate cells but main function is to recruit
- Cytokines= more messengers between cells or in some cases messengers to activate the same cell
- Interferons= small molecules that have a function in antiviral responses
Chemokine families, receptors and cellular expression
Individuals lacking what receptor and relatively resistant to HIV infection and AIDS?
CXCR4 (T cells) CCR5 (monocytes) is a co-receptor for HIV entry, individuals lacking the receptor are relatively resistant to HIV infection & AIDS
A systemic basis for chemokine nomenclature is now based on what?
A systematic basis for chemokine nomenclature is now used (brackets) it is based on the pair of cysteine residues near the N-terminus CC residues adjacent and CXC separated by a single residue classify the chemokines and receptors
Eosinophils or mast cells are associated with what?
Eosinophils or mast cells are associated with the immune responses together multi-cellular, extracellular pathogens and are associated with allergy and asthma
The macrophage of ‘big eater’
Tell me the steps to phagocytosis?
The macrophage expresses receptors for many bacteria constituents
summary of phagocytosis
- Phagocytosis can be activated by attachment to pathogen-associated molecular patterns (PAMPS), which leads to cell activation (signalling)
- Oxygen-dependent degradation depends on reactive oxygen species, which leads to the destruction of bacteria.
- Oxygen-independent degradation depends on the release of granules, containing proteolytic enzymes such as defensins, lysozyme, cationic proteins and antimicrobial peptides
- Opsonin’s such as complement (C3b) and antibodies can act as attachment sites and aid phagocytosis of pathogens
summary role of the macrophage
- Macrophages recognise and engulf microbes – Phagocytosis
- Macrophages are activated by inflammatory mediators e.g., TNF-alpha
- Activated macrophages have enhanced phagocytic activity
- Promotes inflammation by releasing cytokines signal to other cells
- Express MHC class II – present antigens and hypersensitivity response (chronic inflammation)
What is the first line of defence in the immune response and tell me the types of cells involved?
Innate immunity is first line of defense barriers (skin, mucosa), cells (macrophage, granulocyte), proteins (cytokines, chemokines, complement, antibacterial enzymes).
Tell me about TLRs on tissue macrophages?
TLRs on tissue macrophages recognize PAMPs and signaling results in phagocytosis and cytokine/chemokine release
What do complements bind and what does this aid?
Complement binds pathogens aiding their removal by cell lysis or phagocytosis (opsonisation)
Tell me the main fact about phagocytosis?
Phagocytosis by recruited inflammatory macrophages and granulocytes result in removal of pathogen
What do dendritic cells do?
dendritic cells sample antigens and migrate to lymphatic tissue to initiate a primary immune response – this occurs by presenting antigen to naive T cells
Innate vs adaptive immunity
Indicate if the following statements are true or false.
a. Toll-like receptors in macrophages get activated upon contact with yeast cells, whichinduces the macrophage to eat these cells
b. Receptors on macrophages can recognize antibody-coated bacteria and “eat” them.
c. Dendritic cells connect the adaptive and the innate immune system
d. The immune system can both cause and prevent diseases
e. Phagocytes are the main effector cells of the innate immune system
Indicate if the following statements are true or false.
a. Toll-like receptors in macrophages get activated upon contact with yeast cells, whichinduces the macrophage to eat these cells. (True)
b. Receptors on macrophages can recognize antibody-coated bacteria and “eat” them.
(True)
c. Dendritic cells connect the adaptive and the innate immune system. (True)
d. The immune system can both cause and prevent diseases. (True)
e. Phagocytes are the main effector cells of the innate immune system. (True)
