Lecture 2 Flashcards
What are the three main things that can influence how quickly an infection can be eliminated?
- The type of pathogen (degree of pathogenicity)
- The amount of pathogen the host was exposed to
- The immune status of the host (do they have any memory?)
True or False: all multicellular organisms have adaptive immunity?
False: only vertebrates
all multicellular organisms have innate immunity
Give 4 examples of physical that form part of the innate immunity
Skin (tight junctions between skin epithelial cells)
Mucosal linings of intestinal tract and nasal passages
Cilia
Coughing and Sneezing, acidic pH, antimicrobial peptides on surface, commensal bacteria provide competition)
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Give 4 examples of chemical barriers that form part of the innate immunity
Acidic pH (stomach, skin surface)
antimicrobial peptides on skin
Defensins and cathelicidin (can be found on skin, in saliva) disrupt bacterial membrane and cell wall synthesis
Lysozyme in saliva and tears cleaves peptidoglycan in bacterial cell wall
Why is the innate immune system non-specific?
PRRs on surface of innate immune cells recognise PAMPs (E.g. Lipopolysaccharide)
What are the main cells involved in the innate immune response?
Macrophages, dendritic cells (both are phagocytes)
Natural killer cells (NK cells)
Granulocytes (neutrophils, eosinophils, basophils)
Describe the main steps of phagocytosis by APC (5 steps)
- APC recognises PAMPs on pathogen via their PRR
- internalisation of pathogen in a phagosome
- fusion with lysosome to form phagolysosome
- killing and digestion of pathogen
- antigen presentation on MHC II
recognition of PAMP via PRR and subsequent phagocytosis results in signalling that upregulates expression of MHC II and cytokines/chemokines
What are the four main families of PRRs?
- Toll-like receptors
- C-type lectin receptors
- Intracellular nucleic acid receptors
- NLRs
Which 3 innate cells have PRRs on their surface and in endosomes?
Macrophages, dendritic cells, and NK cells
True or false: only innate immune cells have intracellular PRRs?
False: most cells in the body have intracellular PRRs.
Give an example of an extracellular PRR and the PAMP it recognises
Extracellular PRR = TLR4
PAMP = LPS of gram -ve bacteria
Give an example of an endosomal PRR and the PAMP it recognises
Endosomal PRR = TLR9
PAMP = hypomethylated DNA of bacteria and viruses
Give an example of a cytosolic PRR and the PAMP it recognises
Cytosolic PRR = cGAS
PAMP = cytosolic DNA from viruses and intracellular bacteria
Describe the activation of a signalling cascade via Toll-like receptors (TLRs) in response to PAMP binding
External leucine rich repeat (LRR) binds PAMP
causes oligomerisation of receptor and clustering of the receptor intracellular TIR domains (Toll-IL-1 receptor homology)
results in signalling cascade
What is the effect of TLR signalling?
Upregulation of pro-inflammatory cytokines via activation of NF-kB transcription factor.
Upregulation of interferons and antiviral responses through activation of IRF3 and IRF7 transcription factors
Why can different pathogens elicit different immune responses?
Depending on the PRR that recognises the PAMP, different signalling cascades will activate different transcription factors and increase the expression and secretion of different moecules.
What are 5 different types of secretory molecules that may be upregulated by PRR signalling?
1) Cytokines
2) interferons
3) chemokines
4) antimicrobial peptides
5) enzymes
How is an interferon response elicited?
Endosomal TLRs or intracellular RNA/DNA receptors are activated by PAMPs
leads to increased expression of interferons IFN-alpha and beta
What is the result of an interferon response?
Antiviral state
activation of NK cells
activation of cytotoxic T cells
How is an inflammatory response elicited?
TLRs in plasma membrane and NLRs in cytosol bind PAMPs
increased expression of pro-inflammatory cytokines
List 5 cytokines that are upregulated in an inflammatory response
1) IL-6
2) IL-12
3) TNF-alpha
4) IL-1
5) IL-18
What are the four signs of inflammation?
1) Heat - due to activation of hypothalamus
2) Redness - due to increased blood flow
3) Swelling - due to increased permeability
4) pain
What are the local effects of cytokines IL-6, TNF-alpha, and IL-1 in inflammation? (3 main things)
vasodilation
increased vascular permeability
activate macrophages, B and T cells
What are the systemic effects of cytokines IL-6, TNF-alpha, and IL-1 in inflammation? (3 main things)
stimulation of haematopoiesis in bone marrow to increase neutrophils which are recruited
Fever (acts in hypothalamus)
Activation of the acute phase response (complement) in the liver
What is the role of IL-8 in inflammation?
recruit neutrophils and dendritic cells
What is the role of IL-10 in inflammation?
inhibit macrophages and DCs to return to homeostasis
True or false: complement is part of the cell mediated innate immune response?
False: complement is part of the humoral response of the innate and adaptive immune response
What are the 4 main effects of INF-alpha and INF-beta in the interferon response?
Increase antiviral state
Increase antigen presentation (increase expression of MHC class I in all cells, activate DCs and macrophages)
Killing of infected cells (Activate NK cells)
Recruit lymphocytes of adaptive immunity by inducing chemokine secretion
Why are NK cells regarded as innate immune cells?
They possess a range of germline-encoded receptors
What is the role of inhibitory receptors on NK cells?
NK cell inhibitory receptors bind to self molecules, such as MHC Class I. Successful binding of self molecule to inhibitory receptor prevents activation of the NK cell
- when cell is infected with a virus, MHC I is often downregulated by virus to aid survival.
- Lack of MHC I = no binding to inhibitory receptor = activation of NK cell
True or false: NK cells have both inhibitory and activating receptors?
True
What is the role of activating receptors on NK cells?
Detect ligand expressed on infected cells
How does NK cell kill target cell?
perforins and granzymes released at immunological synapse directly at target cell to induce apoptosis (proteases and increase intracellular calcium)
Roughly how many serum proteins involved in complement cascade?
35 proteins
where are the majority of complement proteins synthesised?
in the liver
How is the classical pathway of complement related to the adaptive immune response?
Initiated by antibodies (IgG, IgM)
What are the three main effector function of the complement cascade?
Formation of the membrane attack complex and resulting lysis of the cell/pathogen
production of opsonins C3b and C4b recognised by complement receptor 1 (CR1) on macrophages and neutrophils
production of anaphylatoxins C3a, C4a and C5a that act as chemoattractants in the promotion of inflammation
How do anaphylatoxins C3a, C4a, and C5a promote inflammation?
Recruit immune cells by acting as chemoattractant
Bind to complement receptors to promote secretion of IL-6, TNF-alpha by macrophages
What are the 7 functional categories of the complement proteins?
1) Initiators (C1, MBL)
2) Enzymes
3) Opsonins
4) Anaphylatoxins
5) membrane attack proteins
6) complement receptors
7) regulatory particles
What is produced by PRR signalling that determines what kind of adaptive response is generated?
cytokine profile
True or false: NK cell-mediated killing is an innate immune response?
True
