Innate Immunity Flashcards
Understand the role of different aspects of the innate immune system
Which cells/components play a role in the innate immune system?
Epithelial cells (provide barrier, secrete defensins and cathelicidins[antibiotics])
Phagocytes (non-specifically engulf pathogens)
Dendritic Cells
Complement
Cytokines
NK cells
What are the 2 main structures recognised by the innate immune system?
PAMPs (pathogen associated molecular patterns- structures shared by pathogens and required by them to function/exist)
DAMPs (damage associated molecular patterns- eg ATP, heat shock proteins, uric acid, DNA, heparin)
How are PAMPs recognised?
By Pattern Recognition Receptors (PRRs)
Expressed on APCs, not clonal, triggering activates the cell immediately
Which cells are generally the first to deal with a pathogen that has penetrated epithelial barrier?
Macrophages (differentiate from monocytes)
Which cells are attracted second to the site of pathogen breach (attracted by the macrophages)?
Neutrophils?
What is the innate response by macrophages and neutrophils to a pathogen?
Ingest non-specifically via surface receptors
Degrade in a phagosome (fuse with lysosomes antomicobial enzymes and proteins)
Generate toxic products in an oxidative burst (NO, H2O2, OH etc)
Which cell of the innate immune system is responsible for pus?
Neutrophils (dead ones)=pus
What is the role of Toll-Like Receptors (TLRs) in the innate immune system?
TLRs are cell surface proteins that signal to the cytosol and act via NK-kB on promotor regions to upregulate antimicrobial peptides (B7, IL-1, IL-6, IL-8)
Different types to TLRs recognise different PAMPs
Describe the role of TLR4 in shock
TLR4 recognises bacterial lipopolysaccharide from gram negative organisms
Systemic activation induces cytokines and co-stimulatory molecules that are responsible for sepsis
What is the connection between TLRs and herpes simplex encephalitis?
Some children with HSV encephalitis have been shown to have TLR3 pathway deficiency
TLR3 is expressed in the CNS and controls the IFN response to dsDNA of HSV1
What is the role of TLRs in autoimmunity?
TLR engagement by nucleic acids (eg ANA, dsDNA in lupus) in B cells leads to autoantibody formation
What is the role of Mannose Binding Lectin (MBL) in the innate immune system?
An acute phase protein
Binds a wide spectrum of oligosaccharides (the universal antibody)
Acts as an opsonin (facilitate uptake by macrophages)
Activates complement (structurally similar to C1q, cleaves C2 and C4)
What is the difference between TLRs and NOD-like receptors (NLRs)?
TLRs are surface receptors, NLRs are cytosolic
Detect PAMPs and DAMPs and activate caspases which activate release of IL-1beta and IL-18
What is the major role of IL-1?
Produced by macrophages, monocytes and dendritic cells
Increases expression of adhesion molecules (leukocytes migrating to the site)
Resets hypothalamus thermoregulatory centre (fever)
Stimulates IL-6 production
What is the major role of TNF?
Transmembrane protein with local and systemic effects
Activates endothelium
Increases vascular permeability
Shock when released systemically
What is the major role of IL-6?
Lymphocyte activation (Bcell and Ab formation) Fever
What is the major role of NALP3 inflammasome (Cryopyrin)?
Produced in response to the detection of PAMPs/DAMPs and results in production of IL-1beta and IL-18
What conditions result from NALP3 mutation due to “gain of function” leading to excessive release of IL-1?
Familial cold urticaria syndrome (fever, urticaria, conjunctival injection, arthralgia, leukocytosis , after exposure to the cold)
Muckle-Wells syndrome (fever, headache, rash, arthralgia, progressive sensorineural hearing loss, secondary amyloidosis wwith nephropathy)
Neonatal onset multisystem inflammatory disease (NOMID) (fever, rash, impaired growth, abnormal facies, chronic meningitis, cerebral atrophy, prgressive sensorineural hearing loss, uveitis, lymphdenopathy, splenomegaly)
Treated with Anakinra (IL-1 antagonist)
NAPL1 single nucleotide polymorphisms are associated with which autoimmune diseases?
Vitiligo, thyroid, SLE, RA, T1DM
What is the role of RIG-I helicase receptors?
Cytoplasmic receptors for viral RNA
Respond by releasing IFN-1 alpha and beta
What is the main interaction between the innate and adaptive immune systems?
PAMP recognition leads to uprregulation of co-stimulatory molecules on the APC
CD80/CD86 (B7.1 and B7.2)
engages CD28 on the T cell
Which interleukin leads to development of a NK cell from a common lymphoid progenitor?
IL-15
NK cells are bone marrow derived? Non-thymic!
What is the role of NK cells in the immune system (x2)?
Kill virally infected cells via Ab-dependant Cell mediated cytotioxicity, ot loss of MHC expression
Kill tumour cells via loss of MHC expression
How do NK cells stimulate the adaptive immune system?
Release IFN gamma which stimulates macrophages and favours Th1 differentiation
What is the role of NK cells in the pregnant uterus?
Protect the foetus from viral infection
Prevent attack of paternal MHC
Describe Ab-dependant Cell mediated cytotoxicity involving IgG
NK cells express a receptor for the Fc region of IgG (FC gammaRIII)
IgG binds to viral antigen expressed on cell surface
NK cell becomes activated and kills via perforin-granzyme or Fas pathway
Describe Ab-dependant Cell mediated cytotoxicity involving IgE
Activated eosinophils express the high affinity recpetor for IgE FcepsilonR-I
IgE targets helminths, binds to eosinophil via the Fc
Induces degranulation and release of eosinophilic toxic proteins
Kills the helminth
Describe how NK cells differentiate self from virally/tumour affected cells
2 NK cells receptors (activating and inhibitory- MHC)
If MHC (inhibitory) receptor, joins with activating receptor–> attack inhibited
If MHC presenting viral antigen–> lethal hit
If MHC not present, no inhibitory signal–> lethal hit
Why are red blood cells not attacked by NK cells?
Lack activating receptor
Describe the leukocyte adhesion cascade, and deficiencies in LAD I and LAD II
1) endothelium activation by expozure to TNF, IL-1, C5a, C3a, LTB4, histamine, LPS
2) upregulation of selectins which interact with sialyl-Lewis X on the leukocyte –> rolling (deficiency of sialyl-Lewis selectin ligand in LAD II)
3) integrins and IgSF molecules –> adhesion and then diapedesis (go through endothelium to the tissue) (deficiency of integrins in LAD I)
3)
What are the main three cytokines responsible for the acute phase response?
TNF
Il-1
IL-6
act on the liver to release specific proteins to fight infection (MBL, CRP), prevent tissue damage (alpha-1 anti trypsin), promote healing (fibrinogen)
What is the role of interferons in the innate immune response?
released in response to viral infection by many cells, after viral detection by TLRs, RIG-1 etc
Creates a general anti-viral state in cells:
- induce resistance to replication
- increase MHC-1 expression and antigen presentation
- activate DCs, Macrophages and NK cells
