Flashcards in Lecture 9 Deck (53):
What is innate immunity induced by?
The triggering of pattern recognition molecules which recognize PAMPs
There are four major classes including soluble receptors, membrane bound receptors and two types of intracellular receptors
What are the features of PAMPs?
They are conserved,
essential to survival, common to entire classes of microbes,
complex and unique 3D molecular structure,
typically carbohydrates and lipids rather than proteins, often have a repetitive structure
What are the secreted pattern recognition molecules?
These are typically C type lectins and include mannose binding lectin, C- reactive protein and lipid binding protein
What is the ligand and function of mannose binding lectin?
This secreted pattern recognition molecule has a C-type lectin domain and recognises terminal mannose residues leading to the activation the lectin pathway of complement
What is the ligand and function of C-reactive protein?
This secreted pattern recognition molecule has a pentraxins protein domain and recognizes phosphorylcholine –present in bacterial and fungal membranes- leading to opsonisation and activation of the classical pathway of complement
What is the ligand and function of lipid binding protein?
This secreted pattern recognition molecule has a lipid transfer protein family protein domain and recognises lipopolysaccharide leading to lipopolysaccharide recognition
What are the membrane pattern recognition receptors?
Toll like receptors, CD14, Macrophage mannose receptor, Macrophage scavenging receptor, MACRO
What is the ligand and function of toll like receptors?
These membrane bound pattern recognitions receptor have leucine rich repeat protein domains and recognize multiple ligands, there are 12 in total which all lead to activation of MyD88 adaptor protein which leads to activation of the NFkB transcription factor
What is the ligand and function of CD14?
This membrane bound pattern recognition receptor has a leucine rich repeat family protein domain and recognises lipopolysaccharide and acts as a co-receptor for TLR recognition of LPS
What is the ligand and function of Macrophage mannose receptor?
This membrane bound pattern recognition receptor has a C-type lectin protein domain and recognizes terminal mannose residues leading to phagocytosis
What is the ligand and function of macrophage scavenging receptor?
This membrane bound pattern recognition receptor has a cysteine rich protein domain and recognizes many ligands including LPS, dsRNA, oxidised LDL, anionic polymers recognition of all these ligands results in phagocytosis, LPS clearance and lipid homeostasis
What is the ligand and function of MARCO?
This membrane bound pattern recognition receptor has a cysteine rich protein domain and recognizes bacterial cell walls leading to phagocytosis
What are the intracellular pattern recognition receptors?
NOD, NALPs, RLR and DNA sensors these all have the common function of activation of NFkB, MAP kinases, type 1 IFN, caspase 3 activation and IL-1Beta as well as causing apoptosis in virally infected cells
What is the ligand of NOD?
These intracellular pattern recognition receptors have a LRR domain a NOD (nucleotide binding) domain and a CARD (caspase recruitment) domain allowing them to sense microbial products such as peptidoglycans
What is the ligand of NALPs
These intracellular pattern recognition receptors are a NActh LRR proteins containing an LRR domain, a NOD domain and a PYD (pyrin) domain
These sense cellular damage and stress binding to lots of compounds such as Alum (Al(OH)3) and uric acid seen in gout and it forms in the inflammasome
What is the ligand of RLR?
This intracellular pattern recognition receptor has a RIG-1, CARD, Helicase, RNA-PKR-RNA binding and kinase domains as well as MDA5-CARD domains and LGP2
These sense nucleic acids in the cytoplasm binding to viral and bacterial DNA
What is the ligand of DNA sensors?
DAI has DNA binding domains and AIM2 which has PYD and DNA binding domain which function as DNA sensors
What are PAMPs commonly found on viruses?
Glycoprotein, DNA and RNA
What are PAMPs commonly found on gram positive bacteria?
DNA, Lipoprotein, peptidoglycan and lipotechtoic acid
What are PAMPs commonly found on gram negative bacteria?
DNA, Porin, peptidoglycan, lipopolysaccharide and flagellin
What are PAMPs commonly found on fungi?
Zymosan, Mannan and beta glycan
What are PAMPs commonly found on protozoa?
DNA and GPI anchors (glycolipids)
What are the three signals required for effective memory response by the immune system?
Detection of the danger followed by detection of the antigen which is in turn followed by costimulation
What is the stress response?
This is simply a response to danger where the key component is the rapid production of a number of pro-inflammatory cytokines like IL-1, TNFalpha, IL-6, IL-8 and IL-12
How can the stress response be harmful?
If some of the cytokines are produced in larger amounts then the body can have an adverse reaction
At a mild level the brain is affected and the body temperature is raised to produce fever this can be a useful systemic reaction which increases our ability to fight infection however too much will result in systemic shock which can potentially be fatal
What is the role of the monocyte/macrophage in the stress response/
This cell is the primary initiator of this response as this is the primitive sensing cell in higher vertbrates
Many of the responses controlled by this cell are triggered by the central signalling pathway regulated by NFkB
What is the most important PAMP for the triggering of TNFalpha?
Bacterial lipopolysaccharide, this is an extremely complex molecule that is produced by most gram negative bacteria
It is composed of lipid A chain attached to a branched chain complex carbohydrate with the lipid potion be the essential component of activation of the stress response
What are toll like receptors?
These are pattern recognition receptors that are highly conserved seen in both plants and animals
The primate toll family has 9 members each of which recognize different ligands leading to the activation of the NFkB pathway leading to TNFalpha production
What are the positive effects of TNFalpha?
Raising body temperature
Inducing acute-phase response proteins from the liver
Inducing inflammatory response mechanisms and vascular responses
Stimulates maturation of dendritic cells and migration to lymph nodes
Increases lymphocyte migration site
Increase in platelet adhesion to blood vessel
Containment of infection to the local site
Pain and tenderness
What are the negative effects of TNFalpha?
Neutropenia (loss of neutrophils from blood)
Change in blood volume through its effects on the central nervous system
Vascular leakage and hypotension
Muscle wasting or cachexia (a problem with cancer patients)
What are the clinical consequences of LPS exposure?
It is pyrogenic (fever causing) and highly toxic in primates as it is a potent induce of TNFalpha, it can cause septic shock, gram negative septicaemia which is most dangerous due to its LPS
What are the annoying features of LPS?
It contaminates everything
Is expensive to make clinical grade pharmaceuticals pyrogen free
There is a limited range of expensive tests available for LPS including a limulus amoebocyte assay and the rabbit fever test
What are adjuvants?
These are compounds which enhance the immune response which is essential to provide long-lasting memory response as well as producing a profound immediate response
The most effective adjuvant is complete freunds adjuvant which consists of mineral oil emulsion and killed mycobacteria however the only approved adjuvant in humans is aluminium hydroxide
What is tumour necrosis factor alpha?
This a key cytokine for transmitting the stress signal
It is the most potent pleitropic cytokine and is capable of causing necrosis to tumours and is responsible for shock conditions associated with gram negative septicaemia resulting in it being the target from many anti-inflammatories such as those used in rheumatoid arthritis
How does TNFalpha produce its effects?
This is activated NFkB pathway and has two key receptors, TNF-RI found on endothelial cells and macrophages and contains a death domain which recruits the adaptor TRADD
TNF-RII found on lymphocytes
What are the actions of IL-1Beta?
This can act locally to activate vascular endothelium, lymphocytes, cause local tissue destruction and increases access of effector cells
The systemic effects include fever and production of IL-6
What are the actions of TNF-alpha?
This can act locally to activate vascular endothelium and increases vascular permeability leading to increased entry of IgG, complement and cells to tissues along with increased fluid drainage to lymph nodes
This can act systemically to induce fever, mobilization of metabolites and shock
What are the actions of IL-6?
This can act locally to cause lymphocyte activation, increased antibody production as well as acting systemically to cause fever and induce acute phase protein production
What are the actions of CXCL8/ IL8?
This can act locally as a chemotactic factor which leads to the recruitment of neutrophils, basophils and T cells to the site of infection
What are the actions of IL-12?
This can act locally to activate NK cells and induce the differentiation of CD4 T cells intoTH1 cells
What is the role in inflammation in immunity?
It leads to amplification of the immune response which leads to the stimulation of migration of additional effector molecules and cells from the blood to the affected site
It can produce a local barrier to prevent the spread of infection which induces local blood clotting
It can lead to the production of tissue repair
What TLRs are located in the plasma membrane?
TLR-1/2 and TLR- 2/6 hetero dimers as well as TLR-5 and TLR4
What are the TLRs located in the endosome?
TLR 3, TLR7, TLR 9
What are the ligands of both the TLR-1/2 and TLR-2/6 heterodimers?
The ligands of these receptors include lipomannans (mycobacteria), Lipoproteins, lipotechtoic acid, cell wall beta-glucans (in bacteria and fungi) and zymosan (fungi)
What is the cellular distribution of both the TLR-1/2 and TLR-2/6 heterodimers?
These are typically found on monocytes, dendritic cells, mast cells, eosinophils and basophils
What is the ligand and cellular distribution of TLR3?
this receptor is commonly found on NK cells and recognizes Double stranded RNA as its ligand
What are the ligands and cellular distribution of TLR4?
This receptor is found on macrophages, dendritic cells, mast cells and eosinophils and recognizes both LPS from gram negative bacteria and Lipoteichoic acid from gram positive bacteria
What is the ligand and cellular distribution of TLR5?
This receptor is found on intestinal epithelium and recognizes flagellin, however it cannot recognize this when it is an intact protein but only when it has been broken down
What is the ligand and cellular distribution of TLR7?
This receptor is found on plasmacytoid dendritic cells, NK cells, eosionophils and B cells and recognizes single stranded RNA from viruses
What is the ligand and cellular distribution of TLR8?
This receptor is found on NK cells and recognizes single stranded RNA from viruses
What is the ligand and cellular distribution of TLR9?
This receptor is found on plasmacytoid dendritic cells, basophils, eosionophils and B cells and recognizes DNA with unmethylated CpG which would indicate the presence of bacteria and herpesviruses
What is the ligand and cellular distribution of TLR10?
This receptor is found on plasmacytoid dendritic cells, Basophils, eosionophils and B cells and recognizes and unknown ligand