Inflammation and Immunity Flashcards
What is another name for glandular fever?
Epstein barr (virus?)
What are the 4 cardinal signs of inflammation?
Heat (Calor)
Redness (Rubor)
Swelling (Tumor)
Pain (Dolor)
- Loss of function added by Virchow 19thC ("Father of modern pathology")How are the 4 cardinal signs caused during inflammation?
Heat - local increased blood flown systemic fever (pyrexia)
Redness - ^ blood flow, vasodilation (due to bradykinin, serotonin, histamine, NO)
Swelling - oedema, ^ vascular permeability -> loss of plasma, IG, extravasation of leukocytes
Pain - hyperaesthesia of nerves - due to PGs and bradykinin
What do paracetamol and aspirin act on?
Prostaglandins - prevent their production
What does tissue homeostasis consist of?
Constant balance of injury and healing, keeping the cell towards the healthy end of the
healthy -> diseased -> necrotic
scale
What are monocytes/macrophages? How may they be distinguished?
Sentinels of the immune system
- Big single nucleus
- Vesicles due to endocytosis/phagocytoisis of other materials
How do tissues monocytes function?
> Constantly ingest small amounts of environment to test for pathogens or foreign material
When activated, become phagocytic (termed macrophages) and release pro-inflamaotry cytokines (IL1, IL6, TNFa, interferons)
Mature to become part of the adaptive immune response
Become NON-phagocytic, MHC2 antigen presenting cells
Play a role in immune differentiation - instructing lymphocytes
release IL12, IL6, IL23, IL27, IL10
Give examples of regulatory cytokines
IL10, TGFb
Give an example of a species specific difference in leukocyte levels
Cows have low neutrophils - they are released rapidly form the bone marrow in response to stress
Where are neutrophils stored?
Blood and bone marrow
What is the role of naive neutrophils?
Phagocytic - contain proteases, oxidative burst potential, Cytokines IL8, FCyRIII “Stick” part of Ab.
What happens upon activation of neutrophils?
Chemotaxins released (chemokines, cytokines, complement components, leukotrienes) Adhesion to endothelium, migration to tissues
Which pathogens are neutrophils particularly important for?
Bacteria
What are acute phase proteins? Give 5 examples.
Present in normal plasma, ^ synthesis by liver in response to IL1, IL6, other pro-inflam cytokines
- Purpose not really understood! But measured for diagnostics.
1. Serum amyloid A - recruits neutrophils, cholesterol transport, induces enzymes for ECM proteolysis
2. Fibrinogen - blood clotting for extra-vascular matrix
3. A-acid glycoprotein - binds basic drugs, steroids, protease inhibitors
4. C-reactive protein - 50,000x ^ in acute infection - binds phosphocholine (lipid membrane component of microbial/cellular origin) assists complement binding, opsonises bacteria
5. MBL (mannonse binding lectin) - activates complement
What are the 4 proteolytic cascades?
- Coagulation system - blood clotting (fibrinogen -> fibrin)
- Kinin system -
- Complemet system - MAC
- Fibrinolysis systm - Breaking down clot
What does the tetanus vaccine contain?
Tetanus toxin (inactivated) - Abs produced to bind to toxin
Does MAC formation occur only on bacterial cells?
Can occur on self cells - if virus infected this is adaptive, if healthy this is non adaptive
What is serum sickness?
Too many Ab/Ag complexes in the blood -> type 3 hypersensitivity reaction against animals own serum, esp. horses
What can initiate the MAC cascade?
MBL (mannose binding lectin) - sugar found in yeast/funghi
Ab/Ag complexes
Pathogen surfaces
What is the end result of the MAC cascade?
Formation of a MAC complex in the cell membrane - leads to lysis of cells due to ion and H20 infiltration
What are the two initial substances required for the kinin system cascade?
Prekallikrein and Prolylcarboxypepidase (in neutrophils and endothelium?) Factor XIIa
What are the outcomes of activation of the kinin cascade?
Bradykinin - acting on endothelial cells ^PG (-> pain) ^NO (-> vasodilation and ^permeability)
- recruits and activates neutrophils
- activates monocytes and causes cytokine release
What are the two initiating pathways of the clotting pathway? Where do the converge?
Extrinsic (damage to tissues outside the vessel wall) and intrinsic (damage to the vessel wall)
Both lead to activation of factor X
What does the clotting cascade cause?
Fibrinogen -> Fibrin –(FACTOR VIII)-> Blood clot
What initiates the intrinsic pathway? Which breeds may have problems with this?
Exposed collagen and von Willebrand factor
- Dobermans prone to lack von WIllebrand factor meaning cuts -> excessive bleeding
What is the initial substance in the fibrinloysis system? Which drugs are associated with this?
Plasminogen - Clot removal drugs for heart attack patients ^ plasminogen
What convert plasminogen to its active form?
TPA - tissue plasminogen activating converts plasminogen -> plasmin, which breaks down fibrin in the clot to degradable products
What is the process following endothelial damage?
Exposed sub-endothelial collagen and von Willebrand factor recruits circulating factor VIII, collagen and vWF and PLATELETS Platelets adhere to collagen (ATP dependent) Activated platelets release - ADP - 5HT (^tone -> ^BP) - PAF - vWF - Platelet factor 4 - TXA2 (vasoconstrictor)
What type of cascade are all 4 blood plasma cascade systems?
Proteolytic
- all have cross over links too.
What is the 2 component signal initially proposed to explain how the body discriminates pathogen, nonthreatening foreign antigen and self?
- Antigen - 3D B-cell epitope, linear T-cell epitope
2. PAMPS - pathogen associated molecular patterns - receptors of the innate immune system
Where are the majority of TLRs for PAMPs found?
Surface of monocytes and surface of endosome within monocytes
Give an example of a PAMP
Lipopolysacharide
Flagellae
What is the function of C-type lectin - Dectin1?
Responds to fungal sugars
- monocytes, induces oxidative burst, IL10, CXCL2
- dendritic cells, stimulates maturation, IL6, IL23
Give examples of PRRs
MAC
NOD like receptors in the cytoplasm
- assemble into an inflammasome, activating IL1 and enabling its release
What is gout caused by? What can exacerbate it?
Urate crystals due to lack of enzyme (metabolic disorder)
- ATP/ADP levels trigger it
- ^protein exaccerbates due to ^ urate production
When may reactive oxygen species be produced?
Frustrated phagocytosis of large particles eg. silica, irate, parasites
Neutrophils stimulate monocytes to produce these
ROSs -> inflammasome assembly
What patterns are seen in cases of sterile inflammation?
Damage Associated Molecular Patterns
What may cause sterile inflammation?
Monosodium urate, calcium pyrophosphate, alumn crystals (eg. vaccines -> good Ab response), Asbestos
What are the 4 mechanisms of pyrexia formation?
- Production of endogenous pyrogens (Interferon, TNFa)
- Binding to poiod receptors on nerve cells in hypothalamus
- Activation of COX2 in hypothalamus -> ^PGE2
- Altered firing rate of temperature sensitive neurone in anterior hypothalamus
Outline sickness behaviour
Motivational state responsible for re-organising perceptions and action to enable ill individuals to cope better with infection
- v motility
- social withdrawal, reduced responsiveness
- reduced food/water intake
- ^ slow wave sleep
- altered cognition
- ^pain sensitivity
> mediated by effects of pro-inflammatory cytokines (esp IL1) on CNS
IL1, IL6, TNF, interferon released in response to PAMPs
What is inflammation?
A conserved response of living tissues to external threats or damage - the first step in healing of diseased or injured tissue
Which stimuli can cause inflammation?
Many - infection, toxins, physical agents, products released from dead or dying cells (STERILE INFLAMMATION)
Why should unregulated inflammatory response be kept in check?
Can cause further tissue damage
What is the action of B cells? Where are they stored?
Secrete antibodies
Follicles in the lymph nodes
What is the purpose of antibodies?
Recognise 3D shapes by the epitope
Multiple binding sites enables complex formation (agglutination)
What do T cells recognise?
Short peptide segments on antigen presenting cells
What are the 2 main subgroups of T cell? What is their function and where are they found?
CD4+ Helper T cells - make cytokines, activate and control immune responses - EXTRACELLULAR
CD8+ Killer T celler - make cytotoxic substances swell as cytokines - INTRACELLULAR
What type of MHC do each of the T cells interact with?
CD8 - MHCI
CD4 - MHCII
What is the MHC:T cell junction referred to as?
Immunological synapse
What does MHCII antigen presentation lead to?
- activated CD4 helper cells
- helper cells secrete cytokines to direct immune response
- Activate NK cells (innate virus response)
- Help expansion of cytotoxic T cells
- Help B bell antibody production
- Essential for immune memory
What does B cell antibody class switching require?
T cell help via cytokines
Which section of antibody binds antigens?
Variable light chain
Other section is the constant heavy chain.
Which section of the antibody changes in class switching?
Heavy “constant” chain
Which order does class switching occur?
MDG(bacteria)A(mucosal)E(parasite/allergy)
Do all species have the same number of Ab classes?
No - eg. horses have 7
How may antibodies be antibacterial?
- recognise unique proteins and polysaccharides
- prevent adhesion and invasion
- opsonise bacteria ready for phagocytosis
- activate complement
> specific antibodies may neutralise secreted toxins eg. tetanus
What responds to PAMPs?
PRRs - patterns recognition receptors
What are tissue macrophages (from monocytes) activated by?
TLR (toll like receptor) activation
What are the properties of an activated macrophage?
^ innate antimicrobial function - enhanced phagocytosis - enhanced production of ROS - enhanced NO production - enhanced phagosome lysosome fusion ^adaptive immune function - ^ MHC expression for antigen presentation - ^ interferon production - ^ cytokine/chemokine productino
How do neutrophils destroy pathogens?
Oxidative burst - NAPDH oxidase, superoxide dismutase and myeloperoxidase involved int he reaction
Which subsection of complement inserts into the cell membrane?
C3a
How long to macrophages/dendritic cells live?
Long time
How do macrophages migrate around the body?
Blood and lymph
How do macrophages destroy pathogens?
Phagocytosis/Pinocytosis - WEAK oxidative burst
How are macrophages involved in the adaptive immune response?
Antigen Presentation
How long to neutrophils live?
Short life span
Where are neutrophils stored?
Bone marrow/blood
What happens to neutrophils following initiation of an inflammatory response?
Rapid migration to tissue at inflamed sites - cannot recirculate
- potent oxidative killers following phagocytosis of pathogens
Which cells and cytokines are involved in virus immune response?
NK cells and T cells - Interferon Gamma
Epithlium releases Interferon b to alert surrounding cells
Fibroblasts release interferon b
Macrophages/plasmacytoid dendritic cells - Interferon a, IL1, IL6
What do interferons do?
Alert neighbouring cells to virus infection via receptors -> genetic changes ^ resistance to viruses
- Degrade RNA in RNA viruses
- Block protein production
- ^ expression of MHC
- Activate immune cells and NK cells
- Mediate fever response and sickness behaviour
What are respiratory viruses particularly good at?
Blocking interferon communication between cells
Also surviving at lower temperatures
What do NK cells monitor?
Production of MHC - if MHC production v -> apoptosis
What activates NK cells and what do they produce?
Interferon gamma (IFNy) and IFNy!
How may antibodies protect from viruses?
Bind to agglutination receptors and prevent binding onto cell surfaces (and thus prevent entry into the cell)
Initiate MAC formation in the infected cell -> apopotosis
Which cells express MHCI? What is it’s action?
ALL cells
- highest concentration on leukocytetes
- Interferon ^ expression of MHCI
- Presence of MHCI Inhibits NK cell killing
- Presents antigen to CD8 killer cells
- Healthy cels will present self antigen in the peptide groove, whereas infected cells may present foreign antigen
How do CD8+ T cells respond to MHCI?
If foreign peptide is presented will destroy cell so that virus infected cells cannot reproduce
- ^no of CD8 memory cells protect from reinfection
What is another method of destroying virus infected cells?
CASPASE cascade
Perforin and granzymes
