Immunology 4 Flashcards
Examples of pro-inflammatory mediators? Functions?
Nitric oxide, prostaglandins/leukotrienes,histamines - cause vasodilation, increased vascular permeability, smooth muscle contraction and pain
Cytokines (TNFα, IL-1, IL-6, IFNγ) - increase vascular permeability and cause endothelial cell activation
Chemokines - recruit and activate wbcs by chemotaxis
What is it called when neutrophils squeeze between endothelial cells?
Diapedesis
What are neutrophils?
Short-lived phagocytic cells circulating in blood that have intracellular granules and multi-lobed nuclei
Function of neutrophils?
Recruited into inflamed sites by cytokines/ other pro-inflammatory mediators
Kill extracellular pathogens
Produce pro-inflammatory cytokine (like TNFα)
What are the killing mechanisms of neutrophils?
Phagocytosis
Degranulation
NETs
How do neutrophils phagocytose pathogens?
Pathogens release chemokine-like signals that attract neutrophils
Neutrophils use PRRs to bind to PAMPs on pathogens
Phagocytosis via anti-microbial proteins OR NADPH oxidase-dependent mechanisms
Anti-microbial protein mechanisms in phagocytosis?
Granules with anti-microbial proteins:
Acidification - makes pH of phagolysosome 3.5-4.0 and makes bacteriostatic and bactericial products
Anti-microbial peptides - defension and cationic proteins
Enzymes - lysozyme and acid hydrolases
Competitors - lactoferrin (binds Fe) and vitamin-B12 binding protein
NADPH oxidase-dependent mechanism in phagocytosis?
AKA respiratory burst produces toxic Reactive Oxygen Species (ROS), like superoxides and nitric oxide
Neutrophil activation
Aseembly of NADPH oxidase complex
Production and release of ROS into phagolysosome
What does neutrophil degranulation involve?
Release of anti-bacterial proteins from neutrophil granules into EC environment
What are the outcomes of neutrophil degranulation?
Direct killing of EC pathogens
Kill ‘self’ cells causing tissue damage and potentially systemic inflammation
What are NETs?
Neutrophil Extracellular Traps
Activated neutrophils release intracellular structures (NETs) into EC environment
How do NETs work?
Immobilise pathogens and prevent them from spreading, facilitates phagocytosis
How is it known that neutrophils are important in killing bacteria and fungi?
Patients suffering from immunodeficiency disease affecting neutrophils get recurrent bacterial/fungal infection
Examples of immunodeficiency diseases affecting neutrophils?
Chédiak–Higashi syndrome - defective phagocytosis
Chronic granulomatous disease - deficiency in NADPH oxidase
Leukocyte adhesion deficiency - defective integrin expression
Pathological consequences of neutrophils producing excess TNFα?
Inflammatory bowl disease, psoriasis, rheumatoid arthritis, asthma, cancer, infectious disease, auto-immune pathologies
How are these pathological consequence of excess TNFα treated?
Some are co-treated with monoclonal antibodies or other molecules that neutralise TNFα (highly inflammatory cytokine)
Examples of complement proteins?
Kinins
Coagulation factors
Fibrinolytic system
What is the complement system?
Family of approx. 30 proteins circulating in blood
Produced in liver
Enter infected/inflamed tisses
How are complement proteins activated?
Activated directly OR indirectly by pathogens.
When triggered, specific complement proteins can enzymatically activate other complement proteins in a CASCADE reaction
Briefly describe mannose-binding lectin pathway
Inactive C3 (acute phase protein) cleaved by upstream complement protein to from ACTIVE C3a and ACTIVE C3b
Explain the mannose-binding lectin (MBL) pathway
Pathogens express mannose sugars on cell surface - ligand for MBL; human cells do not express mannose
Produced complex of C4b + C2a which cleaves C3 into C3b and C3a - both trigger downstream events
Explain the alternative to the MBL pathway
C3 is unstable so spontaneous degradation into C3b and C3a occurs
C3b rapidly degrades if not attached to a pathogen
If attached to pathogen, factor B attached to C3b
Factor D converts factor B into factor Bb
The factor Bb attached to C3b reproduce C3b
What do C3a, C5a and the membrane-attack complex all do?
Kill pathogen
Pathogen opsonisation
Wbc recruitment and inflammation
Describe complement mediated killing
C5b binds to pathogen surface
C6, C7, C8, C9 assemble with C5b to form MEMBRANE ATTACK COMPLEX
Inserted into target cell wall causing osmotic lysis of cell
What is complement-mediated opsonisation?
Coating of pathogens with humoral factors (opsonins) to faciliate phagocytosis
Opsonin example is C3b
Describe complement-mediated inflammation and wbc recruitment
C3a and C5a are ANAPHYLATOXINS - promote inflammation by acting directly on blood cells
OR by stimulating mast cells to produce pro-inflammatory mediators and chemokines
Complement system regulation?
Only cleaved complement proteins are active
Active complement proteins have short half-life
Some complement proteins only produced during APR
Some complement proteins do not bind to human cells
Complement inhibitors/ regulatory protein limit activation of the system
What are dendtritic cells?
The bridge between the innate and adaptive immune system
“Professional” antigen presenting cells
How do dendritic cells work?
Present in peripheral tissues in immature state
Phagocytose antigens, cell debris, particles, etc
Mature and migrate into secondary lymphoid tissues - play key role in antigen presentation
