3. Innate immunity Flashcards
Innate immunity
Present from birth “inbuilt”
Not enhanced by 2nd exposure, no memory
Uses cellular and soluble components
Innate immunity timings
Rapid response
Mins-hours
Cooperates with and directs adaptive immunity
Innate immunity “pattern” recognition strategies
PAMP
DAMP
Natural Killer cells
How is PAMP a pattern recognition strategy?
Detect conserved microbial structures
How is DAMP a pattern recognition strategy?
Detect consequences of cell infection or injury
How are Natural Killer cells a pattern recognition strategy?
Detect ‘missing self’
What are the innate immunity defence barriers?
Anatomical (physical)
Physiological
Phagocytic
Inflammatory
What are the anatomical defence barriers in innate immunity?
Skin- mechanical barrier, acidic environment
Mucous membranes- mucous traps microorganisms, cilia expel
What are the physiological defence barriers in innate immunity?
Body temp./ fever - provides suboptimal conditions for pathogen replication
Low pH- acidic pH of stomach kills many ingested microorganisms
Chemical mediators- lysozyme, interferons, complement
What are the phagocytic defence barriers in innate immunity?
Cells ingest material
What are the inflammatory defence barriers in innate immunity?
Local vascular permeability increases
Cell types in innate immunity
Neutrophil Eosinophil Basophil Monocyte/ macrophage Mast cell Dendritic cell Natural killer cell
What do neutrophils perform?
phagocytosis and killing of microbes
What do eosinophils perform?
Phagocytosis
Granule release
Help B cell responses (IgA production)
What do basophils perform?
Granule release
May act as antigen presenting cell for type 2 immunity
What do macrophages perform?
Phagocytosis
Killing
Cytokine release
Act as antigen presenting cell
What do mast cells perform?
Granule release:
Histamine
Other Inflammatory mediators e.g. cytokine
What do dendritic cells perform?
Antigen capture and presentation
What do natural killer cells perform?
Lysis of infected cells
Major phagocytic cell types
Neutrophil
Macrophage
Describe neutrophils
Polymorphonuclear leukocyte
Main type of leukocyte
Short lived
How do neutrophils move?
Circulate in blood then migrate into tissues
Which cells are 1st to be recruited to a site of tissue damage/ infection?
Neutrophils
Describe macrophages
Less abundant (than neutrophils)
Dispersed throughout tissue
Signal infection by release of cytokines
What do neutrophils need to do to fight infection?
Move from circulation into infected tissue
Bind to pathogen
Phagocytose pathogen
Kill Pathogen
Describe the movement of neutrophils into tissue
Neutrophil rolls along surface of capillary, weakly binding, selection mediated
If endothelium receives sign of infection: neutrophil binds tightly to integrins on surface
Migrates through endothelium
Opsonisation
Coating of micro-organisms with proteins to facilitate phagocytosis
Opsonins
Molecules that bind to antigen, and phagocytes
What function as opsonins?
Antibodies
Complement
What are the 2 classes of neutrophil killing mechanisms?
Oxygen Independent
Oxygen Dependent
What are the oxygen independent killing mechanisms?
Enzymes (Lysozyme and hydrolytic enzymes) Antimicrobial peptides (defensins)
What are the oxygen dependent killing mechanisms?
Respiratory burst of: Superoxide anion Hydrogen peroxide Singlet oxygen Hydroxyl radical Nitric oxide Reactive nitrogen intermediates
Neutrophil Extracellular Traps (NETs)
Activated neutrophils release granule proteins and chromatin to form extracellular fibres.
What is the function of neutrophil extracellular traps?
To trap microorganisms, allow enhanced phagocytosis by other cells and stop microorganism spreading in circulation.
Macrophage function
Expresses receptors for many material constituents
Bacteria binding initiates release of cytokines (danger!= recruit more cells)
Macrophage engulfs and digests bound bacteria
What do mast cells secrete?
Histamine
Other inflammatory mediators e.g. cytokines
Where can mast cells be found?
Near mucosa (lung) Near connective tissue (skin/ peritoneal cavity/ blood vessels)
What can mast cells do to bacteria?
Recognise, phagocytose and kill bacteria
How can mast cells be activated?
By complement products (Anaphylatoxins)
In anaphylaxis, body wide degranulation of mast cells leads to
Vasodilation
Increased vascular permeability
Describe natural killer cells (NK cells)
Large granulated lymphocytes: cytotoxic
Lyse target cells
Secrete the cytokine: interferon-gamma
What proportion of peripheral blood lymphocytes are NK cells?
5-10%
Receptors on NK cells
No antigen-specific receptor, but express both activating and inhibitory receptors: balance of signals
NK cells have receptors which bind to antibody-coated cells
So they can kill the cell (Antibody Dependent Cell-mediated Cytotoxicity)
What are NK cells important in defence against?
Tumour cells Viral infections (e.g. Herpes)
If a cell is healthy there is ligation of inhibitory NK receptors
NK recognises cell as self
Inhibits killing of cell
In an infected cell, there is ligation of activating NK receptors
NK recognises “missing self”
Kills target cell
Describe Cytokines
Small proteins secreted for local, short-lived cell-to-cell communication
=”messengers” of immune system
Why do cytokines have short half lives?
Have a biological effect at very low concentration
Need short half life to control effects
What do cytokines bind to?
Specific receptors on other cells
Types of cytokine
Interleukins (IL-x) Interferons (IFN) Chemokines Growth factors Cytotoxic
Interleukin function
Allow communication between leukocytes
Interferon function
Anti-viral effects
Interfere with virus replication
Chemokine function
chemotaxis
cell movement
Growth factor function
Proliferation & differentiation of cells
Cytotoxic cytokines
Induce apoptosis, tumour necrosis factor (TNF)
Proximity to other cells cytokine action
Most work in paracrine
Paracrine
Works on nearby cell
Name 2 alarm cytokines secreted by activated macrophages
IL-1
TNF-alpha
Describe dendritic cells
Network of cells located at likely sites of infection
Recognise microbial patterns, secrete cytokines
Act as antigen presenting cells
Complement system plays a major role in
complementing activity of specific antibody in lysing bacteria
What is the complement system?
Complex series of ~30 proteins and glycoproteins that lead to a triggered enzyme cascade system
Complement system timings
Rapid, highly amplified response
Where are components of the complement system mainly produced?
Liver
How is complement a triggered enzyme cascade system?
Components produced by liver are initially inactive precursors (enzymes)
Part must be cleaved to activate.
Once activated, cleaves substrate in next reaction.
Sequential activation of subsequent enzymes amplifies number of activated molecules
What are the 3 complement activation pathways?
Classic
Lectin pathway
Alternative
What is the classic complement activation pathway?
Antibody bound to antigen (immune complex)
Cleaved “waste” from precursor is a pro-inflammatory molecule
Signals to other cells.
Binds to specific receptors on mast cells, cause degranulation (release histamine)
What is the lectin pathway in complement activation?
Lectins bind to carbohydrates only on bacteria leading to activation of complement
Lectins
proteins that bind to carbohydrate
What is alternate complement activation?
Bacterial surfaces directly activate complement via different components
All 3 complement pathways converge to activated C3b
Which opsonises antigens/pathogens.
Membrane attack complex formed that forms holes in bacterial cell membrane and causes loss of integrity
Functions of complement
Lysis
Opsonisation
Activation of inflammatory response
Clearance of immune complexes
Control of complement
Short half life
Dilution of components in biological fluids
Circulating and membrane bound regulatory proteins
Local inflammatory response may be accompanied by
A systemic response "Acute phase" after 1-2 days Fever Increased production of WBCs Production of acute phase proteins in liver
How is a systemic acute phase response induced?
By cytokines
Acute-phase proteins
C-reactive protein (CRP)
Mannan binding lectin (MBL)
Complement
Fibrinogen (clotting)
Which acute phase proteins activate complement?
C-reactive protein (CRP)
Mannan binding lectin (MBL)
