1 - Innate Immunity Flashcards
Aetiology
Causes of disease
Pathogenesis
How diseases develop
Necrosis
Uncontrolled cell death - hypoxia
Cells swell, organelles rupture and release enzymes into cytosil
Apoptosis
Controlled cell death
Cell shrinks, blebbing
Pyknosis and karyorrhexis
Pyknosis
Compaction of nucleus
Karyorrhexis
Loss of mitochondrial membrane potential, leading to nuclear fragmentation
Commensals
Microorganisms that are always with us
Pathogens
Infectious organisms that cause disease
Afferent arm of immune system
Discrimination of ‘self’ from ‘non self’
Effector limb of immune system
Recognition by receptors triggers inflammation and effector mechanisms to destroy pathogens
Innate immunity
In place before infection occurs
Cells of innate immunity
Phagocytes
Eosinophils
Mast cells
Natural killer cells
Soluble proteins of innate immunity
Cytokines
Acute phase proteins
Complement
Inflammatory mediators
An ulcer is caused by a…
Break in the epithelium
Function of inflammation
Eliminate pathogen
Repair damage
Return to state of homeostasis
Chronic inflammatory response occurs when…
Infections are not cleared rapidly
Features of localised acute inflammation:
Calor
Dolor
Rubor
Tubor
Inflammation
The coordinated response to infection or tissue injury
Results of inflammation:
Vasodilation
Increased vascular permeability
Emigration of leukocytes
Accumulation of cellular, protein rich exudate
Transudate
Fluid leakage
Exudate
Fluid and protein leakage into inter endothelial spaces
5 stages of innate inflammatory immune response
Recognition Vascular response Elimination Resolution Induction of adaptive immunity
PRR
Pattern recognition receptors
Cells with PRRs
Innate immune cells
Complement
Acute inflammatory exudate
Recruitment of cells and soluble factors from blood to site of damage
Fibrinogen is converted to
Fibrin
Induction of adaptive immunity
DC
Dendritic cells take up pathogen fragments (antigens) and migrate to regional lymph node where adaptive immune response is generated
DC
Dendritic cell
Haematopoiesis
Generation of leukocytes in bone marrow
Lymphoid lineage gives rise to…
B cells
T cells
Natural killer cells
NK cells
Natural killer cells
Myeloid lineage gives rise to…
-GRANULOCYTIC Neutrophils Eosinophils Basophils -MYELOMONOCYTIC Monocytes Mast cells Dendritic cells
Macrophages are formed from…
Monocytes- migrate into tissue and mature
Mast cells - when activated …
Degranulate very quickly
Release histamine
Sentinel cells
Sense tissue damage
Macrophages and mast cells
Resident cells
Beneath epithelial surfaces
Macrophages and mast cells
Complement
Soluble protein system
Proteins activate each other sequentially by a cascade of proteolytic cleavage
Functions of complement
Activation of inflammation
Opsonisation of microbes
Lysis of target cells
C3 has an unusual…
Internal thioester bond
C3a
Small fragment
Stimulates vascular permeability
Recruits effector cells to site of damage
Anaphylatoxin
Recruits effector cells to site of damage
C3b
Large fragment Binds covalently to bacteria surface Tags bacteria for phagocytosis Cleaves C5 C5b => cell lysis
Complement fixation
C3b binds covalently to bacterial surface
Activation of complement
Alternative pathway
Classical pathway
Lectin pathway
Alternative pathway
Slow and continuous C3->C3a+C3b Spontaneous hydrolysis (tick over)
ALTERNATIVE PATHWAY
Hydrolysis of thioester bond C3(H2O) Plasma protein Factor B binds Cleaved by Factor D into Ba and Bb --> C3(H2O)Bb = C3 convertase
Properdin (P)
Serum protein
Stabilises alternative pathway C3 convertase
PAMPs
Pathogen associated molecular patterns
Structures shared by classes of microbes
Classical and lectin pathways rely on …
Recognition of PAMPs
TLR
Toll like receptor
CRP
C-reactive protein
MBL
Mannose binding lectin
What inhibits C3 convertase?
Factor H
Lectin pathway
MBL - soluble PRR forms oligomers with MANNOSE and FUCOSE residues on pathogens
MBL associates with MASPs (proteases) activated after binding to pathogen surface
-activate C4 and C2
C4b2a = C3 convertase
MASP
MBL associated serine protease
Classical pathway
Functions in innate AND adaptive immunity
Pathogen sensed by C1 binding to pathogens or antibodies
C1q is a…
How?
Pathogen sensor
- binds directly to bacteria
- via CRP that binds phosphocholine of lipopolysaccharides on pathogen cell wall
- via Fc of immunoglobulin
C1r and C1s
Proteases
Activated when C1q is bound
C1 complex
C1q to C1s or C1r
Cells with Fc receptors
Neutrophil
Macrophage
Eosinophil
NK cell
Eukaryotic cells escape complement activation by making regulatory proteins…
Decay accelerating factor
Membrane cofactor protein
(Degrade C3 convertase or prevent formation)
DAF
Decay accelerating factor
MPC
Membrane cofactor protein
Anaphylatoxins C3a and C5a
Increase blood vessel permeability
Upregulate endothelial cell adhesion molecules
Increase smooth muscle contraction
Degranulate mast cells
Anaphylactic shock
Excessive histamine release
Recognition of microbes by phagocytes
- Complement receptors and Fc receptors
- Binding triggers actin assembly allowing plasma membrane to engulf particle
- Enclosed in phagosome, fuses with lysosome forming phagolysosome
- Pathogen killed, oxidative burst, ROS
Complementary function of phagocytosis cells
Neutrophils-increase rapidly in number with infection, short lives
Phagocytosed by macrophages
Pus contains
Dead/dying neutrophils
Fibrin
Debris
MAC
Membrane attack complex
Membrane attack complex
C3b activates C5, initiates assembly
Hydrophobic regions of C6 C7 C8 become exposed and bind to membrane
C9 polymerises on C5b678 complex to form a channel that disrupts integrity of microbe
Regulation of MAC in human cell
CD59 binds to assembling MAC
Prevents C9 binding and forming pore
Paracrine
Act on other cell types
Autocrine
Act on the same cell type
Endocrine
Act systemically
Redundancy
Functions of cytokines can be performed by other, different cytokines
Pleiotropism
A single cytokine has many different functional effects
Examples of cytokines
Interleukins IL - cell activation and behaviour
Interferons IFN - antiviral, cell activation
Tumour necrosis factor TNF - inflammatory functions
Soluble protein systems
- Kinin-bradykinin (inflammatory mediator)
- Clotting system-thrombin-fibrin
- Fibrinolytic system-breaks down clot in controlled way
Examples of
Lipid inflammatory mediators
Macrophages
Neutrophils
Mast cells
Lipid inflammatory mediators produce
- Arachidonic acid -> prostaglandins and leukotrienes
- Platelet activating factor -> recruit and activate neutrophils and eosinophils
TLR activation
Recruit adaptor molecules (MyD88) Release of cytokines --> acute inflammatory exudate Dendritic cell maturation --> adaptive immunity
CLR
C-type lectin receptor
PRR - fungal infection
NLR
NOD like receptor
Sense stress and form inflammasomes
Recruitment of leukocytes to site of infection
Neutrophils and monocytes recruited by
Binding adhesion molecules on endothelial cells
Chemo-attractants produced in response to infection
Rolling
Thrombin and histamine induce p-selectin on endothelial cells
E-selectin appears induced by IL1 and TNFa
Selections bind glycoprotein ligands on neutrophil
Low affinity - leads to rolling of cells
Tight adhesion
Adhesion molecules of integrin family LFA1 on endothelial cells
Bind to neutrophils
Integrins activated to high affinity state due to chemokines from infection site
Chemokines
Small proteins
Chemo-attractants to regulate leukocyte traffic
Diapedesis
Emigration of leukocytes through endothelium into surrounding tissue
CXCL8
(IL8) recruits neutrophils from blood
Neutrophils guided along chemokine concentration gradient…
Chemokine receptors bind chemokine
Guided by altering adhesive property
Monocytes bind endothelium adhesion molecules
Monocytes integrins VLA-4
Bind
Adhesion molecules VCAM-1
Pyrogens
Cytokines - increase body temperature, cause fever
Acute phase proteins secreted:
From
By
Liver
Cytokines (IL6)
Acute phase proteins - enhance fixation of complement
MBL (mannose binding lectin)
CRP (C-Reactive Protein)
MBL
Mannose binding lectin
CRP
C-Reactive protein
Indication of inflammation
Sepsis
When pathogens enter the bloodstream
What prevents pathogens entering the blood and disseminating?
Blood clotting
Local expression of TNFa
Septic shock
TNFa =>
Vasodilation
Loss of blood pressure
Heart failure
Switch from damage to repair…
Shift towards anti-inflammatory mediators
Triggered by engulfment of apoptotic neutrophils by macrophages
Macrophages function by:
Phagocytosis
Secreted products
Increased MHC molecules
Secreted products of macrophages
ROS and NO
Cytokines
FGF and VEGF
Metalloproteinases
FGF
Fibroblast growth factor
VEGF
Angiogenic growth factor
Metalloproteinases
Enzymes involved in wound healing, angiogenesis, tumour metastasis
Eosinophils in granulation tissue
Release granules containing toxic proteins
Death of parasites, but also damages host tiasue
Inflammatory mediators:
Prostaglandins
Leukotrienes
Fibroblasts:
Recruited by
Induce
FGF
Collagen synthesis
Angiogenesis:
Induced by
Induces
Cytokines VEGF
Pre existing vessels send out capillary sprouts
Steps in angiogenesis
Endothelial cells break off basement membrane Migrate to site of injury and repair Proliferate Differentiate to form lumen Acquire supporting pericytes
Type 1 interferons
IFNa and IFNb Made when cell infected with virus Interferes with viral replication Alerts neighbouring cells Activates NK cells
Type 2 interferons
IFN gamma
Made by activated NK cells
Activates macrophages
NKR
Natural killer cell rexeptors
MHC class 1
Where?
What?
Surface of all nucleated cells
NK cell ligand
Presents antigen to T cells
Missing self
Virally infected cells, MHC class 1 is down regulated NK cell can become activated if activating receptor is engaged
Induced self
Stress (DNA damage or infection) ligands for activating NKR are up regulated NK activation by overriding MHC class dependent inhibition
KIR
Killer immunoglobulin like receptors
NK effector functions
- Release granule contents (perforin) form pores in cell membrane and allow granites to enter
- enhance adaptive immune response, binding Fc antibodies
- source of cytokines that activate macrophages
What do dendritic cells do?
Carry antigens to secondary lymphatic organs
