2. Innate Immunity Flashcards
aim of innate immune response
limit spread, eliminate microorganisms and repair damage
aim for adaptive immunity
to clear pathogens and produce a memory response
Cells of the innate immune system
Phagocytes (neutrophils, monocytes, macrophages, mast cells, eosinophils), antigen presenting cells (monocytes, macrophages and dendritic cells) and other immune cells (NKCs, ILCs, NKTCs)
four main types of defensive barriers/features
anatomical, physiological/chemical, phagocytic/endocytic, inflammatory
examples of anatomical defence barriers
skin, mucosa
how is skin used as a defence barrier
sloughing of dead skin, acidic (pH3-5), commensal microflora that secrete bacteriocins
how are mucosal surfaces used a defence barriers?
cilia propulsion, entrapment, flow of secretions, competition by commensal bacterial, tight junctions
examples of physiological/chemical defences
temperature (fever), low pH (stomach, skin), chemical mediators/antimicrobial proteins
Protein examples
Lysozyme, Lactoferrin, Psoriasin, Surfactant P
lysozyme
found in tears/saliva that cleaves peptidoglycans of bacterial cell walls
Lactoferrin
Binds to essential nutrients, inhibiting bacterial and fungal growth
S100 proteins e.g. Psoriasin
secretions and on skin, Disrupts microbial cell membranes
Surfactant Proteins
respiratory tract, block bacterial surface components
by binding to them, have a lubricating function
Peptide examples
Defensins, Cathelicidins, Histatin, Dermicidin
Defensins
bind negatively charged microbial structures, Aggregate to form pores in cytoplasmic membrane, activate complement pathway, found in neutrophil granules
Cathelicidins
disrupt microbial membranes
what did Metchnikoff use to study phagocytosis?
daphnia and starfish larvae
examples of endocytosis
Pinocytosis
Macro-pinocytosis
Receptor-mediated endocytosis
Phagocytosis
which type of endocytosis is used by most cells?
pinocytosis and receptor-mediated
pinocytosis
Cell drinking. aids osmoregulation. non-specific
Macro-pinocytosis
larger gulps of cell drinking. Aids in processing of Antigens for an immune response
Receptor-mediated endocytosis
specific uptake of ligand, growth factor, hormone, immune complex via a receptor. clathrin associated
Phagocytosis
internalise, kill/destroy/digest particulate matter
phagocytic cell types
Monocytes/Macrophages Neutrophils Dendritic cells Eosinophils B cells/Mast cells
stages of phagocytosis
1- Recognition 2- Ingestion 3- Digestion 4- Exocytosis – also presentation and storage
direct recognition
non-opsonic - Pattern Recognition Receptors (PRRs) on phagocytes bind to Pathogen Associated Molecular
Patterns (PAMPs) or to Damage Associated Molecular Patterns (DAMPs) on particles/microbes
indirect recognition
opsonic - Receptors on phagocytes bind to opsonins coating the surface of particulate matter/microbes
examples of PAMPs
bacteria - cell wall components, flagella. viral glycoproteins, fungi
examples of DAMPs
necrosing cells (ssRNA release), short-chain fatty acids in diet, apoptosing cells (PS, RNA, vitronectin)
C type lectin receptors
Mannose Receptor, Dectin-1, DC-SIGN
Mannose Receptor
- Binds to mannose/fucose/α mannan
- On surface of most Mφs and DCs
- Has 8 extracellular domains and cytoplasmic tail
Dectin-1
- Binds β1-3 glucan on fungi and bacteria
* Expressed on a wide variety of myeloid lineage cells
DC-SIGN
• Binds mannans on bacteria, fungi and parasites
Scavenger receptors
SR-A and B
SR-A
• Found on all macrophages & some endothelial cells, binds modified low-density lipoprotein e.g. oxidised LDL
SR-B
• Includes CD36 found on endothelium, DC, platelets, MC & MF
• Binds variety of altered ‘self’ molecules such as
oxidised LDL or vimentin on the surface of apoptotic cells
• Also recognise some PAMPs
Toll-like receptors
Toll gene identified in
Drosophila, Leucine rich repeats of external domain,
intracellular TLRs
detect DNA/RNA associated with viruses
and strongly induce type I interferons –
cytokines with antiviral effects
extracellular TLRs
expressed mainly by immune cells and are strongly
associated with bacterial/fungal infections
which cell types express all TLRs?
monocytes, macrophages, dendritic cells
which type of TLR do B cells, T cells and granulocytes express?
TLR4
NOD-like receptors (NLRs)
- Family of 23 members divided into 3 main groups (B,C and P)
- Interact with intracellular PAMPs and DAMPs
- Activate the NFkB pathway and autophagy
RIG-like receptors
- Bind viral dsRNA and so detect viral replication
* Initiate anti-viral cytokine (type 1 interferons)
AIM2–like receptors (ALRs) and cGAS/STING
• Bind DNA molecules from bacteria and viruses
• Induce production of anti-viral and inflammatory
cytokines
inflammasome
NLRs and ALRs clump together to initiate pro-inflammatory cytokine production
pyroptosis
self-death by pro-inflammatory cytokines
pro-inflammatory cytokines
Interleukin-1 and 18
examples of opsonins
IgG (antibody), fragments of Complement & lectins
antibody receptors
Fc. Recognise the constant region
(i.e. not antigen binding) of antibodies
complement receptors
Bind to components of the classical, alternative and lectin complement
pathways
examples of complement receptors
CR1, CR2, CR3, CR4, C3a/4a and C5aR
process of phagocytosis
pseudopodia form & surround particle, fuse
engulfing particle in membrane-bound vesicle. requires energy and cytoskeletal rearrangement (surface receptors need to cluster)
Oxygen Independent digestion
- Acidification
- Lysozyme
- Other enzymes
- Defensins
- Lactoferrin
- Cathelicidins
- S100 proteins
Oxygen Dependent digestion
• Reactive oxygen
intermediates
• Reactive nitrogen
intermediates
both lead to respiratory burst
Other oxygen independent Enzymes
• Acid hydrolases: phosphatases, sulphatases, glycosidases,
deoxyribonucleases
• Lipases: eg phospholipase A2
• Neutral proteases: collagenases, elastase, cysteine proteases
examples of free radical scavengers
Catalase, superoxide dismutase and glutathione
what can ROI and RNI damage?
proteins, lipids, DNA and cell membranes
how does ROI cause respiratory burst?
Rapid increase in O2 consumption, surge of targeted activity in phagosomes and
phagolysosomes, free radical reactive to microbial components
how does RNI cause respiratory burst?
inducible Nitric oxide synthase (iNOS)
activated by microbial products and some
cytokines, expression in vasculature and neurones, argenine oxidised to citrulline and nitric oxide within phagocytes
professional phagocytes
macrophages, monocytes and neutrophils
where are ROI/RNI found in professional phagocytes?
macrophages/monocytes - lysosomes
neutrophils - primary and secondary granules
what happens to pathogens that escape digestion stages?
undergo pyroptosis or autophagy by intracellular PRR recognition
what happens to products of phagocytosis?
Heavy metals tend to be
‘stored’ and PAMPs and DAMPs once processed are often presented to the adaptive
immune response
5 hallmarks of inflammation
rubor (redness) et tumor (swelling) cum calor (heat) et dolor
(pain), & loss of function (functio laesa)
purpose of inflammation
increasing blood flow, permeability of vasculature – allowing leukocyte migration to aid limiting the spread of infection, tissue damage and to promote healing
NETs
Neutrophil Extracellular Traps
immune cells that produce inflammatory mediators
Mast cells, Basophils and Macrophages
examples of inflammatory mediators
• Prostaglandins, Leukotrienes, • Histamine - thromboxanes • Cytokines • Chemokines
Cytokines
movement of cells
interleukin
communication/messaging between white blood cells
Chemokines
movement towards a
chemical
interconnected mediator producing
systems
kinin, clotting, fibrinolytic and complement
examples of cytokines
Interleukin-1, 6, 8, 10, 12 (IL-1, IL-6 etc), Tumour
necrosis factor a (TNF-a), Transforming growth factor β (TGF-β)
and interferon γ (IFNg)
alarm cytokines
IL-1, IL-6 and TNFα - causing local and systemic activation of fever, increased vascular permeability, production of acute phase proteins and increased adhesion molecule expression
anti-inflammatory cytokines
IL-10 and transforming growth factor beta (TGF-β)
- down-regulate responses
IL-12 and IL-18
induce the differentiation of pro-inflammatory subset of T
cells
IL-8
potent chemokine for neutrophils
IFNγ
contributing to chronic inflammation
by recruiting Mφs to sites of damage/infection
(IFNa and b)
have antiviral properties within
infected cells
protein structure of chemokines
4 cysteine residues & sequence of amino
acids involving first two of these
Chemotaxis
migration & activation of
range of cells towards the source (along a concentration gradient)
Eicosanoids
unsaturated fatty acids derived from
arachidonic acid
- e.g. Prostaglandins, Leukotrienes and Thromboxanes
Kinin system
• Hageman factor (Factor XII) activated following tissue injury
• Activates pre-kallikrein to form kallikrein which cleaves kininogen
to form Bradykinin
• Bradykinin = basic protein that increases vascular permeability,
causes vasodilation, pain and contraction of smooth muscle
Clotting system
• Hageman factor activated following
tissue injury
• Activated by damage to blood vessels
and leads to large amounts of Thrombin
• Thrombin then acts on soluble fibrinogen….fibrin and clot
formation and fibrinopeptides which increase vascular
permeability and neutrophil chemotaxis
Fibrinolytic system
• Triggered by damage to endothelial cells and
activation of Hageman factor
• Removes clots from the injured tissue
• Active end product = plasmin
• Plasmin is a potent proteolytic enzyme which
breaks down the fibrin clots into degradation
products which are chemotactic for neutrophils
• Also contributes further to inflammation by activating
the classical complement pathway
• Important to block leakage & repair, must maintain
circulation – fibrinolytic system
3 activation pathways of complement cascade
classical, lectin and alternative
3 major outcomes of complement cascade
Opsonise particles to increase phagocytosis Regulate inflammatory & immune responses Lyse target cells and microorganisms
MAC and its components
membrane attack complex - C5b, C6, C7, C8 and polyC9
activation of classical pathway
Antibody (IgG or IgM) or c reactive protein (CRP) binds to antigen and attracts C1
what metal ion is needed in complement cascades?
Mg2+
what stabilises C3bBb?
properdin
activation of alternative pathway
spontaneous cleavage of C3 - autohydrolysis due to being an unstable inactive precursor
activation of lectin pathway
mannose binding leptin associated with serine proteases
ILC1 + NKs
secrete pro-inflammatory TH1-like cytokines (IFNg and TNFa)
ILC1
immunity to
extracellular pathogens
NKs
immunity to intracellular pathogens and tumour cells
ILC2
immunity to worms, wound healing, secrete TH2
type cytokines that activate eosinophils
ILC3
lymphoid tissue development, intestinal health,
immunity to extracellular bacteria and fungi, secrete
regulatory cytokines
3 mechanisms of target cell killing
- kill targets using perforins
- express Fas ligand to induce apoptosis
- antibody dependent cellular cytotoxicity
how do eosinophils kill target cells?
Granules contain Cationic peptides, Major
basic protein and Peroxidase all of which
can be released directly onto the surface
of extracellular pathogens (worms) - do not phagocytose
g/d T cells
Important in gut antigen recognition of bacterial antigens (particularly
lipids) through non MHC restricted means (CD1)
B1 cells
B cells expressing CD5 - Mainly produce low affinity antibody (IgM) mostly against
bacterial antigens (particularly carbohydrates) and are called
natural antibodies
receptors for opsonins
antibody receptor (Fc region), complement receptors - mainly CR1,3,4
acute phase protein examples
c-reactive protein, mannose binding lectin, serum amyloid a
