monika raulf - ruhr university bochum...2019/04/10 · lecture 10.04.2019 tasks of the immune...
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Innate immunity
Monika Raulf
Lecture 10.04.2019
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Tasks of the immune system Body protection against damaging influences
Deployment of a strong defence
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Skin Mucosa Sweat Digestive fluids Lysozyme Lactoferrin Cilia Cough, Sneezing, Vomiting, Diarrhoea
The line of defence
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Innate immunity ⇒ natural/mechanistic barriers Skin, mucus moves by cilia (air- or fluid-flow along the epithelia; normal gut flora)
⇒ chemical barriers • proteolytic enzymes in body fluids • digestive enzymes (in stomach pH 1.9 – 2.6), lysozyme (enzyme able to cleave peptidoglycan of bacterial cell walls) sweat (pH 4.0 – 6.8) • low pH-value
⇒ two „Key player“-cell types Monocytes/macrophages + granulocytes → Endozytose ⇒ Complement system
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Problem:
How can the host differ between the large amount of different pathogens?
Immune defense
Answer:
Development of multiple receptors, which detect conserved motifs of pathogens, that do not occur on Eukaryotes.
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Pattern recognition receptors (PRR) 4 main groups (classified on the basis of their cellular localization and their function)
- free receptors in the serum (e.g. MBL) - membrane-bound phagocytic receptors (e.g. Dectin-1, Scavenger receptors)
- membrane-bound signaling receptors (e.g. TLR*1) - cytoplasmic signaling receptors (e.g. NODR*2)
*1 lead to an activation of the pro-inflammatory pathway *2 NOD = Nucleotide-binding Oligomerization Domain
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Comparison of the characteristics of recognition molecules of the innate and adaptive immune systems
Receptor characteristics Innate immunity
Adaptive immunity
Specificity inherited in the genome yes no
Expressed by all cells of a particular type (e.g. macrophages) yes no
Triggers immediate response yes no
Recognizes broad classes of pathogens yes no
Interacts with a range of molecular structures of a given type yes no
Encoded in multiple gene segments no yes
Requires gene rearrangement no yes
Clonal distribution no yes
Able to discriminate between even closely related molecular structures no yes
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Pathogen-associated molecular patterns (PAMPs)
Pathogen-associated molecular patterns
• Endotoxin (lipopolysaccharide) • Peptidoglycan • bacterial lipoprotein • 1→3β-D-glucan • Lipoteichoic acid • Flagellin • HSPs • dsRNA • Cpg • DNA
are recognized by pattern recognition receptors (PRRs) Monika Raulf 8
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What is endotoxin?
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Structure of the lipopolysaccharides (LPS, endotoxins)
Hex
Hex Hex Hex
Hex Hep
Hep Hep Kdo
Kdo
Kdo
p
p
p
p
GlcN
GlcN
p
Variability
n
O-antigen Nucleus region
external internal
Lipid A (repeat 40 units)
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Interaction of the organism with endotoxin Route of exposure
• Contact with blood
• Oral
• Inhalative
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Interaction of LPS with cells
gram-negative bacteria
cell membrane
body barrier (e.g. respiratory tract)
LPS
LBP
LBP
sCD14
LBP = LPS-binding protein (Acute-Phase-Protein)
= Lipopolysaccharides, LPS
CD14
macrophages
NFkB
LBP
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Signal transduction way in detail
LPS
LBP
MyD88
IRAK
DNA nucleus
Transcription
IL-1β IL-6
IL-8 TNF-α
P
NFк B
Iк B
TRAF 6
Iк K
CD 14
Cytoplasma
RNA
Translation
MD 2
TLR 4
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Release of pro inflammatory cytokines
gram-negative bacteria
cell membrane
LPS
Body barrier (e.g. respiratory tract)
LBP
sCD14 macrophage
LBP
BPI
CD18
BPI
CD14
LBP CD14
blockade
LBP = LPS-binding protein (Acute-Phase-Protein)
= Lipopolysaccharides, LPS
BPI = Bactericidal-Permeability-Increasing-Protein
TNF-α
IL-1β IL-8
IL-6
NFkB
neutrophils
activation
O 2
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The receptor Toll was identified in Drosophila
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TLRs are members of the IL-1R superfamily and are membrane spanning molecules found on the cell surface and in endosomes
Cytokines Pathogen-associated molecules Endogenous damage signals
Cell-membrane
TIR IL-1-family TLR 1-11
IL-1RII
TIR
Signal transduction
Cytokines
IL-1R, IL-18R, T1/ST2, IL-RAcP, IL-18RAcP
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LPS (Lipid A)
TLR4
TIR
NF-κB IκB IL-8
nucleus NF-κB
Lipid protein Peptidoglycan
TLR2
Toll-like-Receptors
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Microbe
LPS
CD14
Toll-like receptor Seven α-helical
transmembrane-receptors
Mannose receptor
N-formylmethionyl Peptide
Chemokine
Lipid Mediators
Detection of the microbes, mediators
Cell response
Appropriate results
increased integrin activity; cytosceletal changes
Cytokine production, reactive oxygen intermediate (ROIs)
Phagocytes of microbe into phagosome
Migration into tissues
Killing of microbes
Killing of microbes
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DAMPs = Damage-associated molecular patterns (molecules that are responsible for endogenous adjuvant activity) PAMPs = Pathogen-associated molecular patterns; exogenous molecules which share a number of different recognizable biochemical features
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from Yang D. et al. : Alarmins link neutrophils and dendritic cells. Trends Immunol 2009; 30: 531-537
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Rock KL et al. Innate and adaptive immune responses to cell death. Immunol Rev 2011; 243: 191-205
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Innate immunity – relevant cells
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1. First Cellular Frontline
2. Cellular Defence line Phagocytes
Macrophages (in tissue (mononuclear))
• long-lasting • at activation cytokines* and other mediators are released, which allure among others neutrophile granulocytes
Neutrophile granulocytes = PMN=polymorphonuclear neutrophil leucocytes (just in blood, not in tissue)
*important for local inflammatory response and mediation of the induced, not adapted reaction
• short-living
(development)
Monocytes (in blood)
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Cellular response
Polymorph neutrophils
1) Phagocytic cells: • Neutrophile granulocytes (60-70%) → bacteria
2) NK-cells (natural killer cells)
• Monocytes (→ macrophages) (5%) • Eosinophilic granulocytes (1.5%) → parasites
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Phagocytosis, activation of anti bacterial mechanisms
Killing of parasites (by antibodies coated)
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Like mast cells, to find in blood
Release of granule, which contain e.g. histamine and other active substances
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Phagocytosis and activation of anti bacterial mechanisms Antigen presentation
Antigen admission in the periphery Antigen presentation in the lymph node
Found in tissue and blood; characteristic markers: CD1a, CD11c, MHC II
DC take up proteins by pinocytosis and present fragments of these to T-cells
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Phagocytosis
Microbe coated with antibodies which
bind to Fc receptors on the sell surface
The macrophage wall encased the microbe
Fusion of the membranes and generation of a
vesicle = phagosom
Lysomes fused with the phagosom: generation of a phagolysosom
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Opsonisation I „Seasoning the victim“
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A bacterial infection triggers an inflammatory response
from: „Immunologie“, Janeway et al.
Microbes activate macrophages releasing
cytokines and chemokines
Vascular dilatation and enhanced permeability of the vascular wall caused redness,
swelling and heating
Inflammatory cells invaded the tissue and released inflammatory mediators,
which provoked pain
Fluid
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Inflammatory response
• Reinforcement of the first line of defence (macrophages) by further effector-molecules and -cells • Construction of a physical barrier, which prevents the distribution • Encouragement of the cure of the damaged tissue
⇒ Marker of the inflammation: pain, redness, heat, swelling
⇒ The release are the cytokines
Induced by detection of pathogens and at tissue damages
Three important functions of the inflammation in the fight against infection:
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Cytokines MW ~ 25 kDa • released of different cells • bind on specific receptors
Special class Chemokine = chemo attractors, e.g. IL-8
Three structural main families • haematopoietic family, e.g. IL-6 • TNF family • Chemokine family
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Effect • autocrine • paracrine • endocrine
Effect of the cytokines
bloodstream
target cell
hormone molecules
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From the cytokine to the biological function
Cytokine
Receptor
Intracellular signal kascade
Cell nucleus
Gene activation
Biological function
Redundant function TNF
IL-1
IL-6
fever
Pleiotropic effect
IL-1
fever
cytokine production
proliferation
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Pro-inflammatory cytokines have a broad spectrum of functions
from: „Immunologie“, Janeway et al.
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Effect of cytokines I
• IL-1 = Fever, T-cell- and macrophage-activation
• IL-2 = Increase of T-cells
• IL-3 = Haematopoiesis (Basophile)
• IL-4 = Th2-cell activation, B-cell activation, IgE-switch
• IL-5 = Growth and differentiation of eosinophils
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Effect of cytokines II
• IL-6 = Acute phase proteins, increase of T- and B-cells
• IL-9 = Mast cell activation
• IL-10 = Inhibition of macrophages and T-cells
• IL-12 = Differentiation of Th1, Activation of NK-cells
• IL-13 = B-cell activation, Inhibition of macrophages
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Effect of cytokines III • TNF-α = Local inflammation
• IFN-γ = Macrophage-activation, MHC-expression high, antiviral
• IFN-α/β = antiviral, MHC I high, Th1
• IL-8 = Chemotaxis of neutrophils and T-cells
• MCP = Chemotaxis of monocytes
• MIP-1α = Chemotaxis of monocytes, T-cells and eosinophils
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Chemokine = small chemoattract proteins that stimulate the migration and activation of cells
They induce a directed chemotaxis at adequate reactive cells
Abbreviation: CCL and CXCL
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Chemotaxis: „Come to the rescue“
Steps of an inflammatory reaction: • Chemotactic substances (e.g. C5a, LTB4, IL-8) are released or activated and diffuse from the site of infection to the surrounding tissue and the capillaries • Pavementation: Adhesion of the phagocytes to the endothelia (epithelia) of the blood vessels • Diapedesis: Resolving of the basement membrane by the phagocytes and pass through the vascular wall • Chemotaxis: Inflow/immigration against the concentration gradient
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Chemokine are a family of proteins with similar structures, binding on chemokine receptors, which belong on the other hand to the big family of the G-protein-coupled receptors
• all chemokine own similar amino acid sequences and their receptors are all integral membrane proteins with seven membrane traverses Helices. Classification in two large groups: C-C – Chemokine CCR (1-9) e.g. MCP-1 (spec. monocytes) C-X-C – Chemokine CXCR (1-5) e.g. IL-8 (spec. neutrophils)
IL-8 and MCP-1 possess similar, but complementary functions • IL-8 leads PMN to leave the blood circulation and to immigrate in the surrounding tissue • MCP-1 however, affects monocytes and influences their wandering of the vessels and therewith their development to tissue macrophages • also fMLP (bacterial peptide) = Chemokine for neutrophils
binds on
bind on
(C=Cystein)
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Unspecific (innate) immune response
• genetically fixed (innate)
• not directed toward specific pathogens but against pathogen associated molecular patterns PAMPs
• reduces invasion of pathogens into the tissue
• reacts immediately, slows down distribution of pathogen until specific immunity has evolved
• e.g. : humoral: protease, complement, Interferons… cellular: macrophages, granulocytes…
humoral = solubilized in blood (lat. umor = Liquid)
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Important immune responses
B
B
B B
T
T
T T
Penetration of infective agents (antigens) Skin, mucosal membrane
Macrophage
Release of cytokines and chemotactic factors as IFN-α, IL-1 and IL-6, TNF, etc.; Neopterin
T- and B-lymphocytes helper cell
Lymphocyte activation
Lymphocyte- proliferation
T-cell-mediated immunity Production and release of antibodies (Immunglobulines M, G, A and E)
Release of cytokines as IFN-γ and IL-2
Receptor-detection of antigens in association with MHC II
Antigen-presentation in association with MHC II
Antigen-processing
Phagocytosis
innate
adaptive
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Co-stimulatory molecules
Cytokines
Pathogens
Intake
Detection
naive T-cell
Innate immune system
Th1
Adaptive Immune system
IFNg
Th2
IL-4
Antigen presentation
IL-4
TLRs
APC
IL-4, IL-5, IL-10, IL-13
Effector-cytokines
IL-2, IFNγ
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Which cells are involved in the antigen presentation?
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