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Immunology – Part II
26. April 2017, Ruhr-Universität Bochum
Marcus Peters, [email protected]
Innate Immunity
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Nomenclature
Cytokine: proteins that are made by cells and affect the
behavior of other cells. „Hormones“ of the immune system
Abbreviation: IL for Interleukin=Cytokine
Chemokine: Small chemoattractant proteins that stimulate
the migration and activation of cells.
Abbreviation: CCL and CXCL
Clusters of differentiation: groups of antibodies identifying
the same cell-surface molecule.
Abbreviation: CD
Leucocytes: all white blood cells, these are differentiated by
their microscopic appearance and expression of CD
molecules
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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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Conserved structures of pathogens are detected
by „Pattern Recognition Rezeptoren“
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ad
ap
tive
in
na
te
Innate immunity evolved early in evolution
MASP=MBL associated serine protease
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Stages of the immune response to infectious
microbes
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Innate Immunity – First Defense
Prevention of infiltration of pathogens into the body:
• Mechanic barrier (skin, mucosa)
Airway epithelium:
red = mucus secreting goblet cells
yellow = ciliated epithelium
• Chemical barrier (pH-value, enzymes)
• blood, lymph 7,4
• saliva 6,4
• stomach 1,9 – 2,6
• urine 4,5 – 8,2
• sweat 4,0 – 6,8
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Innate Immunity - Second Defense
Humoral immune response
3) Complement system (chemotaxis of leucocytes,
opsonization of pathogens, destruction of pathogens)
1) lysozyme: enzyme that is able to cleave peptidoglycan of
bacterial cell walls
2) Antimicrobial peptides: e.g. Defensin (direct bactericidal
activity by pore formation in the cell wall)
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The complement system as a part of the
innate immune response
• more than 30 proteins soluble and membrane-bound
plasma and other body fluid proteins are involved
• complement mediate the effect of antibodies
• facilitate the destruction of pathogenic microorganisms
by phagocytes or by lysis (Opsonisation)
• direct cell-destructive properties*
• many complement proteins are proteases, which are
activated by proteolytic cleavage (Zymogens)
*are tightly regulated
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Different ways of how the complement system protects against an infection
1. Production of activated complement proteins,
which bind covalently to pathogens and „opsonise“
them, so that an incorporation by phagocytes,
which carry CR, will facilitate (opsonization) .
2. Smaller fragments that can be released after
complement activation act as chemoattractants
(attract phagocytes and activate these)
(anaphylatoxin).
3. Destruction of pathogens by pore formation
(bacteriolysis).
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Classical pathway MB-lectin pathway Alternative pathway
Antigen-antibody-
complex
Lectin binds on the surface
of the pathogen
Pathogen surfaces
Complement activation
Attraction of
inflammatory cells
Opsonisation of
pathogens
Destruction of
pathogens
Three different mechanisms of complement activation
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Inflammatory mediated peptides, attraction of
phagocytes
Classical way MB-lektin way Alternative way
Antigen: antibody-complexes (pathogen surfaces)
Mannan binding lectin binds mannose
on the pathogen surface Pathogen surfaces
C3-convertase
binds on complement receptors on the
phagocytes
Membrane offending complex, lyse of specific
pathogens and cells
C1q, C1r, C1s, C4, C2 MBL, MASP-1, MASP-2, C4, C2 C3, B, D
C4a*, C3a, C5a C3b Terminal complement
components
C5b, C6, C7, C8, C9
Opsonisation of
pathogens
Removal of
immunocomplexes
Reco
gn
itio
n
Re
gu
latio
n
Effe
ct
Essential components and effector impacts of the
complement system
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Innate Immunity – Third defense
NK cells
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Innate Immunity - NK cells
Natural killer cells
Found in tissue and blood
Characteristic marker CD56, Fcg III Receptor
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Figure 2-49
From innate to adaptive immunity
Time line of development
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Figure 2-50 part 1 of 2
Inhibition of NK cell activation by normal cells
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Figure 2-50 part 2 of 2
Activation of NK cell by altered cell surface
Mechanism I
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Activation of NK cell by altered cell surface
Mechanism II
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Activation of NK cell by altered cell surface
Mechanism II
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Innate Immunity – Third defense
Mast cells
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Innate Immunity - Mast cells
mast cells
cells found in tissue
characteristic markers: c-kit, Fce Receptor,
cytoplasmatic granula stains blue with Methylen-Blue
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Mast cell
IgE
allergen
Activation of mast cells in allergic disease
FceR
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Yellow scorpion
(Leiurus quinquestriatus)
(LD50 value of toxin approx. 0,50 mg/kg)
But mast cells have also some very useful functions…
Mast cell deficient mice
J Clin Invest. 2011;121(10):4180–4191.
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Innate Immunity – Third defense
Eosinophilic granulocytes
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Innate Immunity - Eosinophilic granulocytes
Eosinophilic granulocytes
cells found in tissue and blood
characteristic marker: EPO eosinophil peroxidase
cytoplasma stains red with EosinY
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Atopic asthma is a disease where inflammation is
triggered by eosinophils
Large airway
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However, similar to the mast cell eosinophilic
granulocytes can have some useful functions too…
Schistosome larva
Eosinophilic granuloctes attacking IgE coated parasite
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Innate Immunity – Third defense
Phagocytes
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Innate Immunity - Phagocytes
Phagocytic cells:
• macrophages of tissues
• monocytes of blood
• neutrophilic granulocytes
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TRENDS in Immunology Vol.26 (2005)
Phagocytosis of yeast particles by neutrophils (left)
and macrophages (right)
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Formation of neutrophil extracellular traps (NET)
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Innate Immunity – Third defense
Dendritic Cells
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Innate Immunity – Dendritic Cells
Dendritic cells
Found in tissue and blood
Characteristic marker CD1a, CD11c, MHC II
uptake of antigen
via endocytosis
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The blood contains different subsets of dendritic cells
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Biological properties of plasmacytoid dendritic cells
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Dendritic cells bridge innate and adaptive immune response
via presentation of antigens to T-lymhocytes
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Dendritic cells bridge innate and adaptive immune response
via presentation of antigens to T-lymhocytes
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PRR Receptors of Innate Immune Cells
• Pattern recognition receptors (PRR) detect
pathogen associated molecular patterns PAMPs
Two types of PRR are known:
1. Toll like receptors =TLR
2. Lectin-receptors
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The receptor Toll was identified in Drosophila
Receptor Toll was identified 1996 as a
key receptor for immune response
against fungi
Human Toll-like recepors (TLR) are
homologous to Drosophila toll-
protein and have a key function in
mediation of the immune response
Toll Toll-like
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TLR1/2:triacyl-
Lipoprotein
TLR2/6:diacyl-
Lipoprotein
TLR3: dsRNA
TLR4: LPS
TLR5: Flagellin
TLR7: ssRNA
TLR8: ssRNA
TLR9: unmethylated
CpG oligonucleotides
TLR10: ??
Known ligands for the Toll-like receptors
By Jeff Dahl - GFDL,
commons.wikimedia.org/
TLR11: uropatho-
genic bacteria
TLR12: Profilin of
T. gondii
TLR13: rRNA
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O’Neill et al.
IRAK=Interleukin-1 receptor-associated kinase
MKK= Mitogen-activated protein kinase kinase
IKK=IκB kinase
TIR domain=Toll-Interleukin receptor
MyD88=Myeloid differentiation response
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The importance of the TLR signal transduction is
apparent in MyD88 knock out mice when they
become infected with bacteria
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Phagocytes induce inflammation
After activation of TLRs by PAMPs phagocytes release a specific
pattern of cytokines triggering inflammation that results in
Inflammation:calor (heat), dolor (pain), rubor (redness) and tumor
(swelling)
vessel
Tissue
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Proinflammatory cytokines have a broad
spectrum of functions
endocrine paracrine
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An example for the endocrine activity of IL6
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LPS
of gram-
negative
bacteria
IL-1 IL-6 TNF-a IL-8
TLR-4
TLR-2
Lipopeptide
of gram-
positive
bacteria
Inflammation
Additionally controlled
by Inflammasome activation!
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Maturation of Interleukin-1b by the Inflammasome
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NALP Inflammasom
Pyrin-Domain: 95 amino acids
„death domain superfamily“
Nucleotid binding Domain:
Important for oligomerization!
NACHT associated Domain
Leucin rich repeats-Domain
important as stress sensor!
Caspase Recruitment Domain
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Activation of the inflammasom leads to recruitment
of Caspase-1
pro IL-1b IL-1b
binds to Pyrin
Domain after
oligomerization!
Known activators
for inflammasom
-Uric acid
-ATP
-Alum
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Dysregulated Inflammasome activation is involved in
Inflammatory disease
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Another group of pattern recognition receptors
are the c-Typ Lectins
- Carbohydrate Recognition
Domain (CRD)
-Type 1 (more than one CRDs)
- Type 2 (only one CRD)
- Binding of sugar is Ca2+
dependent
-Can facilitate endocytosis of
antigens
-Some have also signaling
properties
Quelle: Figdor et al. 2002
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