NATURAL IMMUNITY
Dr. habil. Kőhidai László
Department of Genetics, Cell- and Immunobiology
Semmelweis University
Immunology EPh
2014.09.15.
The immune response
Natural (innate)
Acquired (adaptive)
Provides immediate
defense
Develops with time
Innate immunity
 First line defense
 Limited specifity
 Immediate response (no latency)
 Linear amplification
 No memory
 Cellular and humoral defense
Immume homeostasis
Innate
Adaptive
dendritic cell
macrophage
T lymphocyte
complement system
antibacterial peptides
granulocytes
cytokines
gd T cell
CD5+ B cell
cytokines
NK cell
B lymphocyte
antibodies
Pathogen
Target
Virus
Viral
RNA, DNA
peptide
Cell infected Macrophage
by virus
Signal
IL12 TNFa
Bacteria, fungi etc.
Epithel
Granulocyte
Endothel
Comple
ment
C3a C5a
chemokines
Effector
Target
destroyed
NK cell
Phagocytes
Defensins
MAClysis
Virus
infected ell
Bacteria,
fungi
Bacteria, fungi
Grambact.
viruses
Soluble recognition molecules of innate
immune system
Defensins
Pentraxines
C reactive protein (CRP)
Serum amyloid protein (SAP)
Collectines
Mannose binding lectins
Ficolin
Surface active proteins
Lipopolysaccharide binding
proteins (LBP)
bacteria, fungi
killing
ECM protein,
complement
microbial cell wall
(polysacch., nucl. acids)
Microbial cell wall
complement
(phosphoryl choline,
saccharides)
LPS
LPS sens.
First line defence
MPS (mononuclear phagocyte system)
Barriers:
skin, mucous membranes,
secretions
Cells: macrophages, neutrophils, NK cells,
mast cells, dendritic cells
Molecules: complement system
First line barriers
Mechanical: skin, mucous membranes, cough, sneeze
Chemical: skin pH: 5,5 stomach pH: 1,2-3
Biological: in the mouth saliva contains antibacterial
agents
lysozyme
lactoperoxidase
lactoferrin
antibody - IgA
in toothpaste
Limited specificity
3 strategies in recognition
Pathogen
Missing
Altered
non-self
self
self
Characteristic markers
of pathogens
Immunreaction is
blocked in case of self
markers
Non healthy self
markers
(missing in the host)
(missing in
microorganisms)
Missing MHCI - NK cells active
Missing C3 convertase – alternative complement activation starts
Missing sialic acid – phagocytes, alternative complement activation
NK CELLS: dual receptor system
KIR/
KAR
Tumor or virus
infected cell
no MHC
APOPTOSIS
www.alergias.med.br/ immunolfig02.html
Limited specificity
3 strategies in recognition
Pathogen
Missing
Altered
non-self
self
self
Characteristic markers
of pathogens
Immunreaction is
blocked in case of self
markers
Non healthy self
markers
(missing in the host)
(missing in
microorganisms)
Phagocytes have two types of receptors on their surfaces
Opsonic receptors:
Fc and complement receptors
Pattern Recognition Receptors
(PRRs)
Opsonization
vs.


Facilitation of phagocytosis
antibody
Fc receptor
complement
protein
complement
receptor
OPSONIZATION
bacterium
phagocyte
Fc receptors
Immunoglobulin = Ig
IgG
Fc region
Fcγ receptors
Fcε receptors
bind IgG
facilitate phagocytosis
(regulate B-cell activation)
bind IgE
high affinity receptor is expressed on mast
cells and basophils
role in allergy
(low affinity receptor has regulatory function)
Fc receptor mediated phagocytosis
Limited specificity
PAMP
antibody
PRR
Fc receptor
Complement
protein
Complement
receptor
OPSONIZATION
bacterium
phagocyte
pattern
PAMP
pathogen-associated
molecular patterns
recognition
PRR
pattern recognition
receptors
Membrane receptors
Secreted
receptors
Intracellular
receptor
Membrane PRR
I. Scavenger receptors
- CD14: LPS receptor
II. Lectin receptors
- macrophage mannose receptor
III. Toll like receptors
- carbohydrates, lipids, nucleic acids
LPS receptor
Gay et al. Nature Reviews Immunology , 2006
Toll-like receptors (TLR)
Nucleic acid and lipid/protein TLR ligands are recognized in
different cellular compartments.
Lipid or protein TLR ligands: recognized on the plasma membrane
e.g. LPS, flagellin
Nucleic acid TLR ligands: recognized by TLRs in the endosome.
www.natap.org/2006/AASLD/AASLD_57.htm
Intracellular cytoplasmatic
PRRs
RIG-I-like helicases (RLHs,
RLR) recognize viral 5’Triphosphate ssRNA
-Nod-like Receptors (NLRs)
recognize peptidoglycan
constituent of Gram positive
and Gram negative bacteria
Nature Reviews Microbiology 5, 491-504
Recognition – at multiple levels
1.Secreted PRR
4. Multiple
recognition
3.Membrane PRR
5.Intracellular PRR
2.Opsonisation
Brown GD. Dectin-1: a signalling non-TLR pattern-recognition receptor. Nat Rev Immunol. 2006 Jan;6(1):33-43.
Specificity of TLR
Inflammatory respponses
Main steps of macrophage
activity
-
expression of receptors
-
release of mediators
-
internalization of bacteria
-
phagolysosome formation
Immediate response (no latency)
Microbicidal activity of professional phagocytes
NADPH-ox =
NADPH oxidase
SOD
SOD =
superoxide
dismutase
MPO =
myeloperoxidase
www.uni-koeln.de/dictyostelium/07_human.shtml
Superoxide: O2 + e
Hydrogen peroxide: O2- + e- + 2H+
Hydroxyl groups: H2O2 + e- + 2H+
O2

H2O2
OH- + H2O
Takes place even whithout
PHAGOCYTOSIS !
FEVER
Fever is caused by exogenous (e.g. bacterial subst.) and
endogenous pyrogenes (products of macrophages).
- Major endogenous pyrogens: IL-1, IL-6, TNF-alpha
- Minor endogenous pyrogens: IL-8, MIP-1, MIP-2, interferons
Brain:
Circumventricular organs
IL-1
TNF-
Commensal bacterial flora
- all the natural bacteria that live on and in a healthy person
(skin, oral cavity, upper respertory tract, lower GI tract, the
urogenital tract) = 1013 cells
- about 1012 bacteria living in the human gut
- in oral cavity e.g. Streptococcus species
Benefit to the host: Compete with pathogens for colonization
(by competing for nutrition and attachment
sites to the epithelium)
Differential expression and compartmentalization
of TLRs
No TLR: commensal bacteria are
tolerated– NO recognition
Intracellular bacteria – intracellular
TLR
TLR: Bacteria passing the
epithelia
Nature Reviews Immunology 8, 411-420 (June 2008)
All bacteria that cross the epithelium are recognized
by immune cells
DANGER !!!
Immature
dendritic cell
How antigens reach lymph node?
Bridge between innate and adaptive immunity
Innate immunity
Adaptive immunity
TLR
Dendritic cell
COSTIMULATION: required for initial activation of T cells
Adaptive immune system
NOT ONLY A SIMPLE FIRST LINE defence
TLR based CONNECTION between natural
and adaptive immunity
PAMP:
DAMP:
Pathogen
associated
molecular
pattern
Damage
associated
molecular
pattern
Nature Reviews Immunology 8, 279-289 (April 2008)
!
Danger only in
case of necrotic
cell death
!
Nature Reviews Immunology 8, 279-289 (April 2008)
RAGE:
(Receptor for
advanced
glycation
endproducts)
TREM:
Triggering
receptor
expressed
on myeloid
cells 1
synergize
with TLR4
http://www.invivogen.com/family.php?ID=242&ID_cat=13&ID_sscat=107
Aknowledgements
Dr. Holub, M. – for her lecture material „Natural Immunity”
used as source