1. GASTROINTESTINAL SYSTEM
CONTACT SURFACES
Physical, chemical, biological borders
Oral cavity
Esophagus
Stomach
Alimentary tract
GASTROINTESTINAL SYSTEM
EYE
Sinuses
Trachea
Lungs
AIRWAY SYSTEM
WALDEYER RING
Tonsils, adenoids
Palatinal, pharyngeal
lingual and tubar tonsils
SKIN
Kidney
BladderVagina
UROGENITAL SYSTEM
Demage
Infection
Mucus
glycoproteins, proteoglycanes, enzymes

2. DEFENSE LINES OF NATURAL IMMUNITY
ANATOMICAL BORDERS
Skin Inhibits entry of pathogens, pH3 – 5 inhibits growth
Mucosa Normal bacterial flora competes for binding sites and nutrients Mucus keeps away pathogens from the surface
Cilia remove pathogens
PHYSIOLOGICAL BORDERS
Temperature Physiological body temperature and fever inhibits growth of certain pathogens
Low pH Most pathogens are destroyed in the stomach
Chemical Lysosyme degrades bacterial cell wall
Type I interferons induce anti-viral resistance
The complement system is able to lyse bacteria and promotes phagocytosis
PHAGOCYTOSIS/ENDOCYTOSIS
Many cells can take up microorganisms by receptor-mediated internalization
Special professional phagocytes (monocyte, neutrophil, macrophage) are able to internalize, kill and degrade microorganisms
INFLAMMATION
Tissue demage and infection results in the leakage of anti-bacterial proteins and peptides to the affected tissue
Phagocytic cells leave the blood stream and enter inflammed tissues

3. AS AN IMPORTANT FIRST LINE OF DEFENSE
THE EPITHELIUM
AS AN IMPORTANT FIRST LINE OF DEFENSE
EPITHELIAL MONOLAYER

4. ORGANIZATION OF IMMUNE CELLS UNDER EPITHELIAL SURFACES
Dendritic cell
Epithelial cells
Stroma cells
Granulocyte
Macrophage
NK cell
NKT cell DC
TISSUE – SPECIFIC CELLULAR COMMUNICATION NETWORKS
PERIFÉRIÁS SZÖVETEK
PERIFÉRIÁS LIMFOID SZERVEK

5. MONOCYTE – MACROPHAGE – DENDRITIC CELL
FAGOCYTE SYSTEM
GRANULOCYTES
MONOCYTE – MACROPHAGE – DENDRITIC CELL
Defence against infectious
diseases
Elimination of tumor cells
Transplantation
Gatekeeper function
Sensing commensals and pathogens
Rapid activation of innate immunity
Priming adaptive immune responses
Maintenance of self tolerance

6. COLLECTION OF ENVIRONMENTAL INFORMATON, CONCENTRATION
TISSUE MACROPHAGES AND DENDRITIc CELLS INTERNALIZE SOLUBLE MATERIAL AND PARTICLES
ION CHANNELS
ABC TRANSPORTERS
CARBOHYDRATES
PROTEINS
C-TYPE LECTINS
MMR/CD206
DC-SIGN/209
Langerin/CD207
OPSONIZING RECEPTORS
FcR, CR
INFECTED
DEAD CELLS
SCAVENGER RECEPTORS
CD36, SR-A
LIPID RECEPTORS
LDL-R, CD91
LIPIDS
UPTAKE
Macropinocytosis
Receptor-mediated endocytosis
Fagocytosis
COLLECTION OF ENVIRONMENTAL INFORMATON, CONCENTRATION

7. EXPRESSION OF THE RECEPTOR DETERMINES INTERACTION WITH LIGANDS
Chemoattractant cytokines called chemokines direct migration of leukocytes to the appropriate anatomical sites
EXPRESSION OF THE RECEPTOR DETERMINES INTERACTION WITH LIGANDS

8. Engagement of PRR triggers phagocytosis and cytokine production
PHAGOCYTOSIS, RECOGNITION RECEPTORS, SIGNAL TRANSDUCTION, EFFECTOR MECHANISM
Pattern recognition
Receptors (PRR)
Engagement of PRR triggers phagocytosis and cytokine production
Lectins: receptors ( or plasma proteins) that bind to carbohydrates. On macrophages one finds mannose rec. And glucan receptors.
Scavenger receptor binds various substrates generally negatively charges (sulfated polysaccharides, nucleic acids, lipoteic acid bound in the cell wall of Gram positive bacteria)

9. BY THE INNATE IMMUNE SYSTEM
RECOGNITION
BY THE INNATE IMMUNE SYSTEM

10. PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS
Toll receptor-mediated signaling
Toll receptor
PHAGOCYTES (macrophages, dendritic cells, neutrophil granulocytes) RECOGNIZE PATHOGENS BY PATTERN RECOGNITION RECEPTORS
RECOGNITION IS ESSENTIAL
Macrophage, dendritic cell – ACT AS TISSUE SENSORS (GATE KEEPERS)
Neutrophil granulocytes – MIGRATE FROM THE BLOOD TO THE SITE OF INFLAMMATION

11. INNATE/NATURAL IMMUNITY
RECOGNITION
Richard Pfeiffer, a student of Robert Koch – ENDOTOXIN
There must be a receptor that recognizes endotoxin
Lipopolysaccharide (LPS) receptor remained elusive
The Dorsoventral Regulatory Gene Cassette Spätzle/Toll/Cactus controls
the potent antifungal response in Drosophila adults
Bruno Lemaitre, A Hoffmann et al, Cell, 1996
Spätzle: Toll ligand
Toll: Receptor
Cactus: I-kB
Dorsal: NF-kB
Drosomycin is not synthesized

12. complement INNATE (NATURAL) IMMUNITY Toll-receptors C. elegans
RECOGNIZING RECEPTORS
PROTECTIVE MECHANISMS Enzyme systems
Multicellular (Metazoa)
Sea urchin 600 million years
Toll-receptors
C. elegans
Drosophila
700 million years
complement
IN PLANTS

13. TOLL RECEPTORS RECOGNIZE VARIOUS MICROBIAL STRUCTURES
Bacteria
CpG DNA
Virus
TLR3
dsRNA
TLR9
TLR7
TLR8
ssRNS
TLR2
Peptidoglycane
Gram+
TLR5
Flagellin
TLR4
LPS
TLR6
Gram-
Interferon
producing cell
PC/DC
IFN
Macrophage/Dendritic cell
ALL STRUCTURES ARE ESSENTIAL FOR THE SURVIVAL OR REPLICATION OF THE PATHOGEN

14. DANGER SIGNALS ARE TRANSLATED TO CYTOKINE SECRETION THROUGH VARIOUS MOLECULAR SENSORS IN DC SUBTYPES4 6 6 2 1 1 5 10 3 7 9 7 8
NLR
RLH
RLH
NLR=NOD/NALP (IL-1β)
RLH=RIG-1/MDA5 (IFN)
Plasmacytoid DC
IFNαβ
NK/DC
IL-1β
IL-12/23
IL-10
Th1/Th17/Th2
Conventional DC
TLR1 – bacterial lipoprotein (together with TLR2)
TLR2 – bacterial lipoprotein, peptidoglycane, lipoteicholic acid
(heteromer with TLR1 and TLR6)
TLR3 – viral dsRNS, polyI:C
TLR4 – bacterial LPS
TLR5 – bacterial flagellin
TLR6 – bacterial lipoprotein (with TLR2)
TLR7 – viral ssRNA
TLR8 – GU rich viral ssRNS, imidazoquinolin (antiviral drug)
TLR9 – unmethylated CpG DNA
TLR10 – mdified viral nucleotides

15. TLR CONSERVED RECEPTORS/SENSORS THAT DETECT DANGER SIGNALS
MEMBRANE
TLR3
Fibroblast
Epithelial cell DC
LRR
CELL MEMBRANE
Bacteria
MEMBRANES OF INTRACELLULAR VESICLES
vírus
TIR
domain
Leucin rich repeats
TIR: Toll-Interleukin Receptor
signaling domain

16. SIGNALING
IN INNATE IMMUNITY

17. TOLL RECEPTORS ACTIVATE PHYLOGENETICALLY CONSERVED SIGNAL TRANSDUCTION PATHWAYS
Fungus
Toll
Cactus
Tube
Spätzel
Peptid
Protease
Pelle
Relish
Bacterium
LPS
LPB
CD14
TLR4
TRIF
IRF3
STAT1
IFN
TLR3
TLR4
CD14
MyD88
NFkB
IRAK
IL-1R associated
Kinase
TIR-domain-containing adapter-inducing interferon-β
Inflammation
Acute phase response
Danger signal
IL-6
Drosophila
Macrophage

18. IL- 6 THE ACUTE PHASE RESPONSE
Mannose binding lectin/protein
MBL/MBP
COMPLEMENT
C-reactive protein
COMPLEMENT
Liver
Serum Amyloid Protein (SAP)
Mannose/galactose binding
Chromatin, DNA, Influenza
Fibrinogen
IL-6 induces the production of acute phase protiens

19. Sensing of LPS by TLR4 leads to activation of the
Transcription factor NFkB and the synthesis of
inflammatory cytokines.
First panel: LPS is detected by the complex of TLR4, CD14, and MD2 on the macrophage surface. Second panel: the activated receptor binds the adaptor protein MyD88, which binds the protein kinase IRAK4. IRAK4 binds and phosphorylates the adaptor TRAF6, which leads via a kinase cascade to the activation of IKK. Third panel: in the absence of a signal, the transcription factor NFkB is bound by its inhibitor, IκB, which prevents it from entering the nucleus. In the presence of a signal, activated IKK phosphorylates IκB, which induces the release of NFκB from the complex; IκB is degraded. NFκB then enters the nucleus where it activates genes encoding inflammatory cytokines. Fourth panel: cytokines are synthesized from cytokine mRNA in the cytoplasm and secreted via the endoplasmic reticulum (ER). This MyD88-NFκB pathway is also stimulated by the receptors for cytokines IL-1 and IL-18.

20. TLR4 activation can lead to the production of either inflammatory cytokines or antiviral type I interferons.
TLR4 can stimulate two different intracellular signaling pathways, depending on whether the adaptor protein MyD88 or TRIF is recruited to the activated receptor. TLR4 signaling through TRIF leads to activation of the transcription factor interferon response factor 3 (IRF3) and the production of type I interferons. Signaling through MyD88 leads to activation of the transcription factor NFκB and the production of inflammatory cytokines such as IL-6 and TNF-?. TLR3 also uses the TRIF pathway.

21. TOLL RECEPTOR MEDIATED SIGNALLING
NEW THERAPEUTIC TARGET
Figure 3 The 'hourglass' shape of the innate immune response. Although microbial stimuli are chemically complex and although the innate immune response ultimately involves the activation of thousands of host genes, innate immune signals traverse a channel of low complexity. Ten Toll-like receptors (TLRs), four TIR (Toll/interleukin-1 receptor homologous region) adaptors and two protein kinases are required for most microbial perception. This circumstance lends itself to effective pharmacotherapeutic intervention. NF-B, nuclear factor-B; STAT1, signal transducer and activator of transcription 1.