Download 2nd seminar - Innate immunity, inflammation 2015

2ND SEMINAR
BASIC CONCEPTS OF INNATE
IMMUNITY,
INFLAMMATION
CONTACT SURFACES
Physical, chemical, microbiological barriers
EYE
SKIN
AIRWAY SYSTEM
WALDEYER RING
Tonsils, adenoids
Palatinal, pharyngeal
lingual and tubar tonsils
Sinuses
Trachea
Lungs
GASTROINTESTINAL
SYSTEM
Oral cavity
Esophagus
Stomach
Alimentary
tract
UROGENITAL SYSTEM
Kidney
Bladder
Vagina
DAMAGE TO ANY OF THESE BARRIERS
MAY LEAD TO INFECTION
FIRST LINE OF DEFENSE
PHYSICAL, CHEMICAL AND
MICROBIOLOGICAL BARRIERS
GI tract
 Stomach: pH of 3-4; small intestine: pH of 6-8
 Digestive enzymes
 Mucus
 Antibacterial peptides e.g. defensins, cryptidins
 Peristalsis, diarrhoea, vomiting
 Normal flora
H. pylori – making basic pH
Skin
 Tight junctions
 Keratin layer
 Antibacterial peptides e.g. defensins
 pH of 5.5
 Fatty acids
 Normal flora
Burns  susceptibility to infections
Eye
 Tear film (oils, lactoferrin, mucin and lysozyme)
Urogenital tract
 Flushing out
 Vagina: pH of 3.8-4.5, normal flora (Lactobacillus 
lactic acid)
Respiratory tract
 Ciliary movement – constant
outward flow
 Coughing, sneezing
CF - impaired cilia movement
MICROBIOLOGICAL BARRIERS
The normal flora
SKIN, NASO-ORO-PHARYNGS, GUT, VAGINA
Symbiotic, non-pathogenic microbes, living in „peaceful” commensalisms
Beneficial features:
• Digesting non absorbable food compounds e.g. cellulose
• Producing vitamines, antimicrobial molecules, regulating pH
• Compete with pathogenic microbes – survival of the fittest
• Providing constant low-dose antigen exposure
• Helping the development of the immune system
• Maintainig tolerance
BALANCE!
(antibiotics – probiotics)
Some facts about the normal flora:
•
•
•
•
There are 100-times more bacterial genes than eukaryotic genes
Cells of human body: 90% microbes, 10% human
Gut bacteria: 1014 - more than 500 microbial species (approx. 1.5 kgs)
Human cell population: 1013
Gut normal flora play an important role in:
- Development of mucosal and systemic immunity
- Normal development of peripheral lymphoid organs
- Maintenance of basic level of immunity
ORGANIZATION OF IMMUNE CELLS UNDER EPITHELIAL SURFACES
Epithelial
cells
Stroma cells
Dendritic cell
NK cell
NKT cell
DC
Granulocyte
Macrophage
PERIFÉRIÁS
TISSUE–SPECIFIC CELLULAR COMMUNICATION NETWORKS
SZÖVETEK
RECOGNITION
BY THE INNATE IMMUNE SYSTEM
DEFENSE SYSTEMS
ADAPTIVE IMMUNITY
INNATE IMMUNITY
SENSING
Cells
SENSING
RECOGNITION
Receptors
RECOGNITION
SIGNALING
Signaling
pathways
SIGNALING
Cell-Cell
collaboration
RESPONSE
Effector
functions
RESPONSE
RECOGNITION RECEPTORS
OF INNATE IMMUNITY
• Pattern Recognition Receptors (PRRs)
– recognise molecular patterns as danger signals
– can be classified as PRR families:
•
•
•
•
•
Lectins
Toll-Like Receptors (TLRs)
Nod-Like Receptors (NLRs)
RIG-Like Receptors (RLRs)
Scavenger receptors
• molecular pattern: characteristic molecules that are expressed in
high amounts by cells or microbes
– Patogen-Associated Molecular Patterns (PAMPs): molecules that are expressed
unlike human cells, usually essential for the survival or replication of pathogens
– Damage-Assoiated Molecular Patterns (DAMPs): molecules released after
cellular damage
TOLL-LIKE RECEPTOR FAMILY
DANGER SIGNALS ARE TRANSLATED TO CYTOKINE SECRETION
THROUGH VARIOUS MOLECULAR SENSORS IN DC SUBTYPES
4
2
5
3
1
6
6
1
7
NLR
8
7 9 10
RLR
RLR
Conventional DC
IL-1β
IL-12/23
IL-10
Plasmacytoid DC
TLR1 – bacterial lipoprotein (together with TLR2)
TLR2 – bacterial lipoprotein, peptidoglycane, lipoteicholic acid
(heteromer with TLR1 and TLR6)
TLR3 – viral dsRNA
TLR4 – bacterial LPS
TLR5 – bacterial flagellin
TLR6 – bacterial lipoprotein (together with TLR2)
TLR7 – viral ssRNA
TLR8 – viral ssRNA
TLR9 – unmethylated CpG DNA
TLR10 – modified viral nucleotides
NLRs – microbial products, DAMPs
RLRs – viral ssRNA
IFNα
IFNβ
EFFECTOR MECHANISMS OF INNATE IMMUNITY
KILLER CELLS
PHAGOCYTIC CELLS
COMPLEMENT SYSTEM
PHAGOCYTIC SYSTEM
NEUTROPHIL - MACROPHAGE - DENDRITIC CELL
Gatekeeper function
Sensing commensals and pathogens
Rapid activation of innate immunity
Priming adaptive immune responses
Maintenance of self-tolerance
Defense against infectious
diseases
Elimination of tumor cells
Transplantation rejection
RECEPTORS ON MACROPHAGES
Scavanger receptor
Mannose receptor
FcRI (CD64)
Ag + Ab
complex
TLR4 + CD14
MHCI
TLRs – PAMPs
FcRII (CD32)
MHCII
FcRIII (CD16)
LFA1 (CD11a/CD18)
Cell adhesion
molecules
CR1 (CD35)
CR3 (CD11b/CD18)
Complement
receptors
GLYCOSYLATION OF PROTEINS IS DIFFERENT IN
VARIOUS SPECIES
Prokaryotic cells
Eukaryotic cells
Mannose
Glucoseamin
Mannose
Galactose
Sialic acid
MANNOSE RECEPTORS ON PHAGOCYTES
Bacterium
Mannose
Mannose Receptor
Macrophage/dendritic cells
PHAGOCYTOSIS, RECOGNITION RECEPTORS, SIGNAL
TRANSDUCTION, EFFECTOR MECHANISM
Pattern recognition
Receptors (PRR)
UPTAKE
Macropinocytosis
Receptor-mediated
endocytosis
Phagocytosis
COLLECTION OF
ENVIRONMENTAL
INFORMATON
Engagement of PRR
triggers phagocytosis
and cytokine
production
PHAGOCYTOSIS
INNATE IMMUNITY
Pathogen recognition
 PRRs (TLRs, lectins, NLRs, RLRs, scavenger receptors)
Cell activation
 Increased phagocytic activity, intracellular killing (reactive oxygen
species (ROS), lysosomal enzymes), chemokine and cytokine
secretion
Antigen processing
 Phagocytosis/endocytosis  degradation in phagolysosomes
Antigen presentation (later)
ACUTE INFLAMMATION
&
ACUTE-PHASE RESPONSE
ACUTE INFLAMMATION
A rapid response to an injurious agent that serves to deliver
leukocytes and plasma proteins to the site of injury
TRIGGERS OF ACUTE INFLAMMATION:






Infections
Trauma
Physical and Chemical agents (thermal injury, irradiation, chemicals)
Tissue Necrosis
Foreign bodies (splinters, dirt, sutures)
Hypersensitivity or autoimmune reactions
MAJOR COMPONENTS OF INFLAMMATION:
1.
Vascular response:

Increased vascular diameter  Increased flood flow.

Endothelial cell activation

increased permeability that permits plasma proteins and leukocytes to leave the
circulation and enter the tissue  edema

increased expression of cell adhesion molecules e.g. E-selectin, ICAM
2.
Cellular response:

Migration of leukocytes (diapedesis/extravasation), accumulation, effector functions
THE CLASSIC SYMPTOMS OF INFLAMMATION:
•
•
•
•
•
Redness (rubor)
Swelling (tumor)
Heat (calor)
Pain (dolor)
Loss of function (functio laesa)
Resident phagocytes get activated by PRR signalization upon
recognition of danger signals 
• Production of cytokines and chemokines,
• Intracellular killing,
• Antigen presentation (activation of adaptive responses)
ORDER OF INNATE CELLS APPEARANCE IN THE INFLAMED SITE
NEUTROPHIL GRANULOCYTES
• 68% of circulating leukocytes, 99% of circulating
granulocytes
• Phagocytic cells
• Are not present in healthy tissues
• Migration  elimination of pathogens (enzymes, reactive
oxygen intermediates)
• Main participants in acute inflammatory processes
NEUTROPHIL CHEMOTAXIS
MIGRATION OF NEUTROPHILS
Neutrophil Transendothelial Migration (Diapedesis)
Pathogens activate macrophages to release cytokines and are
then phagocytized and digested in phagolysosomes
CHEMICAL MEDIATORS
Local effect
&
systemic effect
CHEMICAL MEDIATORS
 Vasodilation
– Prostaglandins (PG), nitric oxide (NO)
 Increased vascular permeability
– vasoactive amines (histamine, serotonin), C3a and C5a
(complement system), bradykinin, leukotrienes (LT), PAF
 Chemotactic leukocyte activation
– C3a, C5a, LTB4, chemokines (e.g. IL-8)
 Fever
• IL-1, IL-6, TNFα, PGE2
 Pain
• Prostaglandins, bradykinin
 Tissue damage
• Neutrophil and Macrophage products
– lysosomal enzymes
– Reactive oxygen species (ROS)
– NO
NSAIDs and Paracetamol:
inhibiting COX-1 and COX-2
 preventing the synthesis
of prostaglandins
ACUTE-PHASE RESPONSE PROTEINS
Pentraxin family:
CRP – opsonization, complement activation
SAP – opsonization, complement activation,
binding of mannose/galactose
Collectin family:
SP-A/D – collectins of lungs
MBL – part of complement system
During an APR their concentration
increases
up to x1000
Complement proteins
(C1-C9)
Fibrinogen – blood clotting
RESOLUTION OF ACUTE INFLAMMATION