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Transcript
INNATE IMMUNITY I
Innate immunity
•Cells, components and their functions
•Recognition
•Killing
•Other effector functions
Innate immunity
•Cells, components and their functions
• Monocytes/ Macrophages
• Dendritic cells
• Granulocytes
• NK cells
• Mast cells
• Complement components
•Recognition
•Killing
•Other effector functions
WHITE BLOOD CELLS IN THE SMEAR OF HUMAN
PERIPHERAL BLOOD
neutrophil
granulocyte
eosinophil
granulocyte
MONOCYTE
neutrophil
granulocyte
LYMPHOCYTE
basophil
granulocyte
LYMPHOCYTE
MONOCYTES
- origin: pluripotent cells of the bone marrow
myeloid progenitors
-size: 10-15 µm
- nucleus: bean-shaped
-localization: circulation
out of circulation: macrophage
TISSUE - VENTRICLE
MACROPHAGES
-
phagocytic cells
antigen presenting cells (APC)
main types (based on tissue localization):
a) microglia (brain)
b) Kuppfer-cells (liver)
c) histiocytes (connective tissue)
d) osteoclasts (bone)
e) alveolar macrophages (lung)
- function: in cellular and humoral immun response
One of the cells which initiate the immune response
DENDRITIC CELLS
-
origin: myeloid or lymphoid progenitors
-
localization: the immature dendritic cell migrates from the circulation
into the tissues and upon pathogen uptake it differentiates to a mature
dendritic cell and migrates to the draining lymph node and transports
the antigen from the periphery to the secondary lymphatic organs
- DCs are professional antigen presenting cells (APC)
- One of the cells which initiate the immune response
-
types :
a) myeloid DCs: - Langerhans cells (mucosa, skin)
- intersticial DCs (liver, spleen, etc.)
b) lymphoid DCs: - thymic DCs
- plasmacytoid DCs (pDC)
NEUTROPHIL GRANULOCYTES
- highest number in blood (68% of circulating leukocytes,
99% of circulating granulocytes)
- phagocyting cells
- They are not present in healthy tissues, only in the blood
circulation
- tissue damage, migration, elimination of pathogens
(enzymes, reactive oxygen intermediers)
- main participants in inflammatory processes
BASOPHIL GRANULOCYTES
-1% of circulating leukocytes
- large granules in the cytoplasm
- nucleus with 2 lobes
- mast cells, histamin, allergic reactions
- high affinity IgE receptors
- against parasites
EOSINOPHIL GRANULOCYTES
- against parasites
- 2-3% of leukocytes
- allergic reactions
MAST CELLS
-origin: pluripotent cells of the bone marrow
myeloid progenitors
localization: - absent in circulation
- differentiate in tissues
- especially around small vessels
- function: - upon activation they regulate the permeability of the vessels with
their secreted molecules
- native and adaptive immunity
- allergic reactions,
- IgE receptors (cell surface)
-against parasites
-histamin production
NK CELLS
(natural killer)
- origin: - pluripotent cells of the bone marrow
lymphoid progenitors
- bigger than lymphocytes
- several granules in their cytoplasm
- have no antigen binding receptors („null cells”)
- participants of native immunity
Professional phagocytic cells
macrophages
neutrophyl granulocytes
dendritic cells
• the phagocytosed cells or molecules may modify
the functions of the cell
• phagocytosis followed by enzymatic degradation
Professional antigen presenting cells
macrophages
B lymphocytes
dendritic cells
• they express MHCII molecules
• the protein degradation products (peptides) can be presented
to T lymphocytes by MHC molecules
The localization of blood cells
NK cells
Macrophage, dendritic cell – act as TISSUE SENSORS
Neutrophil granulocytes, complement, NK cells – migrate
from the blood to the SITE OF INFECTION
Cells of the innate immune system:
Macrophages:
Macrophages are constitutively present in tissues and recognize microbes that enter
these tissues and respond rapidly to these microbes. They initiate the immune response.
•These cells are phagocytes (eliminate the pathogens)
•Activate the innate immune response (by secreted proteins, called cytokines)
•Activate the adaptive immune system. Macrophages serve as APCs that display
antigens and activate T lymphocytes
•Dendritic cells
are constitutively present in tissues and recognize rapidly microbes that enter these
tissues. Initiate the immune response.
•They have phagocytic capabilities,
migrate to lymph nodes, and display microbial antigens to T lymphocytes,professional
antigen presenting cells (APC)
Neutrophil granulocytes
are phagocytes, their main function is to eliminate the pathogens
They appear only in the circulation under normal condition.
Main actors in inflammatory processes.
THE TWO ARMS OF THE IMMUNE SYSTEM
Monocytes, Macrophages,
Monocytes, Macrophages,
Dendritic cells, Granulocytes, NK
Dendritic cells, Granulocytes, NK
cells and Complement components
cells and Complement components
B and T cells
Innate immunity
•Cells, components and their functions
•Recognition
•Pattern recognition (PAMP)
•Danger signal (DAMP)
•NK cell
•Opsonization
•Killing
•Other effector functions
Innate immunity
•Cells, components and their functions
•Recognition
•Pattern recognition (PAMP)
•Danger signal (DAMP)
•NK cell
•Opsonization
•Killing
•Other effector functions
Innate immunity
as a first line of defense
Innate immune cells recognize frequently found
structures of pathogens,
these are not found in human cells!
Examples: duple stranded RNA
bacterial cell wall components
bacterial flagellin….
Recognition is inevitable
monocytes, macrophages, dendritic cells, granulocytes
(NK cells, T cells, B cells, somatic cells)
PAMP Pathogen-associated molecular patterns
PRR Pattern recognition receptors
PAMPs- Pathogen associated molecular patters
Structures on pathogens recognized by the innate cells
Recognition is mediated by several PRR receptor families with
overlapping functions
PRR types
TOLL
RIG
like receptors
NOD
Scavenger receptors
C-type lectin receptors
Mannose recognizing receptors
Intracellular and extracellular receptors
Some type of PRRs:
Protein glycosilation is highly differnt in species
Eukaryotes
Prokaryotes
Mannose
Glucosamine
Galactose
Siallic acid
Mannose
Phagocytes express mannose receptors
Mannose
Bacterium
Mannose receptors
Macrophage / Dendritic cell
Innate immunity
•Cells, components and their functions
•Recognition
•Pattern recognition (PAMP)
•Danger signal (DAMP)
•NK cell
•Opsonization
•Killing
•Other effector functions
Danger signal
Danger signal!
The innate immune system also recognizes molecules that are released from
damaged or necrotic cells. Such molecules are called damage-associated molecular
patterns (DAMPs).
Innate immunity
•Cells, components and their functions
•Recognition
•Pattern recognition (PAMP)
•Danger signal (DAMP)
•NK cell
•Opsonization
•Killing
•Other effector functions
Killing of the cells infected with intracellular pathogens
1. The activity of NK cells is
enhanced by activatory
receptors
2. Inhibitory receptors block
NK cell activity. Self cells lysis
are protected by inhibitory
receptors.
KAR
3. Infection or tumors may
increase the amount of
activation and/or
decrease the efficacy of
inhibition
Target
MHC+
Target
MHC-
Inhibition of
lysis
KIR
NK
KAR
KIR
NK
KIR –Inhibitory Receptor of NK
cells, association to MHC I
KAR –Activatory Receptor of NK
cells
Innate immunity
•Cells, components and their functions
•Recognition
•Pattern recognition (PAMP)
•Danger signal (DAMP)
•NK cell
•Opsonization
•Killing
•Other effector functions
OPSONIZATION
Opsonization facilitates and accelerates the recognition of the pathogen by phagocytes.
Opsonins form a bridge and connect the pathogen with the phagocyte.
Main opsonins:
• Antibodies
• Complement fragments
• Acute-phase proteins
Pathogen recognition by innate immune system
1. Directly via PRR
2. Indirectly via opsonization
Innate immunity
•Cells, components and their functions
•Recognition
•Killing
•Phagocytosis
•Soluble mediators
•Complement system
•NK cells
•Other effector functions
Professional phagocytic cells
MACROPHAGES
DENDRITIC CELLS
NEUTROPHILS
PHAGOCYTOSIS
MACROPHAGE – killing, antigen presentation
DENDRITIC CELLS – antigen presentation
NEUTROPHIL GRANULOCYTE – killing
PRR
Degradation
ACTIVATION
Bacterium
Phagocyte
Uptake
Intracellular killing
0.5 - 1 hours
The amount of internalized
particles is limited
Antigen presentation
T cell
ACQUIRED IMMUNITY
Innate immunity
•Cells, components and their functions
•Recognition
•Killing
•Phagocytosis
•Soluble mediators
•Complement system
•NK cells
•Other effector functions
Soluble mediators
• are released mainly from macrophages and granulocytes
• are responsible for killing of extracellular pathogens
• ROS - reactive oxigen species
• NO - nitric oxide
• destructive enzymes
• antimicrobial substances
Innate immunity
•Cells, components and their functions
•Recognition
•Killing
•Phagocytosis
•Soluble mediators
•Complement system
•activation
•function
•NK cells
•Other effector functions
Initiation of complement response
1.Alternative pathway - constitutively active - inhibited by self structures
2.Classical patway - activated by antibodies/immuncomplexes
3.Lectin pathway - mannose binding lektin (MBL) or – acute-phase
protein activates it
THE FUNCTION of COMPLEMENT
SYSTEM
• The complement system is a set of
plasma proteins that act in a cascade
•
•
•
•
to attack and kill extracellular pathogens
to recruit inflammatory cells
to opsonizate pathogens
to remove immunecomplexes
Human cells are protected by several cell surface and
soluble complement inhibitors
Immunocomplex
Complement proteins
ACTIVATION OF THE COMPLEMENT SYSTEM
COMPLEMENT SYSTEM
CLASSICAL PATHWAY
MB-LECTIN PATHWAY
ALTERNATIVE PATHWAY
COMPLEMENT ACTIVATION
RECRUITMENT OF
INFLAMMATORY CELLS
OPSONIZATION OF
PATHOGENS
DIRECT KILLING OF
PATHOGENS
FACILITATING
PHAGOCYTOSIS
Immunecomplex removal
MEMBRANE ATTACK COMPLEX (MAC)
MAC in the cell membrane
live
and
bacteria
dead
Innate immunity
•Cells, components and their functions
•Recognition
•Killing
•Phagocytosis
•Soluble mediators
•Complement system
•NK cells
•Other effector functions
ACTIVATION OF NATURAL KILLER CELLS
NK-CELLS
PRR
Virus-infected
cell
RECOGNITION
ACTIVATION
Lysis of infected cell
RECOGNITION OF
ALTERED HOST CELLS
NK cell kill infected cells or tumors by secreted toxic
garnules or by activation of death receptors
Killing of the cells infected with intracellular pathogens
1. The activity of NK cells is
enhanced by activatory
receptors
2. Inhibitory receptors block
NK cell activity. Self cells lysis
are protected by inhibitory
receptors.
KAR
3. Infection or tumors may
increase the amount of
activation and/or
decrease the efficacy of
inhibition
Target
MHC+
Target
MHC-
Inhibition of
lysis
KIR
NK
KAR
KIR
NK
KIR –Inhibitory Receptor ,
association to MHC I
KAR –Activatory Receptor
Adaptive components are also able to activate NK cells
ADCC-Antibody Dependent Cell Cytotoxicity
Activating NK cells through FcR on NK cells recognizing pathogen-bound
Antibodies
Innate immunity
•Cells, components and their functions
•Recognition
•Killing
•Other effector functions
• Acute inflammation
• Localized effects
• Systemic effects
•anti-viral response (interferons)
•opsonization
•antigen prezentation
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
Recognition of PAMP or DAMP induce inflammation
Autocrine and paracrne effect:
Vasodialtion
Increased vascular permeability
extravasation
Endocrine effect:
Brain---fever
Liver---acute phase
reaction
Bone marrow– more
intense cell production
Innate immunity
•Cells, components and their functions
•Recognition
•Killing
•Other effector functions
•acute inflammation
•anti-viral response (interferons)
•opsonization
•antigen prezentation
Crucial factors of
anti-viral response
1.
Type I. Interferons
2.
NK cells
3.
Cytotoxic T cells
4.
Neutralizing antibodies
VIRUS INDUCED TYPE I INTERFERON PRODUCTION
Type I IFN receptor
IFN response
Virus
IFN-
IRF-3
NFB
AP-1
IRF-3
IFN-
paracrine
IFN-
IRF-7
autocrine
Infected cell
IFN response
IFN-
subtypes
IRF: interferon regulatory factor
Induction of interferons
virus-infected cell will release interferons causing nearby
cells to heighten their anti-viral defenses.
are produced by different (~all) cell types usually in
response to the entry of a virus, which has the property of
inhibiting virus replication
Az anti-virális válasz legfőbb összetevői:
1. I-es típusú interferonok
2. NK sejtek
3. Citotoxikus T-sejtek
4. Neutralizáló ellenanyagok
Crucial factors of
anti-viral response
1.
Type I. Interferons
•
Inhibition of RNA Synthesis
•
Inhibition of protein synthesis
•
RNA degradation
•
degradation of viral proteins
1.
NK cells
2.
Cytotoxic T cells
3.
Neutralizing antibodies
EFFECTS OF TYPE I INTERFERONS
vírus
Plasmacytoid dendritic cells produce 1000x more type I interferon than other cells
NATURAL INTERFERON PRODUCING CELLS – IPC
After viral infection they are accumulated at the T cell zone of the lymph nodes
Crucial factors of
anti-viral response
1.
Type I. Interferons
2.
NK cells
3.
Cytotoxic T cells
4.
Neutralizing antibodies
Most important cytocines:
• Inflammatory cytokines: IL1, IL6, TNFα, IL12, IL8
(chemokine)
• Anti-viral cytokine: IFNα, IFNβ
Innate immunity
•Cells, components and their functions
•Recognition
•Killing
•Other effector functions
•acute inflammation
•anti-viral response (interferons)
•opsonization
•antigen presentation
OPSONIZATION
Opsonization facilitates and accelerates the recognition of the pathogen by phagocytes.
Opsonins form a bridge and connect the pathogen with the phagocyte.
Main opsonins:
• Antibodies
• Complement fragments
• Acute-phase proteins
Innate immunity
•Cells, components and their functions
•Recognition
•Killing
•Other effector functions
•Acute inflammation
•Anti-viral response (interferons)
•Opsonization
•Antigen presentation
Professional phagocytic cells
macrophages
neutrophyl granulocytes
dendritic cells
Professional antigen presenting cells
macrophages
B lymphocytes
dendritic cells
they express MHCII molecules
the protein degradation products (peptides) can be
presented to T lymphocytes by MHC molecules