4th LECTURE Public Health BSc CONNECTING INNATE AND ADAPTIVE IMMUNITY: ANTIGEN PRESENTATION Arpad...
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Transcript of 4th LECTURE Public Health BSc CONNECTING INNATE AND ADAPTIVE IMMUNITY: ANTIGEN PRESENTATION Arpad...
4th LECTUREPublic Health BSc
CONNECTING INNATE AND ADAPTIVE IMMUNITY:
ANTIGEN PRESENTATIONArpad Lanyi
MECHANISM OF DEFENSE IN GENERAL
• environmental changes (e.g. infection)
• recognition (by receptors)
• effector functions (e.g. to get rid of pathogens)
SENSINGRECOGNITION
SIGNALING
RESPONSE
INNATE IMMUNITY
CellsReceptors
Signaling pathwaysCell-Cell
collaboration
Effector functions
DEFENSE SYSTEMS
ADAPTIVE IMMUNITY
SENSINGRECOGNITION
SIGNALING
RESPONSE
EFFECTOR MECHANISMS OF INNATE IMMUNITY
NATURAL KILLER CELLS
PHAGOCYTIC CELLS
COMPLEMENT SYSTEM
PHAGOCYTIC SYSTEMNEUTROPHIL - MACROPHAGE - DENDRITIC CELL
Defense against infectious diseases
Elimination of tumor cellsTransplantation rejection
Gatekeeper functionSensing commensals and pathogensRapid activation of innate immunityPriming adaptive immune responsesMaintenance of self-tolerance
Infections Trauma Physical and Chemical agents (thermal injury, irradiation, chemicals) Tissue Necrosis Foreign bodies (splinters, dirt, sutures) Hypersensitivity or autoimmune reactions
Increased vascular diameter increased flood flow
Increased vascular permeability edema
Migration of leukocytes from the blood to the affected tissue
(diapedesis/extravasation), accumulation, effector functions
MAJOR COMPONENTS OF INFLAMMATION:
TRIGGERS OF ACUTE INFLAMMATION:
ORDER OF INNATE CELLS APPEARANCE IN THE INFLAMED SITE
activating surfaceenzyme
Activating surface required!
inactive precursors limited
proteolysis
COMPLEMENT SYSTEM
THE EFFECTOR FUNCTIONS OF THE COMPLEMENT SYSTEM
1. help inflammatory processes:– increase vascular permeability– recruit leukocytes
2. opsonize pathogens facilitate recognition by innate immune cells
3. direct lysis of pathogens/cells (Membrane Attack Complex – MAC)
SECONDARY LYMPHOID ORGANS/TISSUES
• LYMPH NODES
• SPLEEN
• TONSILS (Waldeyer’s ring)
• Diffuse lymphoid layers under the
epithelial barriers:
– SALT (skin-associated lymphoid
tissue)
– MALT (mucosa-associated lymphoid
tissue)• BALT (bronchus-associated lymphoid tissue)
• GALT (gut-associated lymphoid tissue)
Sites of lymphocyte activation and terminal differentiation
THE MEETING OF INNATE AND ADAPTIVE CELLS
ACTIVATION OF T CELLS
T cells can only recognise antigens that are bound to MHC molecules!
THE OUTCOME OF INFECTION IN A POPULATION WITH POLYMORPHIC MHC GENES
MHC-Gen
vv
vv
vv
v
vv
v
v
v
v
v v v
v
vv
v
vv
v
vv
Example: If MHC X was the only type of MHC molecule
Population threatenedwith extinction
Pathogen that evades MHC
X
MHCXX
Population is protected
MHCI
Displays intracellular antigensto cytotoxic T cells
Peptides of endogenous proteins bind to class I MHC molecules presented to cytotoxic T cells
Tc
Endogenous Ag
RECOGNITION OF ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES
TCR
Peptide
MHCI
APC
MHCI is expressed by all nucleated
cells
STRUCTURE OF CLASS I MHC MOLECULES
A polymorphic α chain and and a non-polymorph β2 mikroglobulin
α1 és α2 domains are responsible for peptide binding
MHC class I accommodatepeptides of 8-10 amino acids
Cleft geometry
MHC class II accommodatepeptides of >13 amino acids
b2-M
a-chain
Peptide
a-chain
b-chainPeptide
• Synthesized antigens – endogenous antigens (virus, tumor)• Internalized antigens – exogenous antigens (any protein)
• Degrade protein antigens to peptides = processing• Protein-derived peptides are presented by MHC (HLA) membrane
proteins antigen presentation
• MHC molecules present both self and non-self protein-derived peptides
• MHC class I molecules are expressed in all nucleated cells• MHC class II molecules are expressed by professional antigen
presenting cells
ANTIGEN PRESENTING CELLS
CYTOSOL-DERIVED PEPTIDES ARE PRESENTED BY MHC-I FOR T-CELLS
Degradation of endogenous proteins takes place in the proteasomes, they are presented on cell surface by
MHC I
MHC do not recognize or distinguish self and nonself peptides
Antigen presentation goes in the absence of pathogen or T cells as well
!
System optimalization 2:
MHCI present the intracellular area. Next step, how could the MHC molecules (and the T cells)
monitor the extracellular enviroment?
a2
a1
b2
b1
PEPTIDE
STRUCTURE OF CLASS II MHC MOLECULES
MHCII
Expressed by professional antigen presenting cellsMacrophage, dendritic cell, B cell
a2
a1
b2
b1
PEPTID PEPTIDE
α1 and β1 domens are responsible for peptide binding
A polymorphic α and a polymorphic β chain
STRUCTURE OF CLASS II MHC MOLECULES
MHC class I accommodatepeptides of 8-10 amino acids
Cleft geometry
MHC class II accommodatepeptides of >13 amino acids
b2-M
a-chain
Peptide
a-chain
b-chainPeptide
Presentation of extracellular peptides by MHCII
Peptides of endogenous proteins (virus, tumor) bind to class I MHC
molecules
Tc
Endogenous Ag
RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES
Exogenous Ag
Th
Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC
molecules
The recognition of the MHC-presented peptide antigen is not enough for T cell activation!
DIFFERENTIATION OF CD4+ T CELLS• The polarization of helper T cell
response is regulated by multiple factors:– origin of the presented peptide– nature of the APC– microenvironment– etc.
• In case of an infection both Th1 and Th2 cells are generated in different sites of the secondary lymphoid organs
• Imbalance occurs in case of special disorers:– Th1 dominance: e.g.
mycobacterial infection– Th2 dominance: e.g. allergy, SLE
cellular,pro-
inflammatory
humoral,anti-
inflammatory