4th lecture public health bsc connecting innate and adaptive immunity: antigen presentation
TRANSCRIPT
4th LECTUREPublic Health BSc
CONNECTING INNATE AND ADAPTIVE IMMUNITY:
ANTIGEN PRESENTATION
SinusesTracheaLungs
AIRWAY SYSTEM
EYE
Oral cavityEsophagusStomach
Alimentary tract
GASTROINTESTINAL SYSTEM
DAMAGE TO ANY OF THESE BARRIERS MAY LEAD TO INFECTION
KidneyBladderVagina
UROGENITAL SYSTEM
WALDEYER RINGTonsils, adenoidsPalatinal, pharyngeal lingual and tubar tonsils
SKIN
CONTACT SURFACESPhysical, chemical, microbiological barriers
FIRST LINE OF DEFENSE
PHYSICAL, CHEMICAL AND MICROBIOLOGICAL BARRIERS
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)
Respiratory tract Ciliary movement – constant outward flow Mucus secretion Coughing, sneezing
CF - impaired cilia movement
GI tract Stomach: pH of 3-4; small intestine: pH of 6-8 Digestive enzymes Mucus secretion Antibacterial peptides e.g. defensins, cryptidins Peristalsis, diarrhoea, vomiting Normal flora
H. pylori – making basic pH
Urogenital tract Flushing out Vagina: pH of 3.8-4.5, normal flora
(Lactobacillus lactic acid) Testis: spermin and zink in semen
The normal flora
SKIN, NASO-ORO-PHARYNX, 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
MICROBIOLOGICAL BARRIERS
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
BALANCE!(antibiotics – probiotics)
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
MECHANISM OF DEFENSE IN GENERAL
• environmental changes (e.g. infection)
• recognition (by receptors)
• effector functions (e.g. to get rid of pathogens)
SENSING
RECOGNITION
SIGNALING
RESPONSE
INNATE IMMUNITY
Cells
Receptors
Signaling pathways
Cell-Cell collaboration
Effector functions
DEFENSE SYSTEMS
ADAPTIVE IMMUNITY
SENSING
RECOGNITION
SIGNALING
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
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
Mannose
Eukaryotic cells
Glucoseamin
Mannose
Galactose
Sialic acid
EXAMPLE FOR PAMP: MANNOSE
Prokaryotic cells
protein glycosylation is different in:
Macrophage/dendritic cells
Mannose Receptor
Mannose
MANNOSE RECEPTORS IS A PRR EXPRESSED ON THE SURFACE OF PHAGOCYTES
Bacterium
PHAGOCYTOSIS
INNATE IMMUNITYPathogen recognition PRRs (TLRs, lectins, NLRs, RLRs, scavenger receptors)
Cell activation Macrophage: phagocytosis, intracellular killing (reactive oxygen species (ROS), lysosomal enzymes), secretion of chemokines and cytokines (via gene activation)
Antigen processing Phagocytosis/endocytosis degradation in phagolysosomes
Antigen presentation (later)
ACUTE INFLAMMATION
A rapid response to an injurious agent that serves to deliver leukocytes and plasma proteins to the site of injury
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
RESOLUTION OF ACUTE INFLAMMATION
THE TYPE I INTERFERON RESPONSE: ANTIVIRAL STATE
plasmacytoid dendritic cells
Plasmacytoid dendritic cells (pDCs) produce 1000x more type I interferon than other cells (Natural Interferon Producing Cells – NIPC)
After viral infection they are accumulated at the T cell zone of the lymph nodes
NK CELLS
Similar functions to cytotoxic T cells but:
• larger than lymphocytes• no rearranged antigen-
specific receptors• contain large cytoplasmic
granules• respond fast, circulate in
a partly activated state
RECOGNITION AND KILLING BY NK CELLS
Contents of lytic granules:
• Perforin: forming pores in the target cell membrane lysis
• Granzyme: inducing apoptosis in the target cell
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)
PRIMARY (CENTRAL) LYMPHOID ORGANS
Places of the maturation (antigen-independent development) of lymphocytes:
• bone marrow: generation of lymphoid progenitors, maturation of B cells
• thymus: maturation of T cells (and NK cells)
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
SLO: 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
• 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
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
Golgi
ER
citoplazma
THE ENDOGENOUS ANTIGEN PROCESSING PATHWAY
Tc
ProteasomeLMP2/LMP7
Intracellular PROTEINS
TAP1/2gp96 calnexin
α-chain
α-chain+β2m MHC+peptide
MHC-I + Ag peptide
MHC-I +self peptide
CLOSEDFLEXIBLEcytoplasm
MHC-I, LMP2/7, TAP
IFN induced coordinated expression
Golgi
ER
CLIP
MCII
CIIV
DMA/B
li
M H C IIli
Th
INVARIANT CHAIN (Ii)
1. Chaperone – conformation
2. Inhibition of peptide binding
3. Transport/retention
CLOSEDFLEXIBLEIi+αβ
CLIP
DMA/B
DMA/DMB
1. Support the peptide receptive conformation
2. Exchange of CLIP for exogenous peptides
MHC-II + Ag peptide
MHC-II +self peptide
THE EXOGENOUS ANTIGEN PROCESSING PATHWAY
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