BIOL 520 Advanced
Immunology W2009
BIOL 520 Advanced
Immunology W2009
Lecture 1Overview Immunology
Lecture 1Overview Immunology
Immunology
• Recognition of self and non-self– Antigens
• Elimination of non-self– Exogenous targets
Microbes Allergens Foreign material
– Endogenous targets Tumors
Two Arms of Host Defense
• Innate immunity– Natural immunity– Defense system
functional at birth– Preformed or
available within hours after infection
– Pattern recognition– Widely present in
nature
• Adaptive immunity– Acquired– Available within
days– Specificity– Memory– In higher
vertebrates
Innate Adaptive
Key Players in Immunology
Innate Adaptive
Cells PhagocytesEpithelial Cells
NK Cells
Lymphocytes(B-Ly, T-Ly)
Defense Proteins ComplementAntimicrobial (Poly)Peptides
Antibodies
Most Immune Cells are Found in Blood
Granulocytes
Monocytes
Lymphocytes
Natural Killer Cells
Some Immune Cells are Found in the Tissue
Mast cellsDendritic Cells
Hematopoiesis
Pluripotent Stem Cell
LymphoidProgenitor
GEMMProgenitor
Lymphocytes
NK-Cells
Erythrocytes
Megakaryocyte
Monocyte
Macrophage
Neutrophil BasophilEosinophil
Platelets
B-LyT-Ly
Plasmacell
ActivatedT-cell Dendritic cell
Defense Cells Have Specific Tasks
• Epithelial cells– Barrier (physical,
chemical)– Communcate
• Phagocytes– Ingest– Kill– Digest
• NK-cells– Lyse infected cells or
tumor cells
• B-lymphocytes– Produce antibodies
• T-helper lymphocytes– Strengthen defense
cells to improve their function
– Regulate immune responses
• T-killer lymphocytes– Lyse with specificty
infected cells or tumor cells
Epithelial Cell Defense
TLR
Microbial Products(LPS, PG, etc)
Antimicrobial Peptides
Cytokines
TLR: Toll-like receptor (pattern recognition)LPS: lipopolysaccharidePG: peptidoglycan
Opsonophagocytosis
1. Opsonization2. Attachment3. Engulfment4. Phagosome
formation5. Phagolysosome
formation6. Killing and digestion 1.
2./3.
4. 5.
6.
NK Cell Mediated Killing
• Triggered by two mechanisms– Antibody dependent cytotoxicity– Recognition of altered surface
molecules
• Mediated by:– Perforin
• Pore-forming toxin• Permeabilizes target cell membrane
– Granzyme• Enzyme• Induces apoptosis (cell suicide)
– TNF• Apoptosis
Packaged in
Granules
Recognition of Foreign Material
• Pattern Recognition• Toll Like receptors
– TLR1-10
• All involved in Immune defense– Intracellular region with
homology to IL1 receptor
• Activated directly by microbial products not normally found in host
• Specific antigen recognition
• Antigen Receptor• B cell receptor
– antibody molecule
• T cell receptor– TCR
TLRs and Their Ligands
Intracellular
Extracellular
Cytoplasmic membrane
PeptidoglycanTLR2
Effects of TLR Activation• Cytokine up-regulation and secretion
– Pro-inflammatory cytokines– Chemokines
• Reactive oxygen and nitrogen metabolites
• Antimicrobial peptide production– HBD2
• Up-regulation of surface molecules enhancing adaptive immune responses– Co-stimulatory signals– MHC-II
• Apoptosis
InnateImmunity
AdaptiveImmunity
Basic Structure of an Antibody Molecule
• 2 light and 2 heavy chains
• Disulfide bonds• Hinge region• N-terminus: variable,
antigen binding• C-terminus: constant
region, effector function– 5 isotypes
• IgD, IgM, IgG, IgA, IgE
Basic Functions and Distribution of Antibodies
Functional Activity IgM IgD IgG IgA IgE
Neutralization + - ++ ++ -
Opsonization + - +++
+ -
Sensitization for killling by NK cells
- - ++ - -
Sensitization of mast cells - - + - +++
Complement activation +++ - +++
+ -
Distribution IgM IgD IgG IgA IgE
Transport across epithelium + - - +++
-
Transport across placenta - -- +++
- -
Diffusion into extravascular sites
+/- - ++++
monome
r
T Cell Receptor• 2 chains
– Connected by disulfide bond
– Variable region– Constant region– Short cytoplasmic
tail
• Mostly and chain
• Some specialized T-cells have and chain ( T cells)
T-Cell Antigens
• Short contiguous amino acid (aa) sequence
• Processed antigens– Antigen must have
been unfolded and degraded
– Primary aa structure
• Only when bound to a specialized antigen presenting molecule (MHC)
APC
MHC
T-Ly
TCR Recognizes Antigen Presented by MHC Molecules • MHC: major
histocompatibility complex• First identified in
transplantation immunology • T cells recognize antigen
bound to an MHC molecule • Two types of MHC molecules
– MHC I: presents endogenous peptides
• Virus encoded• Produced by intracellularly
replicating microorganisms• Tumor antigens
– MHC II: presents exogenous peptides
• Uptake through phagocytosis and degradation in phagolysosome
MHC I CTL
MHC II TH
CTL and MHC I TH and MHC II
Apoptosis of Target Cell Immune modulation of target cellTH1, TH2: Activation
TH3: Inhibition
Immune Cells Interact via Cytokines and Surface
MoleculesInnate Adaptive
Cells PhagocytesEpithelial Cells
NK Cells
Lymphocytes(B-Ly, T-Ly)
Defense Proteins ComplementAntimicrobial (Poly)Peptides
Antibodies
Cytokines
• Soluble glycoproteins• ~ 25 kD• Cell to Cell communication
– Autocrine, paracrine,endocrine• Act by binding to specific receptors
– Receptor expression varies– Receptors can be shared by different
cells– Different cells can respond differently
Interleukins
Chem
okin
es
Growth Factors
Cytokines
Antimicrobial Peptides
• Natural peptide antibiotics• Amphiphilic
– Cationic– Hydrophobic
• Microbial killing through membrane permeabilization
+ + +
+ + +
+ + +
Complement
• System of plasma proteins• Activates a cascade of proteolytic
reactions and subsequent protein aggregation on the microbial surface but not on host cell surface
• Coat microbes with a substance that is bound by phagocytes (opsonization)
• Form pores on microbial surfaces triggering killing
• Release small peptides that contribute to inflammation
Lymphatic Tissue
• Central– Bone marrow – Thymus
• Secondary– Spleen– Lymph nodes– GALT (gut associated
lymphatic tissue)• Tonsils• Peyer’s patches• Appendix
Production
Interactionwith Ag
Maturation
Thymus
Immature T-Cells
Mature naive T-Cells
Hassall’s corpuscule
(Cell destruction?)
Bone marrow precursor
Blood stream
Lymph Node
The Spleen
Organization of the Spleen
• White pulpa– Leukocytes
arranged around the blood vessels and sinuses
• Red pulpa:– Blood vessels and
sinuses
• Marginal Zone– Border between
white and red pulpa
Peyer’s Patches
Time Course of the Immune Response
Infection Triggers an Innate Inflammatory Response
Dendritic Cells Initiate Adaptive Immune Responses
Adaptive Immune Responses Augment Innate Immune
Responses
References
• Janeway’s Immunobiology, 7th edition, 2008• Textbook of Hematology, McKenzie, 2nd
edition, 1996• Microbiology: An Introduction; Tortora et al, 8th
edition, 2004• http://www-medlib.med.utah.edu/WebPath/HE
MEHTML/HEMEIDX.html• http://www.siumed.edu/%7Edking2/erg/smallin
t.htm• Primary literature: available per request