Harvard-MIT Division of Health Sciences and Technology
HST.176: Cellular and Molecular Immunology
Course Director: Dr. Shiv Pillai
Innate Immunity
Adaptive Immunity
Invertebrates and vertebrates
Vertebrates
Responses in minutes and
Responses in days and
Hours
weeks
Non-clonal pattern recognition
Clonal antigen receptors
Receptors
Limited diversity and specificity
Mind-boggling diversity
and specificity
No Memory
Memory
"Non-Specific Protection"
- E p it h e lia l s u r f a c e s
- M u c u s
- L y s o z y m e
- D e f e n s in s / o t h e r a n t im ic r o b ia l p e p t id e s - A c i d i n s t o m a c h
- C o m m e n s a l o r g a n i s m s
Innate Immunity
• Secretions: mucus, lysozyme, defensins
• Cells: macrophages, granulocytes, Natural
Killer cells; (also dendritic cells, B-1
and MZ B cells, and γδ T lymphocytes)
• Agglutinins: mannose binding lectin, Creactive protein (and natural IgM
antibodies
• Complement: Alternative pathway, lectin
pathway (and classical pathway for IgM)
Cells that mediate innate immune responses
•
•
CELLS OF MYELOID ORIGIN
– Macrophages
– Granulocytes
• Neutrophils (aka polymorphonuclear leukocytes)
• Eosinophils
• Basophils
– Mast Cells
– Dendritic cells
CELLS OF LYMPHOID ORIGIN
– Natural Killer (NK) Cells
– γδ T cells
– B-1 B cells
– Marginal Zone (MZ) B cells
HSC
E,G,M,L
Erythroid
precursors
and myeloid
and lymphoid
progenitors
G, M, L
Granulocyte
precursors and
monocyte and
lymphoid
progenitors
M, L
B, T,
NK,
(LD)
Platelets
Megakaryocytes
and other
precursors
Erythrocytes
Basophils
Eosinophils
Monocyte
progenitors
and
lymphoid
precursors
Neutrophils/Polymorphs
Monocytes
Pro-B, Pro-T,
Pro-NK cells
B lymphocytes
T lymphocytes
COMMON LYMPHOID PROGENITOR
NK cells
MONOCYTES
TISSUE MACROPHAGES
MAJOR CLASSES OF PATHOGENS
Viruses
Bacteria
Protozoa
Fungi
Worms
SURFACE STRUCTURES OF GRAM POSITIVE BACTERIA
LIPOTECHOIC ACID
TECHOIC ACID
CARBOHYDRATES
PEPTIDOGLYCAN
PLASMA MEMBRANE
SURFACE STRUCTURES OF GRAM NEGATIVE BACTERIA
"O" side chain
Lipid A
}
LPS
OUTER MEMBRANE
PEPTIDOGLYCAN
INNER MEMBRANE
For whom the …..Tolls
• TLR2
• TLR4
• TLR5
• TLR9
peptidoglycans and bacterial
lipoproteins (N-acyl Sdiacylglyceryl cysteine)
Lipopolysaccharide (endotoxin)
Flagellin
Unmethylated CpG DNA
Other PRRs
• F-Met-Leu -Phe receptor
f-Met peptides
– (a serpentine GPCR)
• Mannose receptor
Mannans
• Receptor for Lipotechoic acid
Lipotechoic acid
– (scavenger receptor family)
+
C3
C3b
C3a
Complement inhibitor
C3b COVALENTLY
ATTACHED TO MICROBES
ACTIVATES
ALTERNATIVE
PATHWAY OF COMPLEMENT
MICROBE
HOST CELL
MBL BOUND TO MANNANS INITIATES THE LECTIN PATHWAY
OF COMPLEMENT ACTIVATION
Microbe
Mannose binding lectin
M A S P
MASP2
1
C4b
C4
+ C4a
C2
C2a + C2b
C4b2a
C3b + C3a
C3
C4b2a3b
C5
C5b-9 Membrane Attack Complex
C5b + C5a
C o s t im u la t o r y
lig a n d s
C y t o k in e s
a n d
c h e m o k in e s
P H A G O C YT E
1 . IN C R E
2 . S E C R E
C H
3 . EXP R E
A C T IV A T IO N
A S E D
K IL L I N G
A B IL I T Y
T IO N O F C Y T O K IN E S A N D
E M O K IN E S
S S I O N O F C O S T IM U L A T O R Y
L IG A N D S
Costimulatory ligands
IL-8
IL-1
TNF
1. TNF, IL-1, IL-6 and IL-8 contribute to inflammation
-increased vascular permeability, influx of phagocytes
2. "Acute Phase" response induced via hepatocytes by IL-6
Transcriptional induction of:
Fibrinogen
α -2 macroglobulin
Complement proteins
C-reactive protein
3. TNF and IL-1 can also reset the hypothalamic thermostat and contribute
to an increase in body temperature
IL-6
"DANGER !!!"
NO "DANGER"
ACTIVATION!
No Activation
T Cell
Signal One
Signal Two
Signal One
No Signal Two
TCR
peptide
peptide
MHC
MHC
Dendritic cell
Costimulatory
ligand
For more information and examples, see Immunobiology, by Janeway, C., Travers, P.,
Walport, M. and Capra, J., Garland Publishing, 5th edition, 2001 & Cellular and Molecular
Immunology by Abbas, A., Pober, J., and Lichtman, A., W B Saunders; 4th edition,2000.