Lectures 10 (linked to 12) Cytokines and Immune Response September 17 & 24, 2004 Chris Schindler
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Transcript of Lectures 10 (linked to 12) Cytokines and Immune Response September 17 & 24, 2004 Chris Schindler
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Lectures 10 (linked to 12)Cytokines and Immune Cytokines and Immune
ResponseResponse
September 17 & 24, 2004
Chris [email protected]
Reading: Janeway - as indicatedAbbas - Chapter 11
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Blood: 4-10,000 WBC per 1 L
How did they get there?Where are they going?What regulates them?
Think Cytokines, Growth Factors & Chemokines!!!!
Lymphocytes - 10-15 %
(T-, B- & NK cells)
Monocytes - 0-15 %
(Macs & DCs)
Granulocytes - 35-80 %
PMNs35-80 %
Eos0-8 %
Basos0-2 %
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• Small (10-30 kDa) secreted peptides (usually glycosylated).
• They bind to specific receptors on target cells to elicit a specific biological response.
• Expression of cytokines and their receptors is usually tightly regulated.
• Other more anachronistic terms include monokines and lymphokines.
What are cytokines and chemokines?
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• They direct the development, maturation, localization, interactions, activation and life span of immune cells.
• Thus they play an essential role in regulating immunity (adaptive and innate).
What do cytokines, chemokines and growth
factors do?
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• Growth Factors (e.g., CSF-1, SCF) • IL-1 Family (e.g., IL-1, IL-18 & “Toll-like”) • TNF Family (e.g., TNF-, CD40L, FasL, LT-) • TGF- Family (e.g., TGF- ) • Chemokines (e.g., CC and CXC families)• Hematopoietins / a.k.a. Four Helix Bundle
(e.g., IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, GM-CSF, IFN-, IFN-/)
• Also steroid hormones and prostaglandins
How many flavors regulate immunity?
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• There are functional similarities within ligand families (see summary).
• There are important functional differences between ligand familes (see summary).
• These functional characteristics are determined by the class of receptors these ligands bind.
• These ligands function at three distinct ranges:– Autocrine*– Paracrine*– Endocrine*
*Make sure you have an example of each
Other important facts about Cytokines, Chemokines & Growth
Factors
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• Properties of cytokines and chemokines.Pleiotropism - activate numerous types of responses, e.g., differentiation,
growth, activation and chemotaxis. Redundancy - i.e., functional overlap.Synergy - between cytokines to maximize a response. *Antagonism - to regulate duration and potency of response. It is critical
to maintain a delicate balance to avoid autoimmunity.
• Innate vs. Adpative ImmunityInnate Immunity
Per-wired first line of defense (more primitive)Recognizes ~103 pathogen derived molecules (analogous to antigens)Most important during initial minutes and hours of infectionMacrophages, Granulocytes and NK cells
Adaptive ImmunitySecond, but very potent line of defenseAntigen specific response - recognizes ~107 antigensConstitutes immunological memory for specific antigensT-cells and B-cells
Additional important concepts
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• The innate response is often quite effective
• The subsequent adaptive immune response is important for many viral pathogens and very important for immunization strategies
Cytokines and the innate response to a viral infection
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Innate Viral Interfering Activity is Discovered in Cultured Cells
(1950s)
X
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Fractionating Viral Interfering Activity Leads to the Discovery of Interferons
(IFNs)
Leukocyte IFNsFibroblast IFNImmune IFN
• a.k.a IFN-’s• most prevalent• made by all cells• > 10 members
• a.k.a IFN-• very potent• made by all cells• only one member
• a.k.a IFN-• critical for adaptive Immune• made by T-cells & NK cells• only one member
Type II IFN Type I IFN
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P
STAT1
STAT1
P
P
P
P
P
P
inflammation*macrophage act.*chemokines*IRF1 (antiviral transcription factor)
MIG (a chemokine)
GBP (anti-viral protein)
iNOS (nitric oxide synthase)
CIITA (transcription factor that induces MHC)
Type II IFN Signaling Paradigm
Gamma-activated sequence
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Figure 6-23
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Figure 2-48
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Figure 2-49
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Identification of “High IFN Producing Cells” (HIPCs) in vivo
A small subset of WBCs produce most of the circulating IFN-Is
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Cytokines and the innate response to a skin infection
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Figure 2-3
Wound Infection: Innate Adaptive
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Figure 2-5 part 1 of 2
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Figure 2-8 part 1 of 2
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Figure 2-39
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Figure 2-15
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QuickTime™ and aGIF decompressor
are needed to see this picture.
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• Injection of LPS (a molecular pattern molecule found on G- bacteria) is a model system for sepsis.
• The host response to sepsis is often referred to as the Acute Phase Response (APR).
Cytokines and the response to sepsis
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Local vs. systemic infection
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TLR-4 and company enable macrophages to sense and respond to LPS (to be covered in detail in a later lecture)
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Figure 2-39
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Serum cytokine production (from Macrophages) during Septic Shock
Hours after LPS injection
Seru
m C
yto
kin
e L
evel
TNF-
o 1 3 6
IL-1 IL-12
Note, this is one of the few times you can meaningfully measure serum cytokine levels!!
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Figure 2-46
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IL-4 TNF- Trimer
TNF Monmer/Receptor MonomerFig. 2-38 IL4/IL4 Receptor
IL-4 & TNF- and their corresponding receptors, are in two different families and have two distinct types of structures.
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Top half of Fig. 2-47
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V. Cytokines you need to know
IL-2 (big family e.g. IL-7 & IL-15)IL-4 (small family inc. IL-13)IL-6 (large family inc. G-CSF)IL-10 (growing family)IL-12 (small family inc. IL-23)IFN- IFN- (large family)
IL-1IL-18
LT-TNF-CD40LFasL
TGF- (very large family)
Chemokines (see Fig. 11.6)InflammatoryNon-inflammatory
See Figs. 11.1 (p244), 11.2 (p245), 11.3 (p248) Tables 11-3 (p249), 11.4 (p264) in Abbas
Innate Adaptive
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Type I & IICytokine Receptors
(Hematopoietin R.)
Toll (TLR) /IL-1Receptors
TNF RelatedReceptors
TGF-Receptors
ChemokineReceptors
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