lecture 3 inflammation and tolerance : generated

Cytokine

A signal from noncovalent binding of a ligand to a cell-bound receptor.

Cytokine signaling result

Often changes the target cell's transcriptional program.

Why can cytokines act at low concentrations?

They have high affinity for their receptors.

Pleiotropy

One cytokine causing different effects on different target cells.

Redundancy

Different cytokines causing a similar effect on the same target cell.

Synergy

Two cytokines together producing a greater-than-additive effect.

What is an example of cytokine synergy?

IL-4 + IL-5 inducing class switch to IgE.

Antagonism

One cytokine blocking another cytokine's effect.

What is an example of cytokine antagonism?

IFN-γ blocking IL-4-induced class switch to IgE.

Cascade induction

One cytokine causing a target cell to produce additional cytokines.

Endocrine signaling

Cytokine secreted into blood, acts on distant cells.

Paracrine signaling

Cytokine secreted, acts on nearby/adjacent cells.

Autocrine signaling

Cytokine acts back on the same cell that secreted it.

Juxtacrine signaling

Signal stays membrane-attached and contacts an adjacent cell's receptor directly.

What can cytokines change about a target cell's localization?

Expression of adhesion and chemokine receptors.

What are the four broad effects cytokines can have on target cells?

Move, change gene expression/proliferate, survive or die, turn on defenses.

Basic inflammatory response step 1

Injury releases chemical signals and activates macrophages.

What do activated macrophages release early in inflammation?

Cytokines and vasodilators.

Basic inflammatory response step 2

Fluid, complement proteins, and clotting elements are released.

Basic inflammatory response step 3

Chemokines attract neutrophils and macrophages to the site.

Basic inflammatory response step 4

Neutrophils and macrophages phagocytose microbes.

What do complement fragments C3a and C5a do in inflammation?

Act as inflammatory mediators.

Which cell releases histamine in inflammation?

Mast cells.

What does histamine do in inflammation?

Increases vascular permeability.

Bradykinin source

Generated from endothelial damage.

What do selectins mediate in leukocyte recruitment?

Initial rolling adhesion to endothelium.

What do integrins mediate in leukocyte recruitment?

Firm adhesion for migration out of vessels.

Neutrophil swarming

Coordinated chemokine/lipid-guided migration to tissue damage.

What lipid mediator is required for neutrophil swarming?

LTB4.

What activates PRR signaling pathways?

Binding of a PAMP.

What four gene categories does PRR signaling activate?

Antimicrobial peptides, type I interferons, inflammatory cytokines, chemokines.

Which adaptor does TLR3 use?

TRIF.

Which adaptor does TLR7 use?

MyD88.

What does TRAF3 lead to?

Activation of IRF3/IRF7.

What do IRF3/IRF7 induce?

Type I interferon transcription.

What does TRAF6/TAK1 activate?

NF-κB and MAP kinase pathways.

What does IκB degradation release?

NF-κB, which enters the nucleus.

What does NF-κB drive transcription of?

Cytokines, chemokines, antimicrobials.

IL-1 family function

Promotes inflammation.

What stimulates IL-1 family cytokines?

Viral, parasitic, or bacterial antigens.

Which cells secrete IL-1 early in immune responses?

Macrophages and dendritic cells.

What does IL-1 act on locally?

Capillary permeability.

IL-1's inactive precursor form

Zymogen.

What enzyme activates IL-1?

Caspase-1.

What triggers IL-1 receptor signal transduction?

Receptor dimerization.

sIL-1RII function

Acts as a decoy receptor, binding IL-1 without signaling.

Why is sIL-1RII inhibitory?

It lacks a functional signaling (TIR) domain.

sIL-1RAcP (soluble) function

Sequesters the co-receptor needed for IL-1 signaling.

Class I (hematopoietin) cytokine family structure

Receptors made of multiple subunits.

IL-2 function

Signals B and T cell proliferation.

IL-4 function

Regulates T helper cell differentiation.

IL-6 function

Causes B cell differentiation into a plasma cell.

Low-affinity IL-2 receptor composition

α chain alone.

Intermediate-affinity IL-2 receptor composition

β and γc chains.

High-affinity IL-2 receptor composition

α, β, and γc chains together.

What happens to Kd as more IL-2R subunits combine?

It decreases (affinity increases).

TNF family structural feature

Members can be soluble or membrane-bound.

What conformational change activates TNF receptor-1?

Ligand-induced trimerization.

What pathway does TNF receptor-1 activation trigger?

NF-κB.

TNF-α producing cells

Activated macrophages.

TNF-α function

Proinflammatory signaling.

TNF-β (lymphotoxin-α) producing cells

Activated lymphocytes.

FasL function

Induces apoptosis upon binding its receptor.

CD40L function

Delivers a T-cell differentiation signal to B cells.

BAFF and APRIL function

B-cell development and homeostasis.

IL-17 family function

Proinflammatory signaling.

Which T cell lineage generally secretes IL-17?

Th17 cells.

Where are IL-17 receptors found?

Neutrophils, keratinocytes, other nonlymphoid cells.

IL-17 family's role in immunity

Works at the innate/adaptive interface.

Type I interferons

IFN-α and IFN-β.

Which cells can secrete type I interferons?

Any infected cell, and innate cells.

What state do type I interferons induce?

An antiviral state.

How do type I interferons inhibit viruses?

Ribonuclease synthesis and inhibition of protein synthesis.

Type II interferon

IFN-γ.

Which cells produce IFN-γ?

Activated T cells and NK cells.

What does IFN-γ modulate?

Adaptive immunity, skewing toward antiviral response.

JAK/STAT step 1

Ligand binding induces receptor dimerization.

JAK/STAT step 2

JAKs phosphorylate each other and the receptor.

JAK/STAT step 3

JAKs phosphorylate STAT transcription factors.

JAK/STAT step 4

Phosphorylated STATs dimerize and enter the nucleus.

What do STAT complexes induce after type I IFN signaling?

Interferon-stimulated genes (ISGs).

ISG effect 1

Inhibition of protein synthesis.

ISG effect 2

Degradation of mRNAs.

ISG effect 3

Inhibition of viral transcription.

ISG effect 4

Inhibition of virus particle assembly.

Chemokines

Small cytokines that induce cell movement.

What receptor type do chemokines bind?

G-protein-coupled receptors (GPCRs).

Which direction do cells move relative to a chemokine?

Toward the chemokine source.

Chemokine receptor promiscuity

Many receptors bind more than one chemokine.

Name two anti-inflammatory cytokines.

IL-10 and TGF-β.

What happens with too much immune suppression?

Increased susceptibility to infection.

What happens with too much inflammation?

Tissue damage/immunopathology.

Tolerance

Prevention of an immune response against self.

Central tolerance

Deletion of self-reactive lymphocytes before maturity.

Where does central tolerance for B cells occur?

Bone marrow.

Where does central tolerance for T cells occur?

Thymus.

What happens to most self-reactive clones in central tolerance?

They die via apoptosis.

What can some self-reactive T cell clones become in the thymus?

Regulatory T cells (Tregs).

Peripheral tolerance

Regulates autoreactive cells that escape central tolerance.

What does binding foreign antigen in the periphery cause?

Clonal selection (effector T cell activation).