Ch11/12 Immune Mechanisms

What are the two directions of immune modulation that xenobiotics can cause?

Immunosuppression or immune overstimulation

Innate immune amplification mechanism

1. Toxicant

2. Tissue injury

3. DAMPs

4. Macrophages

5. Cytokines/chemokines

6. Neutrophils

7. ROS/proteases

8. Further damage

What do activated Kupffer cells produce?

• ROS

• NO

• Proteases

• TNF-α

• Chemokines

This aggravates liver injury

Neutrophils mechanism

1. Chemokines recruit neutrophils

2. Integrin-mediated adhesion/extravasation

3. ROS + proteases

4. Second wave of injury

Hapten mechanism

1. Reactive xenobiotic + protein

2. Covalent drug-modified protein

3. Antigen recognition

4. Adaptive immune response

Allergy

• Immune response directed against drug/hapten or drug-modified antigen

• Xenobiotic has modified a normal protein so that it is recognised differently

Autoimmunity

• Immune response directed against true-self antigens

• Immune system attacks the body’s own components

What are the three cytokine categories?

• Pro-inflammatory cytokines

• Growth factors

• Chemokines

What determines the TNF outcome?

• Cell type

• Timing

• Duration of insult

• Whether survival signalling is inhibited

Chemokine egs

• MIP-1/2

• IL-8

• CINC

• MCP-1

What happens during immunosuppression?

• Reduced immune function

• ↓ resistance to infections

• Can alter susceptibility to disease

  
  

What causes immune overstimulation?

• Inflammation

• Allergy/hypersensitivity

• Autoimmune reactions

Immunosuppression

Reduction/inhibition of normal immune-system function

What can xenobiotics interfere with to cause immunosuppression?

• Generation of immune cells

• Maturation of immune cells

• Proliferation/activation of immune cells

• Immune signalling

Molecule causing immunosuppression eg

Benzene

How can benzene interfere with immune-cell production?

1. MPO-mediated bioactivation

2. Inhibition of generation/maturation of immune cells

3. Immunosuppression

Eg of molecule involved in AhR-mediated immunosuppression

TCDD (dioxin)

What are the consequences of TCDD activating the Aryl hydrocarbon receptor (AhR) excessively?

• Thymus atrophy

• Reduced resistance to viral infections

• Suppression of some autoimmune responses

• Possible induction of regulatory T cells

• Inhibition of maturation/expansion of T4 and T8 cells

What are pathogen-associated molecular patterns (PAMPs)

Signals associated with microorganisms

PAMPs eg

Microbial molecular structures

What are damage-associated molecular patterns (DAMPs)

Endogenous molecules released or exposed when cells/tissues are damaged

Kupffer cells

Resident macrophages of the liver

Liver toxicity via Kupffer cells mechanism

1. Xenobiotic damages hepatocytes

2. Hepatocytes release signals such as DAMPs and chemokines. PAMPs can also activate Kupffer cells

3. Kupffer cells become activated and/or are recruited from blood

4. Activated kupffer cells produce:

• ROS via NADPH oxidase

• NO

• Proteases

• TNF-α

• Chemokines

Chemokines such as MIP-1α, TNF-α, and other chemokines help recruit inflammatory cells

6. Neutrophils prodce:

• ROS

• Powerful proteolytic enzymes

  • Eg. elastase

Neutrophil recruitment mechanism

1. Chemokines → neutrophil activation

2. ↑ integrin expression

3. Integrins bind adhesion molecules on endothelial cells

4. Extravasation

5. Neutrophils enter damaged tissue

   
   

Neutrophil integrins egs

• LFA

• Mac-1

Adhesion molecules eg

ICAM molecules

Hapten

Small molecule that becomes immunogenic when attached to a larger carrier protein

Cytokines

Small signalling proteins that coordinate communication between cells

Which processes are cytokines important in?

• Inflammation

• Immune activation

• Tissue injury

• Cell proliferation

• Differentiation

• Repair

Chemokines

Specialised cytokines that primarily control cell migration/chemotaxis

What are the general properties of cytokines?

• Transient increase in production

• Short half-life

• Primarily local action

• Autocrine and paracrine signalling

• Produced/release by individual cells rather than stored

• Rapidly transcribed when needed

• Multiple functions

• Receptor-mediated signalling

• Activation of pathways such as:

  • MAP kinase

  • STAT

TNF-α

Major pro-inflammatory cytokine that is particularly important in toxicant-induced inflammation

Which cells primarily produce TNF-α?

• Macrophages

• Monocytes

What are chemokines?

Cytokines that regulate directed migration of immune cells

What do chemokines do?

Create signals that attract inflammatory cells toward the site of tissue damage

Which immune cells can chemokines recruit?

• PMNs/neutrophils

• Monocytes

• Macrophages

• Dendritic cells

• T cells

Cytokine-induced neutrophil chemoattractant (CINC) function

Attracts neutrophils

Monocyte chemoattractant protein (MICP-1)

Attracts monocytes