Immune System Overview Mechanisms of Immunosuppression

Immune System Overview Mechanisms of Immunosuppression
By:Bob Luebke
Immunotoxicology Branch
Experimental Toxicology Division
NHEERL, ORD

Role of the Immune System in Homeostasis

* Bidirectional interaction with other systems
o Reproduction
o Endocrine
o CNS

Basics of Immunology
The Immune Response
Innate Immunity
Adaptive (Acquired) Immunity
-Phylogenetically ancient
-Limited recognition
-Rapid (minutes – hours)
- No cell proliferation required
-Limited memory (? mammals)
-First appeared in jawed fishes
- Infinite array of specificities
- Slow (days)
-Requires proliferation and differentiation
-Long-lasting memory

Basics of Immunology
* The adaptive immune response to antigen
Organs of the Immune System
Immune System Anatomy
Organs of the Immune System
Thymus: source of naive T cells
Fate of T Cells in the Thymus
Positive selection: optimal binding to self Ag prevents apoptosis
Negative selection: superoptimal binding to self Ag induces apoptosis
B cells: Tolerance to “Self”
Anergy: low expression of
IgM on surface; can’t bind Ag
Clonal ignorance: too few
copies of Ag in the periphery

Thymus size and architecture:
* May be very sensitive to xenobiotics
* Also sensitive to acute toxicity

Methods for Assessing Direct Immunotoxicity Associated with Exposure to Chemicals
Organs of the Immune System
Spleen: Antigen trapping and presentation, clonal expansion, cellular export
Organs of the Immune System
Lymph nodes: Antigen trapping and presentation, clonal expansion, cellular export
Cells of the Immune System
Innate Immune System: Granulocytes
Neutrophil (“PMN”)
* First responders
* Phagocytosis and killing of bacteria
* Inflammation

Eosinophil
* Allergy
* Killing parasite larvae
Basophil
* Circulating mast cells
* Allergy/anaphylaxis

Innate Immune System: Granulocytes
Neutrophil (“PMN”)
* First responders
* Phagocytosis and killing of bacteria
* Inflammation
Cells of the Immune System
Innate Immune System: Monocytes
Monocyte/macrophage
Macrophage with ingested
asbestos fiber (encarta.msn.com)
* Phagocytosis and killing of bacteria
* Antigen processing
* Inflammation
Adaptive Immune System: Lymphocytes
Activated B cell
Peripheral blood
Activated T cell (SEM)
* B cells: Mature into plasma cells, secrete antibody (IgM, IgG, IgA, IgE, IgD)
* T cells: T helper - produce stimulatory and regulatory cytokines
* T cells: T cytotoxic/suppressor – contact-dependent cytotoxicity,

regulation of immune response
* NK cells: direct killing of cells (innate arm of IS)

Plasma Cells Produce Antibodies
* IgM: Primary response, efficient agglutination
* IgG: Recall response, highest concentration
* IgA: Mucosal surfaces, trapping of microbes
* IgE: Allery/anaphylaxis

Factors Affecting Immunocompetence
* Age
* Gender
* Genotype
* Nutritional status
* Life style choices
* Acute toxicity
CONCEPT: Individual immunocompetence, in the absence of xenobiotic exposure, is complex, dynamic and affected by fixed and variable factors. At the population level, the “normal” range is broad.

Immunocompetence in the Young: Innate immunity
* Neutrophils
* NK cells
Immunocompetence in the Young: Adaptive immunity
* Humoral immunity
* Cellular immunity
* Resistance to infection
Advanced Age and Immunocompetence

* Innate Immunity
* Adaptive immunity
* Resistance to infection

Gender and Immunocompetence
Genotype and Immunocompetence
Lifestyle and Immunocompetence
* Recreational drug use
* Excessive use of alcohol
* Smoking
* Stress

Xenobiotic Exposure and Immunocompetence
Immune
System
Exposure
Suppression
Infection
Neoplasia
Modulation
Allergy
Autoimmunity

Consequences of Xenobiotic Exposure on Immunocompetence
“Pre-immune” Mechanisms of Defense
Immune Mediated Resistance to Infection
Organism Factors Influencing Host Resistance
Mechanisms of Chemically-induced Immunosuppression
Mechanisms of Suppression:
Effects on Supply of Cells
Mechanisms of Suppression: Effects on Supply of Cells
UVB (320-280 nm) exposure
Mechanisms of Suppression: Tolerance Induction (and then some)
Mechanisms of Suppression: Tolerance Induction (human studies)
Mechanisms of Suppression: Modulation of cytokine production
Mechanisms of Suppression: Th1/Th2 Polarization
Mechanisms of Suppression: Disruption of innate immunity
Human and Mouse Macrophage Responses to Ozone in vivo
Mechanisms of Chemically-induced Immunosuppression
Mechanisms of Suppression:
Summary
* Reduced supply of immune system cells
* Misdirection of the immune system
* Direct effects on cells
* Combination of effects
Decreased Host Resistance: Implications for Human Health

Immune System Overview Mechanisms of Immunosuppression