Download Immunotoxicology

Introduction to Toxicology
EV 460/660 & BI 460/660
Fall 2014
Toxic Effects on the Immune System
Brief Review of Immune System Structure and Function
1.
Overview of immune system, anecdotal comments
2.
Nonspecific defense mechanisms
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B.
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External -- skin – anatomic barrier and lysozyme secretion
-- digestive tract – gastric HCl
-- respiratory tract – mucociliary elevator, PAM cells
-- urogenital tract – urine acidity, vaginal lactic acid
Internal
-- phagocytic cells – neutrophils, monocytes,
tissue macrophages (histiocytes), Kupffer cells, microglia
-- natural killer (NK cells) – type of lymphocyte, cancer surveillance, release perforins
(perforate cell membrane), and anti-viral infected
-- interferons – inhibit viral replication
-- complement proteins – promote destruction of bacteria (destroy cell membranes),
attract phagocytes & other effects of inflammation
-- pyrogens – from WBCs & macrophages – elevate set-point temperature
-- inflammation reactions – tissue damage, mast cell release of histamine – vasodilation,
increased capillary permeability, phagocyte migration, erythema, edema
Specific defense mechanisms -- lymphocytes
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antigens – foreign molecule capable of stimulating specific immune response
-- large molecules – typically proteins or protein component (glycoprotein or
lipoprotein)
-- produce a complete immune response – e.g. both reacts with antibodies and
stimulates production of additional antibodies
haptens – incomplete antigens – must bind to protein to produce complete response
lymphoid tissues/organs
-- primary – bone marrow, thymus
-- secondary – spleen, lymph nodes
lymphokines/cytokines – interleukins – regulatory secretions, diverse functions
humoral immunity – B cells
-- antigen stimulation leads to antibody (Ab)/immunoglobulin (Ig) production
-- antibody classes – IgG, IgE, IgD, IgM, and IgA
-- memory B cells and acquired immunity
cell-mediated immunity – T cells
-- cytotoxic T, helper T, suppressor T, and memory T cells
Toxic Effects on the Immune System (immunotoxicity)
1.
Overview of immunomodulation by xenobiotic chemicals
-- immunosuppression – decreased responsiveness of immune mechanisms
-- may lead to enhanced susceptibility to disease (also see below)
-- immunoenhancement – increased responsiveness of immune mechanisms
-- may lead to immune-mediated disease
two types of immunoenhancement – hypersensitivity (toxin/toxicant-induced allergies)
autoimmunity (toxin/toxicant-induced autoimmunity)
2.
Immunosuppression
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B.
potential risks
-- increased susceptibility to infectious disease
-- increased risk of cancer
-- decreased effectiveness of immunizations
multitude of documented mechanisms – some examples
-- atrophy of or cytotoxicity to lymphoid tissues – e.g., thymus or bone marrow
-- reduced proliferation of lymphocytes
-- altered function of complement proteins
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Hypersensitivity
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-- impaired T cell binding to macrophages
-- reduced antibody production
-- altered lymphokines/cytokines function
-- decreased NK activity
-- decreased phagocyte activity
classes of known immunosuppressant toxicants
-- halogenated aromatic hydrocarbons
most extensively studied – PCBs (polychlorinated biphenyls), PBBs (polybrominated
biphenyls), PCDFs (polychlorinated dibenzo-furans), PCDDs (polychlorinated
dibenzo-dioxins)
-- polycyclic aromatic hydrocarbons
most extensively studied – DMBA (dimethylbenz[a]anthracene), BaP (benzo][a]pyrene
-- heavy metals
most extensively studied – Pb, As, Hg, Cd
-- insecticides
best evidence – organochlorines
equivocal evidence – organophosphates and carbamates
common characteristic – necessity of prior exposure in order to elicit a reaction
-- types I, II, and III reactions lead to production of specific antibodies
-- type IV reaction leads to generation of memory T cells
Type I response – immediate hypersensitivity or anaphylactic reactions
-- due to IgE production, IgE acts on mast cells
-- example xenobiotics – penicillin, toluene diisocyanate (TDI)
Type II response -- antibody-dependent cytotoxic hypersensitivity reactions
-- due to IgM or IgG production
-- antibody attack directed against antigen attached to RBC or platelet, cytotoxic T cell or
complement lyses of blood cells
-- example xenobiotic – trimetallic anhydrides (TMAs)
Type III response – immune-complex mediated hypersensitivity reactions
-- due to IgM or IgG production
-- antibody attack directed against soluble antigen in serum, Ab-Ag complexes lodge in
tissues and activate complement, may lead to widespread tissue damage, common locations of
damage include lung, kidneys, and joints
-- example xenobiotics – TDI & TMAs
Type IV response – cell-mediated hypersensitivity or delayed hypersensitivity
-- due to formation of memory T cells
-- primarily dermal reactions
-- example xenobiotics – oils of poison ivy/oak, TMAs, formaldehyde
classes of compounds known to produce hypersensitivity reactions
-- polyisocyanates – ex. TDI
-- acid anhydrides – ex. TMA
-- metals – Pt, Co, Ni, Cr
-- formaldehyde
Autoimmunity
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immune recognition of “self” vs. “non-self”
recognized autoimmune diseases include: myasthenia gravis, multiple sclerosis, lupus
chemically-induced autoimmunity due to modification of host tissues or immune cells by
the chemical, not the chemical acting as an antigen/hapten
both autoimmune diseases and susceptibility to chemically-induced autoimmunity are
thought to have significant genetic components
toxicants known to be associated with autoimmunity
-- vinyl chloride – reaction results from abnormal protein synthesized in liver, leads to
scleroderma, fibrosis of liver, lung, and spleen
-- mercury – results from damage to protein of glomerular basement membrane, leads to
glomerular nephropathy
-- silica – effect is believed to be mediated via an adjuvant mechanism, leads to scleroderma
F.
toxicants implicated in autoimmunity
-- scleroderma – solvents (toluene, xylene), silicones
-- systemic lupus erythromatosus – trichloroethylene, silicones, (several pharmaceuticals)