Immunotoxicology Flashcards
final exam
role of neutrophil
bacterial, phagocytosis, inflammation
role of basophil
allergy, helminth infection
role of mast cell
allergy, parasitic infection
role of eosinophil
allergy, parasitic infection
role of macrophage
bacterial, phagocytosis, inflammation
role of dendritic cell
present antigen for immune response; bridge the gap between innate and adaptive immunity
role of b cells
antibody production; neutralize pathogens, allergy
role of t cells
protect from pathogens, destroy infected cells, produce CD4+ and CD8+ t cells
role of natural killer cells
tumors, infected cells
immunotoxicology
any adverse effect on the structure or function of the immune system, or on other systems as a result of immune system dysfunction
problems that can occur due to immunotoxicology
- immunosuppression: Impaired immunity → Enhanced susceptibility to infection
- immunoenhancement: Autoimmunity, Hypersensitivity, Chronic inflammation
what is azathioprine used for?
immunosuppressive agent used to treat diseases such as rheumatoid arthritis and IBD
mechanism/effect of azathioprine
- pro-drug converted to active metabolite, 6-mercaptopurine (in liver)
- XO and TPMT convert it to an inactive metabolite that is cleared from the body
- active metabolite is structurally similar to purine bases, so incorporated into DNA and RNA, which causes:
- Strand breaks, inhibition of DNA
repair, inhibition of replication - Inhibition of B and T cell proliferation
- Induces apoptosis
adverse effect of azathioprine and what causes this adverse effect (mechanism)
Dose-dependent adverse effect caused by elevated concentrations of 6-TGNs – myelotoxicity
- 6-mercaptopurine is converted to 6-TGN by HPRT and GMP synthase, which can cause life-threatening pancytopenia (when too much)
- elevated 6-TGN can be due to and inherited TPMT deficiency (less inactivation of 6-MP)
- or when with allopurinol, which inhibits XO
what is clozapine used for?
anti-psychotic medication for schizophrenia when other meds don’t work
mechanism/effect of clozapine side effect
this occurs in a dose-independent manner (don’t know why this occurs):
- converted to nitrenium ion by MPO, which is highly expressed in neutrophils
- ion leads to GSH and ATP depletion, which leads to oxidative stress
- this leads to apoptosis and neutropenia (aka neutrophil depletion)
effect of tobacco smoke
- have both immunosuppressive and immunoenhancing effects
- causes lung inflammation by increasing the recruitment of innate cells, which then release more mediators (Th1/Th17/CD8+ T cells)
- also reduces macrophage ability to phagocytose and/or kill bacteria, making them more susceptible to respiratory infection
effect/mechanism of cannabis
- THCA (inactive) converted to THC (active) by heat
- binds to CB1 (in CNS) and CB2 (immune cells) receptors
immunosuppression - induces apoptosis, inhibits proliferation, suppresses pro-inflammatory cytokines (TNF-a, IFN-y, IL-2), and induces T regulatory cells
- this causes, T cell response to shut down and suppresses autoreactive T cells
which immune cells have the most to least CB2 receptors (at the mRNA level)?
- B cells
- NK cells
- macrophages
- monocytes
- PMN
- T cell
what are some chemicals in the halogenated aromatic hydrocarbon family? which is the most toxic?
- dioxin (TCDD) – most toxic
- PCDFs
- PCBs
dioxin acts through which pathway?
AhR pathway
role of thymus
- primary lymphoid organ
- site of T-cell maturation (immature T-cell migrate from bone marrow)
growth of thymus organ (what is max size, when doe sit reach that size, what happens afterwards)
- reaches max size at puberty
- 30-40g
- declines after
effect of dioxin in cellular models
indices thymic atrophy (decreases size and cellularity)
effect of dioxin in humans
decrease in IgG levels, causes chloracne acutely
autoimmunity definition
When the immune system mistakenly recognizes self-tissue as foreign- and then attack – loss of self-tolerance
main effects of autoimmunity
chronic inflammation and tissue damage
what is self-tolerance
lack of immune response to one’s own tissue antigens
how is loss of self-tolerance achieved? what is the result?
- Autoreactive lymphocytes escape elimination by central tolerance mechanisms, these then go to periphery where they encounter specific autoantigens
- Peripheral tolerance mechanisms (secondary lymphoid organs and/or sites of inflammation) also fail in stopping activation of autoreactive lymphocytes, this leads to specific response against autoantigen-bearing cells, leading to tissue damage.
mechanism of normal immunologic tolerance
- central: deletion, development of regulatory T cells, receptor editing (for B-cells)
- peripheral: anergy (b-cells), apoptosis by self-antigen recognition, and suppression of t regulatory cells
what is anergy?
functional inactivation because co-stimulatory molecule on APC is not delivered
clinical symptoms/mechanisms of autoimmune diseases
Activated T cells release proinflammatory cytokines:
- Activate innate immune cells (such as macrophages and neutrophils) as well as nonhematopoietic cells (such as endothelial cells and fibroblasts) to induce the production of more cytokines
- Autoreactive CD4+ cells, or helper T (Th) cells, also help autoreactive B cells in autoantibody production
- Th cells can also activate autoreactive CD8+ cytotoxic T (Tc) cells
inflammation and damage
postulated mechanism of autoimmunity
- genetic: by influencing the maintenance of self-tolerance
- environment (e.g. tobacco, drugs, UV, solvents, heavy metals): causes tissue damage/inflammation that cause activation of self-reactive lymphocytes through:
- cell death making hidden material available to APCs
- formation of neoantigens from covalent binding of chemicals to tissue
- cell death making hidden material available to APCs
- hormones: some are more common in women
what factors can lead to systemic lupus erythematosus?
genetic and environmental (most is idiopathic – due to drugs) – cigarette smoke, silica, etc.
where and how is damage caused in lupus?
Can involve any organ in the body but usually affects skin, kidneys, joints and heart – damage by immune complex deposition (pathogenesis not well understood)
which drugs can cause drug-induced lupus?
isoniazid and hydralazine hydrochloride
most common clinical presentation of lupus
skin-rash
treatment of drug-induced lupus
discontinuation of offending drug
what is systemic sclerosis (and where does it usually occur)
Autoimmune disease of connective tissue, characterized by fibrosis (usually localized – skin of hands, feet, face)
who is more susceptible to systemic sclerosis?
- women more affected
- occurs middle-age
risk factors of systemic sclerosis
chemicals – vinyl chloride
where is vinyl chloride used?
used to make PVC plastics
main exposure route of vinyl chloride
inhalation (workers)
effect of vinyl chloride
leads to an abnormal protein that is antigenic – systemic sclerosis
hypersensitivity reaction definition and common feature
- over-reaction of the immune system
- prior exposure leading to sensitization to elicit reaction upon subsequent challenge
types of hypersensitivity reactions
– Type I (Immediate hypersensitivity)
– Type II (Antibody-mediated)
– Type III (Immune-complex mediated)
– Type IV (T-cell mediated)
type I hypersensitivity reaction mechanism
sensitization (1st exposure)
1. allergen enters mucosa and is picked up by dendritic cells
2. dendritic cell primes T cell in lymph nodes
3. plasma cell travels back to mucosa and produces allergen-specific IgE antibodies
re-exposure:
4. allergen-specific IgE binds to mast cell and triggers mast cell degranulation
5. leads to asthma, anaphylaxis (allergy)
occupational asthma due to high or low molecular weight agents?
low
use of toluene diisocyanate (TDI)
produce polyurethanes (adhesives, pillows, mattresses, sealants)
exposure of toluene diisocyanate (TDI)
- Cured TDI (foam) is inert and non-toxic
- so by occupational exposure (inhalation)
predicted mechanism for TDI-induced asthma
- it damages lung epithelial cells
- GSH exhausted so leads to oxidative stress
- forms neoantigens from airway proteins and recognition as non-self
- in some people, this can lead to Th2 response hypersensitivity reaction (type 1)
