immunotoxicology Flashcards
what are 3 immune mechanisms that are modulated by xenobiotics
immune cell activation
immunosuppression
immune recognition
what is immunotoxicity
the study of adverse effects on the immune system resulting from exposure to drugs or chemicals
what are the 2 components of the immune system
innate and adaptive
what are the 4 types of cells that come from common lymphoid progenitor
NK B T and dendritic cells
what are the 6 types of cells that come from common granulocyte/macrophage progenitor
eosinophil, basophil, macrophage, neutrophil, mast cell and dendritic cell
what is the cellular components of the innate immune system
macrophages, dendritic cells, granulocytes, mast cells, NK cells
what is the cellular components of the adaotive immune system
T cells B cells
what is the efferent mechanisms of the innate immune system (4)
cytokine production, inflammatory response, phagocytosis, pathogen killing
what is the efferent mechanisms of the adaptive immune system (3)
antibody production, cytokine production, cell killing
how fast is the innate response
quick
how fast is the adaptive response
slow
does innate have specific memory
no
does adaptive have specific memory
yes
what is the main important differences between innate and adaptive (2)
antibody formation and immune memory
where are macrophages
in tissues (only called macrophages when there)
what are kupffer cells
resident macrophages in the liver
what is the largest macrophage population in the body
kupffer cells
what do kupffer cells do main mechanism
remove foreign material from portal circulation that streams into liver
what is a secondary mechanism of kupffer cells
synthesize and release proinflammatory mediators like cytokines, ROS, RNS
what is the main enzyme of macrophages
using NADPH oxidase
what do macrophages produce
NO
what do macrophages release (2)
proteases and cytokines
what cytokines do macrophages release (3)
TNFa, IL-1B and IL-18
what does cytokine release from macrophages do
signal for neutrophil recruitment
what are the 2 waves of attack in hepatic cells
- macrophage catalyzed
- neutrophil catalyzed
why do neutrophils come in wave 2
because cytokine signals tell them do
how do neutrophils fight in wave 2
indiscriminately, even will damage host tissue
what is an example of toxicity of a xenobiotic that macrophages play a role in
CCl4
what happens do CCl4 in the body
CYP2E1 turns it into *CCl3
what happens when you deplete macrophages and then give CCl4
there is less liver injury, so it is protective
how did they get rid of macrophages to test for CCl4 effects
give them GdCl3 cause it depletes macrophages
what happens if you give GdCl3 and CCl4 + why
then there wont be any injury (no macrophages to cause more damage)
what 2 pathways can happen to *CCl3
-add O2 to make *OOCCl3 -add lipid to make lipid radical and CHCl3
what are 2 drugs that the depletion of macrophages attenuates the toxic effects
acetaminophen and CCl4
what is immunosuppression
impairment of maturation and development of immune cells
what is a main example of something used for immunosuppression (xeno)
halogenated aromatic hydrocarbons
what is pancytopenia
low rbc wbc and platelets
what are 4 causes of immune suppression
xenobiotic-induced, panytopenia (bone marrow), thymic atrophy/involution
tumor
what is thymic atrophy/involution / what happens (5)
less T cells being made, less proliferation differentiation cytokine production and cell responses
what is TCDD (another name)
dioxin
what does dioxin do
decreases thymus mass
what does TCDD do
decreases thymus mass
which drugs decreases thymus mass
TCDD/dioxin
what happens if you give dioxin then influenza A
they get more pulmonary damage than mice who werent exposed
what does dioxin do to T cells (4)
t-cell depletion, less t-cell differentiation and proliferation
but more regulatory T cells
what does AhR stand for
aryl hydrocarbon receptor
where is the aryl hydrocarbon receptor
in the cytosol
where is there a lot of aryl hydrocarbon receptor
in the thymus
what happens with aryl hydrocarbon receptor knockout
the mice are resistant to thymic atrophy caused by TCDD/ dioxin
what does TCDD need to activate for it to cause a bad response
the aryl hydrocarbon receptor
what does trp depletion cause
T cell death
what does trp breakdown into
kynurenine
what do tumor cells upregulate
enzymes that breakdown trp
what does kynurenine do
binds to aryl hydrocarbon receptor
what happens when kynurenine binds to aryl hydrocarbon receptor (3)
induces IL-10 release and regulatory T cell development which leads to immune suppresion
what is the role of regulatory T cells
role in regulating or suppressing other cells in the immune system
what does more regulatory T cells lead to (2)
less T cell proliferation, less killer t cell formation
how does trp depletion lead to immunosuppression in cancer
tumor cells upregulate enzymes to turn it into kynurenine, which binds to aryl hydrocarbon receptor to increase IL-10 and T regulatory cells
what is type 1 hypersensitivity
immediate-type hypersensitivity
what is type 2 hypersensitivity
antibody mediated cytotoxic hypersensitivity
what is type 3 hypersensitivity
immune complex mediated hypersensitivity
what is type 4 hypersensitivity
cell mediated hypersensitivity
which type of hypersensitivity is anaphylaxic
type 1
what are the 2 fragments of the IgG molecule
the Fc and the Fab fragments
is the Fc or Fab fragment the one that looks like the two ends sticking out from 1
Fab
is the Fc or Fab fragment the one that looks like main one that 2 things brach from
Fc
which fragments only has constant regions
Fc
which fragments has variable and constant regions
Fab
which one is the heavy and light chain
heavy is on the outer one and light is the inner one
where are the variable regions
right at the end of the Fab fragments
what part of IgG binds to the antigen
the variable region on Fab
what part of IgG activates complement and phagocytes
Fc
what is the main type of antibody we are learning about
IgG
which side is the amino terminal of IgG
the Fab regions
which side is the carboxy terminal of IgG
the Fc regions
which type of populations get lots of type 1 hypersensitivity
in developed nations
what is a prerequisite of type 1 hypersensitivity
need prior sensitization to antigen (so you have antibodies the second time)
what is the specific antigen in type 1 hypersensitivity
IgE
what specifically happens in type 1 hypersensitivity
binding of antigen to antigen specific IgE bound on mast cells, then rapid liberation of active chemicals such as histamine
what do mast release once activated
active chemicals such as histamine
what happens in type 1 hypersensitivity when they are first exposed to the antigen
they make IgE antibodies, they bind to surfaces of mast cells and basophils(by Fc portion), and these cells are now primed to react the next time the cells come into close proximity with the allergen
how does IgE bind to mast cells
by its Fc portion onto a Fc receptor for IgE (which is already on the mast cell)
how does degranulation occur in type 1 hypersensitivity
exposure to antigen causes cross-linking of cell-bound IgEs, so then degranulation happens
which cell type is sensory and decides what is foreign
the B cell
what does the B cell do once it notices a foreign thing
processes it, presents it to T cell
which cell type secreted IgE
plasma cells
what are 2 examples of primary mediates in degranulation in type 1 hypersensitivity + what do they . cause
histamine, proteases
can cause vasodilation
what are 2 examples of secondary mediates in degranulation in type 1 hypersensitivity + what do they . cause
leukotrienes and prostaglandins
what is the mechanism of antihistamines
block H1 and H2 receptors
what is the mechanism of cromolyn sodium
blocks Ca++ influx into mast cells
what is the mechanism of theophylline
prolongs high cAMP in mast cells by inhibiting phosphodiesterase
what is the mechanism of ephinephrine
stimulates cAMP production in mast cells
what is the mechanism of cortisone
blocks histidine to histamine conversion and stimulates cAMP in mast cells
why do lots of drugs to treat type 1 increase cAMP
because degranulation is prevented if cAMP levels remain high
what happens in type 2
specific IgG or IgM antibodies bind to antigens on cells via their Fab regions
what happens once the IgG binds to the cell in type 2
complement activation via Fc region
what does complement activation cause (type 2)
attracts phagocytes, causes damage and lysis
how does IgG cause complement (type 2)
bridges complement via Fc regions
what are 3 examples of complement mediated lysis in type 2
hemolytic anemia, ABO transfusion, Rh disease
what are the antigens in type 2
it can be part of the cell naturally, or a drug!
what are 2 examples of drugs that can be used as antibodies in type 2
penicillin, quinidine
what is opsonization
coating of a particle with proteins that facilitate phagocytosis (targets and tags the cell)
which type of hypersensitivity involves opsonization
type 2
which type of hypersensitivity involves IgE
type 1
which type of hypersensitivity involves mast cell
type 1
which type of hypersensitivity involves cell bound antigen
type 2
which type of hypersensitivity involves immune complex
type 3
what is the first step of type 3 hypersensitivity
antigen and antibodies form complexes in blood
what happens to the immune complexes
they are deposited on blood vessels wall
what happens once the immune complexes are deposited on blood vessels wall
complement is activated and C3a and C5a are released
what happens once C3a and C5a are released
neutrophils are attracted by C5a, they release enzymes that destroy endothelium and RBC escape the vessels
what do neutrophils do it type 3 and how do they come around
attracted by C5a and they release enzymes that destroy endothelium and RBC escape the vessels (inflammation, leaky vessels)
what does procainamide do (which type)
lupus like syndrome (type 3)
what is the mechanism of procainamide in type 3 + what does it cause
forms anti H2A-H2B-DNA antibodies which causes abnormal T cell maturation and proliferation
how does procainamide cause T cell activation
because its reactive metabolite activates T cells
what does procainamide do to T cells
abnormal T cell maturation, proliferation, T cell activation
what is a main serious thing that procainamide can cause (1 word)
agranulocytosis
what is agranulocytosis
lowered WBC count
which type causes agranulocytosis
3
what kind of antibodies does procainamide make
against histones and DNA (H2A-H2B-DNA)
which type of hypersensitivity is T-cell mediated
4
what is the first thing that happens in class 4
macrophages ingests antigen, processes it, and presents it with class 2 MHC protein
what happens after macrophage presents antigen with MHC 2
T helper-1 gets activated, gabba-INF, activates macrophages
what are some things that may be involved with class 4
CD4 and CD8 cells
what is involved with poison oak, ivy, drugs, soaps and heavy metals
CD8 cell is involved (type 4)
what can CD4 cells do
delayed-type hypersensitivity and immune inflammation: induce cytokines and recruit neutrophils, inflammation
what can CD8 cells do
cell mediated cytolysis: granzymes, express Fas ligant - both apoptosis
what are granzymes
proteases that induce apoptosis
what are the 3 main components of type 4
macrophage (APC)
MHC class 2
helper t cells
what cell type has CD4
helper t cells
what cell type has CD8
killer t cells
can xenobiotics activate the immune system
yes
can xenobiotics suppress the immune system
yes
are immune activation mechanisms simple + explain
no they are simple and can involve various types of hypersensitivity reactions or direct cytotoxic mehcanisms
what are 2 things that immunosuppression primarily efects
the thymus (via AhR) and the bone marrow
