B3.021 Prework Hypersensitivity Flashcards
define a hypersensitivity reaction
injurious or pathologic immune reactions
exaggerated and abnormal
what are the 2 mechanisms of hypersensitivity
- an immune response to a microbe or environmental allergy causes tissue injury due to repeated or poorly controlled reactions
- failure of self-tolerance when an immune response is generated to self antigens = autoimmunity
type 1 hypersensitivity
immediate hypersensitivity mediated by IgE binding to mast cells
type 2 hypersensitivity
antibody (non IgE) mediated cell or tissue destruction
type 3 hypersensitivity
antibody/antigen complex deposition causing inflammation and tissue injury
type 4 hypersensitivity
T cell mediated
atopy
true allergy
what % of the pop is affected by type 1?
10-20%
prevalence increasing in industrialized nations
describe sensitization
first exposure to an allergen protein or chemical that binds proteins (hapten)
should not cause a reaction
what happens at the level of leukocytes in sensitization?
aberrantly, Tfh and Th2 cells cause B cells to stimulate class switching IgE against the allergen (via IL4 and IL13) IgE to the allergen is produced long term by the plasma cells and binds to the FceR1 high affinity IgE receptors on mast cells coating mast cells with IgE to that particular allergen
what is the elicitation phase
the hypersensitivity reaction upon repeat exposure
what happens during the elicitation phase?
allergen cross links the IgE on the mast cell FceR1 high affinity IgE receptors
activation of mast cell
release of mast cell contents
what is the contents of a mast cell
vasoactive amines
lipid mediators
cytokines (delayed symptoms)
immediate hypersensitivity
within minutes
mediated by vasoactive amines and lipid mediators
increase in vascular permeability
smooth muscle contraction
late phase hypersensitivity
mediated by cytokines
recruit neutrophils and eosinophils
tissue injury with repeated bouts
describe the components of the IgE receptor
FceR1 high affinity receptor
-present on mast cells (primary) and basophils (role less well established)
3 polypeptide chains
-1 binds the Fc portion of the e heavy chain
-2 are signaling proteins
describe the series of events within a mast cell upon allergen exposure
allergen cross links two IgE molecules causing degranulation, synthesis and secretion
ITAM phosphorylation occurs activating signaling pathways
-release of pre formed mediators
-AA metabolism secreting lipid mediators (PGEs and LTs)
-activation of cytokine transcription genes to secrete cytokines
vasoactive amines
vascular dilation
smooth muscle contraction
proteases
tissue damage
prostaglandins
vascular dilation
leukotrienes
smooth muscle contraction
histamine
vasodilation
increased vascular permeability
transient smooth muscle contraction
mucous production
TNF
endothelial cell activation
inflammation
neutrophil activation
IL-4
induces IgE class switching by B cells
IL-5
eosinophil activation, generation
what is the general mechanism of antihistamines
histamine receptor antagonists
reduce the potential for histamine to bind and cause symptoms
H1 antagonists
1st generation - caused sedation and short acting
2nd generation - less or no sedation, long acting
H2 antagonists
receptors mostly in the gut
mostly used for indigestion and heartburn, but could be added to an H1 antagonist for treatment of allergic conditions
epinephrine (SubQ, IM or IV)
1st line in anaphylaxis vascular smooth muscle contraction increased cardiac output inhibits bronchial smooth muscle contraction stabilize mast cells
corticosteroids (inhaled/oral/IV/IM)
reduce inflammatory mediator production
stabilize mast cells
reduce eosinophils
leukotriene receptor antagonists (oral)
reduce inflammation
relax bronchial smooth muscle
phosphodiester inhibitors (inhaled)
relax bronchial smooth muscle
describe desensitization treatment
repeated increasing dose of allergens to help the system overcome the allergy
inhibit IgE production, induce tolerance
allergy shots
cromolyn (topical or oral)
inhibits mast cell degranulation
what are 3 types of monoclonal antibody therapy for immediate hypersensitivity
anti-IgE
anti-IL-5
anti-IL-4 and IL-13
anti-IgE therapy
binds/inhibits IgE so it cannot bind to the receptors
downregulation of the FceR1 on mast cells
anti IL-5 therapy
binds/inhibits IL-5 to reduce eosinophil production and survival
anti IL-4 and IL-13 therapy
binds/inhibits the shared receptor reducing inflammation and decreasing the effects of both products
distinguish between type 2 and 3 hypersensitivities
2 - antibodies can be directed against cells or extracellular matrix
3 - antibodies/antigens can bind and deposit in blood vessels (renal glomeruli and joint synovium)
*failure of self tolerance
diseases associated w types 2 and 3 hypersensitivity
cytopenias organ inflammation hormone abnormalities skin diseases vasculitis arthritis nephritis
describe type 2 hypersensitivity
complement and Fc receptor induced recruitment and activation of leukocytes
opsonization and phagocytosis
cell function abnormalities by competitive inhibition or activation
describe the process of complement and Fc receptor mediation of type 2 hypersensitivity
Abs bind to activate the neutrophil
complement activation releases C3a and C5a to activate the neutrophil
neutrophils generate ROS and lysosomal enzymes that cause inflammation/injury
discuss the link between strep and type 2 hypersensitivity
can occur after strep infection
Ab cross reacts with myocardium causing myocarditis
describe the process of opsonization and phagocytosis associated with type 2 hypersensitivity
complement activation occurs releasing C3b that opsonizes the cell
Fc receptor on phagocytes recognizes C3b on an opnsonized cell and phagocytosis the infected cell
may occur with erythrocytes and platelets causing anemia and thrombocytopenia
describe cell function abnormalities caused by competitive inhibition or activation in type 2 hypersensitivity
Abs generated against hormone receptors competitively inhibit hormone production
Abs can also mimic hormones
graves disease
thyroid stimulation even in the absence of thyroid stimulation hormone leading to hyperthyroidism
myasthenia gravis
musculoskeletal paralysis disease where Abs are made against the acetylcholine receptor and inhibit transmission of signals to the muscle to move
autoimmune hemolytic anemia
opsonization and phagocytosis of erythrocytes causing anemia
autoimmune (idiopathic) thrombocytopenic purpura
opsonization and phagocytosis of platelets causing bleeding
goodpasture syndrome
complement and Fc receptor mediated inflammation targeting a non-collagenous protein in kidney glomeruli and lung alveolar basement membranes
pemphigus vulgaris
antibody mediated activation of proteases causing disruption of intercellular adhesions
targets desmoglein - protein in intercellular junction of epidermal cells which holds cells together
pernicious anemia
neutralization of intrinsic factor leads to decreased absorption of vitamin B12
results in anemia
rheumatic fever
inflammation and macrophage activation
targets streptococcal cell wall antigen, antibody cross-reacts with myocardium
leads to myocarditis and arthritis
describe type 3 hypersensitivity
disease is caused by deposition of circulating antibody/antigen complexes in blood vessels
-activation of complement
-activation of inflammatory cascade
systemic or localized
results in: vasculitis, nephritis, inflammatory skin reactions
arthus reaction
localized Ag/Ab complex deposition
formation of complexes at the site of antigen injection
local vasculitis (often mistaken as cellulitis but not infectious)
systemic lupus erythematosus
Ab: DNA, nucleoproteins, others
manifestation: nephritis, arthritis, vasculities
polyarteritis nodosa
Ab: microbial antigens, unknown
manifestation: vasculitis
post-streptococcal glomerulonephritis
Ab: streptococcal cell wall antigen
manifestation: nephritis
serum sickness
Ab: protein antigens
manifestation: systemic vasculitis
nephritis
arthritis
goal of type 2 and 3 hypersensitivity treatments
limit inflammation and injury
usually systemic corticosteroids
what is plasmapheresis
removing pathogenic antibodies from circulation to reduce Ab driven damage
what is IVIg
intravenous immunoglobulin IgG in high doses
may induce the expression of and bind to the inhibitory Fc receptor on myeloid and B cells
competes with pathogenic Ab for binding
anti-CD20 antibody
reduce B cell population that is producing the aberrant antibody
what could happen if we block CD40-CD40L communication
block Th and B cell communication to block production of Ab and cytokines
decreased survival of B cells and plasma cells
inhibit disease progression
how does type 4 hypersensitivity work
T cells cause tissue injury
local autoimmune reaction with T cells directed against cellular antigens within local tissues (not systemic)
examples of times when type 4 hypersensitivity might develop
persistent response to environmental triggers (poison ivy, meds, chemicals)
T cell response to microbes (TB)
response to superantigens
describe the process of delayed type hypersensitivity (DTH) (type 4)
reaction occurs 24-48 hours after exposure
T lymphocytes home to the site
-respond to antigen
-T cells and monocyte infiltration
-leukocyte products lead to tissue damage
clinical utility of DTH
determine prior exposure
purified protein derivative (PPD)- TB skin test
-evaluates T cell response to mycobacteria
how is type 4 hypersensitivity unique
chronic and progressive
antigen never cleared
self perpetuating process
multiple sclerosis
myelin proteins
demyelination in the CNS, sensory and motor dysfunction
rheumatoid arthritis
unknown antigens
inflammation of synovium and erosion of cartilage and bone joints
type 1 DM
pancreatic islet cells
impaired glucose metabolism and vascular disease
crohns disease
unknown
inflammation of the bowel wall, ab pain, diarrhea, intestinal bleeding
contact sensitivity
modified skin proteins
delayed type hypersensitivity rash
chronic infection (TB)
microbial proteins
chronic granulomatous inflammation
viral hepatitis
viral encoded proteins
cytotoxic T cells cause cell death, hepatic dysfunction, and fibrosis
TSS
microbial superantigens
cytokine release causing fever and shock
2 ways to treat type 4 hypersensitivity
anti-inflamm
decrease T cell response of effects
-TNF inhibitors (monoclonal antibodies)
- IL receptor antagonists (monoclonal antibodies)
-anti-CD20 B cell (monoclonal antibodies)
