14 - Hypersensitivity Flashcards
Initial Exposure to Allergen
Type 1 Hypersensitivity:
ALLERGIC REACTION
Allergen –> ATOPIC individual
VVV
IgE Antibody
that recognizes that allergen is produces
VVV
Mast Cell Receptors
bind to the IgE
Subsequent Exposure to Allergen
Type 1 Hypersensitivity:
ALLERGIC REACTION
Allergen –> MAST CELL (in mucosa)
VVV
Allergen CROSS LINKS IgE-Fc receptors
VVV
Triggers Mast cell to Degranulate
VVV
Mediators Released
Histamine / Prostaglandins / Leukotrienes / TNF-a / IL-4
&
Basophils are recruited from blood
LATE PHASE REACTION
Type 1 Hypersensitivity:
ALLERGIC REACTION
Caused by the MEDIATORS released from mast cell degranulation
Histamines / Prostaglandins / Leukotriens / TNF-Aa / IL-4
the RECRUIT Inflammatory cells such as:
EOSINOPHILS + NEUTROPHILS
take ~6 hours
WHICH MEDIATOR?
rom the granules of MAST CELLS
Type 1 HYPERsensitivity
Vasodilation
INCREASED Capillary Permeability
Smooth Muscle Contraction** = **BronchoSpasm
HISTAMINE
WHICH MEDIATOR?
from the granules of MAST CELLS
Type 1 HYPERsensitivity
BronchoCONSTRICTION
PROSTAGLANDINS
WHICH MEDIATOR?
from the granules of MAST CELLS
Type 1 HYPERsensitivity
Capillary PERMEABILITY
LEUKOTRIENES
WHICH MEDIATOR?
from the granules of MAST CELLS
Type 1 HYPERsensitivity
Inflammation
Cytokine Release
Stimulate Th2
TNF-A
IL-4
What makes an EFFECTIVE ALLERGEN?
Small inhaled proteins that stimulate
IgE production in atopic individuals
Small / Highly Soluble
Low Dose
Carried on DRY PARTICLES (Pollen)
Ex.
Mold Spores / Dust Mites / Pets / Cockroaches
Why do ATOPIC INDIVIDUALS have
IgE ALLERGY PRODUCTION?
MORE TH2
allergen-specific cells
IL-4
IL-5
IL-10
HOW does MORE TH2-allergen-specific cells in atopic individuals
result in
MORE IgE Production?
IL-4
induce CLASS SWITCHING –> B-cell produces IgE
IL-5
produce EOSINOPHILS
- *IL-10**
- INHIBIT production of* TH1 cells
Why is there more TH2 vs Th1 in atopic individuals?
4 Reasons
FETUS + PLACENTA
express freign paternal AG, must be protected from maternal CTL+NKcells
TNF-A –> stimulates NK/CTL –> Th2 Bias
Placenta secretes IL-4 & IL-10 –> more Th2 bias
CHILDHOOD INFECTION
Th1 response –> memory cells remember allergen & TH1 response
Hygiene Hypothesis
HEREDITY
Genes / Mutant IgE receptors / Mutation in Il-4 Promotor gene
TREG CELLS
FETUS
Why is there more TH2 vs Th1 in atopic individuals?
Placenta & Fetus express FOREIGN Paternal Ag
must be protected from the MATERNAL CTL & NK cells
Th1 –> TNF-a –> stimulates NK & CTL
Th2 Bias Preferred
- *Placenta** secretes IL-4 & IL10
- *Th2 Bias** in mother & fetus
Childhood Infection
Why is there more TH2 vs Th1 in atopic individuals?
Childhood infection = TH1 RESPONSE
- *Memory cells** remember:
- *Allergen & Th1 Response** to allergen
HYGIENE HYPOTHESIS
early microbial infections important
Higher Hygiene = lower infections = Higher Allergies
>3 older siblings or < 6mo at daycare = protection vs allergies
HEREDITY
Why is there more TH2 vs Th1 in atopic individuals?
Certain Genes have been linked with certain allergic disease
(bias towards Th2)
Asthma & Atopic Dermatitis
- *Mutant IgE receptors**
- *CROSS-LINKING** = STRONG signal –> IL-4 Release
Mutation in IL_4 Promoter Gene
Increase IL-4 Production
TH2 stimulated IL-4 –> B-cell produces IgE instead
T-REG CELLS
Why is there more TH2 vs Th1 in atopic individuals?
Repeat stimulation of T-helper Cells –> TREG production
TREGS suppress immune response to allergen by producing:
- *IL-10**
- inhibits* pro-inflammatory Th1 cells
TGF-B
bias towards IgG / IgA production
AWAY from IgE production!
In Atopic Individuals:
their T-REGS are DEFECTIVE in supressing Th2 cytokine production
Which Treatment for Allergies?
Treats BRONCHOCONSTRICTION
BRONCHODIALATORS
B- Agonist
Albuterol
Xanthine Derivatives = Theophylline
Which Treatment for Allergies?
Block CYTOKINE production by HELPER T-CELLS
↓B-cell activation = ↓AB production
CORTICOSTEROIDS
What Treatment for Allergies?
- *ANTIBODY** which grasps Fc Region of IgE Ab
- blocking binding to* Mast Cells
Reliieves allergic symptoms & ↓severity of asthma attack
OMALIZUMAB
What Treatment for Allergies?
Decrease or Prevents
MAST CELL DEGRANULATION
MAST CELL MEMBRANE STABILIZERS
Cromolyn Sodium
What Treatment for Allergies?
Binds to LEUKOTRINE RECEPTORS
or
INHIBITS the formation of Leukotrines
Prevents:
Airway Edema
Bronchoconstriction
Inflammation
LEUKOTRIENE MODIFIERS
ZAFIRLUKAST
Specific ImmunoTherapy
for
Treatment for Allergies
ONLY APPROACH FOR ALLERGY CURE
- *Several Years of** **maintanence injections
- -> TOLERANCE**
Can induce the
shift Th1 instead of Th2
IgG:IgE ratio
can increase 100 fold
Repeated injections –> TREGS which produce TGF-B
which suppress IgE Ab production
ICU DRUG DESENSITATION
Done when a
Drug NEEDS to to be given to a patient who has that DRUG ALLERGY
EVALULATION
indication / ICU BED / plan / IV access
ORDERING
Allergy consult / PRN meds / CRASH CART / Phamacist dilution assist
MONITORING
watch for: HypoTension / TachyCardia / Tightness / Wheezing
Dyspnia / Hives / other allergies
PREPARATION
prepares ALL DILUTION and clearly labeled doses
ADMINISTRATION
each dose given over 30 min via pump @ specific times
30 min after IV dose –> 60 min monitoring after PO dose
Which TYPE OF HYPERSENSITIVITY?
Immediate & Anaphylactic
Mediated by IgE
- *TYPE 1**
- *The Allergic Reaction**
IgE induced by allergen & binds to mast cells + basophils
VVV
Re-Exposure to allergen –> allergen CROSS LINKS bound IgE
VVV
Degranulation & Mediator Release
Which TYPE OF HYPERSENSITIVITY?
Mediated by IgG
Antigens on cell-surface combine w/ AB
COMPLEMENT-mediated lysis
PMN-mediated cell dmg
Ab-Ag induced cell dysfunction
TYPE 2
CYTOTOXIC
Which TYPE OF HYPERSENSITIVITY?
Mediated by IgG
Ag-Ab immune complex deposited in tissue
Complement activated –> PMNs attracted to site
VVV
release LYSOSOMAL ENZYMES
VVV
TISSUE DMG
TYPE 3
IMMUNE COMPLEX
Which TYPE OF HYPERSENSITIVITY?
CELL MEDIATED
Helper T-Cell sensitized by antigen –> re-exposure to Ag
VVV
Lymphokine Release
VV
Inflammation & MACROPHAGE activation
w/ mediator release
- *TYPE 4**
- *DELAYED**
Type 2: CYTOTOXICITY
3 Mechanisms
IgG Mediated Reaction
Complement –> MAC –> LYSE
Complement –> PMN to site** –> **PHAGOCYTOSIS
- *IgG** binds to Ag on membrane –>
- *Ab-Ag induced cell DYSFUNCTION**
Examples of TYPE 2 HYPERSENSITIVITY:
CYTOTOXICITY
RBC CELL:
- *Hemolytic Anemia** / ABO Transfusion Reactions
- *Drugs (PLT also) / Rh Hemolytic Disease**
Cardiac Cell
Infections = Rheumatic Fever
Kidney + Lung Cells
Goodpasture’s Syndrome
Type 3: IMMUNE COMPLEX
FREE FLOATING AG + AB
complexes form in BLOOD
VVV
Deposit into blood vessel = COMPLEX DESPOSITION
VVV
Activate COMPLEMENT = C5a
does not go all the way to MAC
VVV
Attracts NEUTROPHILS –> release enzymes
to DESTROY endothelium
Which type of TYPE 4 HYPERSENSITIVITY disease?
Localized Inflammation
immune complexes @ local site
Repeated Ag Admin = HIGH IgG then SC injection of Ag
ARTHUS REACTION
What disease? Type 3 Hypersensitivity
Immune complexes deposited throughout the body
SYSTEMIC INFLAMMATORY RESPONSE
- *Foreign Drug serum** injected = SLOW Ag Excretion
- *AB production** –> Immune complex formation & deposition
SERUM SICKNESS
What disease? Type 3 Hypersensitivity
Post-Streptococcal Ag-Ab complexes
along the basement membrane of KIDNEY
VV
Complement Active –> Neutrophil recruitment
GLOMERULONEPHRITIS
What disease? Type 3 Hypersensitivity
Rh Factor binds with AB
VV
Immune complex deposit in Synovial membranes
VV
Complement Activation -> Neutrophil Recruitment
RHEUMATOID ARTHRITIS
What disease? Type 3 Hypersensitivity
Ab targetted against
DNA of Face/Kidney/Joints
Systemic LUPUS ERYTHREMATOUS
Type 4: DELAYED
only CELL-MEDIATED type of hypersensitivity
Macrophage + Ag (on MHC2) –> IL-1** + **IL-12
^^^
VV
T-HELPER CELL TH1 –> INF-Y
Activates Macrophage
Delayed = Takes hours or days after contact
& lasts for days
Examples of
TYPE 4 HYPERSENSITIVITY
- *CONTACT HYPERSENSITIVITY**
- *POISON OAK**
TUBERCULIN = TB
