Type 1-3 Hypersensitivity Reactions Flashcards
T1HS reaction mediated by
IgE
Atopic triad for T1HS
What are the other two?
- Asthma
- Atopic Dermatitis
- Allergic Rhinitis
*Food allergy, Insect bites/stings
Describe the two phases of allergic reactions and their components
-
Sensitization phase
- Production of Th2 and IgE
- IgE binds to FcERI on mast cells and basophils
-
Effector phase
- Acute reaction = degranulation
- Late phase reaction = chronic (also influx of Th2 Cd4 cells
What is causing the increased prevalence of allergies?
(three reasons)
Hygeine Hypothesis
- Th1–> Th2 shift
- decreased Treg cell number and activity
(Also changes in indoor air quality and changes in lifestyle)
Mast cells differentiate in response to _____ and ______
What is their main receptor?
CD117 (c-kit) & **SCF **(stem cell factor)
- FcERI (high affinity)
___ is the high affinity mast cell receptor, and ___ is the low affinity one
High = FcERI – Mast cells and basophils
Low = FcERII – BC, TC, monocytes, FDC’s
FcER1 receptors have __ domains and must ___ in order to activate mast cells
4 domains
crosslink
Preformed and de novo inflammatory molecules released by mast cells
Preformed
- Enzymes (tryptase, chymase, etc)
- Toxic Mediators (histamine, heparin)
De novo
- Cytokines (TNFa, IL, GM-CSF)
- Chemokine (CCL3)
- Lipid mediator (Leukotrienes and PAF)
Histamine is formed from ____
It works by binding to _____
It is inhibited by _____
Histidine
H1 receptors
H1 antagonists
H1 receptors are present on…
endothelial cells
smooth muscle
nerve cells
hematopoetic cells
Basophils have a similar function to _____ (they express ____ )
They have a role in _______
Mast cells (express FceR1)
role in TH2 differentiation
Monteleukast (a.k.a. _____) inhibits what thing?
Monteleukast = Singulair®
Inhibits Leukotriene LTC4
Eosinophil granules rich in _________
Examples?
What stimulates the production of these granules?
Basic proteins
- Major Basic Protein
- Eosin. cationic protein
- Neurotoxin
Stimulated by IL-5
Activated eosinophils express
FceR1
Degranulation of eosinophils is induced by…
- Eotaxin
- C5a
- Antigens (via IgE…crosslinking of FceR1)
IL-12 drives differentiation of what?
What is produced after it differentiates?
Th0 -> Th1
Produces IFNg
IL-4 drives differentiation of what?
What is produced after differentiation?
Th0 –> TH2 cell
IL - 4, 5, 13
(involved in allergies)
Main driver for the isotype switch that causes:
IgM/IgD naive B cell –> IgE B cell
IL4
(IL13 plays a role too?)
How does IgE B cell decide if it wants to be a memory cell or plasma cell?
The path of differentiation depends on the cytokines present
What happens when TH0 cell isn’t really exposed to any of the previously mentioned factors (IL-12, IL-4)?
It becomes a Th17 cell and produces IL-17
What is atopy/atopic syndrome?
Genetic predisposition to IgE production
(allergies tend to be familial, predisposition varies from person to person)
5 properties if inhaled allergens
3 examples?
- Proteins (induce T cells)
- Proteases (distupt epith.)
- High solubility/stability
- Low molecular weight
- Low dose
- Contains peptides that bind MHC2
Pollen, dust mites, cockroach antigens
Chronic manifestations of allergies
-
Systemic anaphylaxis:
- IV entry
- Drugs, serum, venom, peanuts
- Edema, increased vascular perm., tracheal occlusion, shock
-
Wheal and flare:
- SubQ
- Insect bites or during an allergy test
- Local increase in blood flow and vascular permeability
-
Allergic rhinitis (hay fever)
- Inhaled
- Edema and irritation of the nasal mucosa
-
Bronchial asthma
- Inhaled
- Bronchial constriction, increased mucous production, airway inflammation
-
Food allergy
- Oral
- V/D, pruritis, urticaria, anaphylaxis
When does a late phase reaction occur?
What is the chart measuring on the slide that shows early/late phase reactions?
after 6-8 hours
PEFR (peak expiratory flow rate)
4 steps for sensitization to inhaled allergens
- First exposure
- Extraction of antigen
- Presentation to T-cell -> activation of Ag-specific T-cell
- Production of IgE (via IgE B-cells), and binding to mast cell
Diagnostic measures for Allergies
- Skin testing (gold standard)
- Avoidance
-
Ag-specific IgE
- RAST = Radioallergosorbent test
- ELISA
- Total serum IgE (not as reliable?)
Allergy to penicillin can cause ___ or ___ reactions
Type 1 or Type 2 hypersensitivity reactions
Allergy to penicillin steps
- Complement-coated penicillin modified RBCs are phagocytosed by MQ
- MQ present peptides and activate CD4 T cells to become Th2 cells
- B cells activated by antigen and Th2 cells
- plasma cells secrete penicillin-specific IgE (which arms mast cell)
- Penicillin-modified RBCs activate the armed mast cell = anaphylaxis
Systemic anaphylaxis: Allergens and response pathway
Insect venom, drugs, food, IV route stuff
- Antigen gets into bloodstream
- Enters tissue
- Activates Connective tissue Mast cells
- Mast cell degranulation and release of inflammatory mediators
Allergic rhinitis steps (4)
- Inhale Ag
- Activates local mast cells
- BV permeability and activation of epithelium
- Eosinophil recruitment
Pathogenesis-es of asthma
-
Acute = Type 1 hypersensitivity
- Mucosal mast cell captures antigen
- releases inflammatory mediators (contract SM, increase mucous and BVP)
-
Chronic = Type 4 hypersensitivity
- Chronic response mediated by cytokines + eosinophil products
Extrinsic Asthma is mediated by ____
Extrinsic = IgE
= A classical Type 1 Hypersensitivity response
(Intrinsic = no IgE)
Clinical Sx of asthma
- Coughing, Weezing
- Hypersensitive airways
- Increased number of Goblet cells
Tx of allergic reactions
- Avoidance (best)
-
Desensitization
- Increase Ag dose – shift to Th1 response or induce IL10/TGFb secreting Treg cells
-
Drugs
- Inhibitors of inflammation (CS’s, Anti-LTC4, Chromolyn Sodium)
- Bronchodilators
- Antihistamines
- Anti-IgE (omalizumab)
Drug-induced blood cell dyscrasias-
related to _____
Idiosyncratic: often immune-mediated ( _____ most common)
Related to pharmacologic action of the drug
Thrombocytopenia most common
Mechanism of antibody-mediated Blood cell destruction:
- Reaction type?
- Antibodies?
- Type 2 HS
- AB’s
- Drug (hapten) specific
- Antibody binds to cells in presence of drug or drug metabolite
- True autoantibodies
- Fibrinogen receptor (GP2b3a) antagonists
Penicillin modifies proteins on ____ to create _____
human RBCs
foreign epitopes
Production of anti-penicillin AB’s (4 steps)
- Complement coated penicillin-modified RBC’s are phagocytosed by MQ
- MQ present to CD4 cells to become Th2
- Th2 cells + antigen both result in B cell activation
- Plasma cells secrete anti-penicillin IgG (that then binds to the RBC)
Lysis and phagocytosis of penicillin-modified RBC
Penicillin-specific IgG binds to proteins on RBC, which leads to:
- Activation of complement factors C1-C9 = MAC formation
- Activation of C1-C3 = covalent bonding of C3b = phagocytosis of the whole thing into a MQ cell
erythroblastosis fetalis - first pregnancy
- Rh negative mom with RH+ baby
- Primary response, Low affinity IgM (and a little IgG) is made
- just a little RBC destruction from anti-Rh IgG (mom’s)
- Baby is born healthy
Erythroblastosis fetalis - second pregnancy
- Rh negative mom with Rh positive baby (again.)
- Secondary immune response = high affinity IgG traverses the placenta into fetal circulation
- Massive RBC destruction by mom’s anti-Rh IgG
- Anemia in the baby
Tx for Erythroblastosis Fetalis
anti-Rh IgG’s
(Just enough to bind to fetal RBC that are entering maternal circulation and trick’s mothers system into thinking it already has IgG’s against it so she doesn’t make more when the next baby comes)
Coombs test
_Direct _
- Use washed fetal RBC **coated with maternal antibody **
- add coombs reagent (anti-human AB)
Indirect
- Add Rh+ cells to maternal serum
- add coombs reagent
What is Coomb’s reagent
Rabbit anti-human antibody
Arthus rxn is a ____ response
Induced by….
Example?
Localized response
…induced by injection of soluble antigen in pt. with pre-existing AB’s
Example = desensitization of IgE-mediated allergies
Arthus reaction steps (4)
What is the end (tissue) result?
Over what amount of time does this occur?
- Local injected antigen in a patient with existing IgG
- Immune complex activates complement
- C5a binds to C5 receptor on mast cell
- Binding of immune complex to FcrIII receptor on Mast cell = degranulation
Result = Local inflammation, BV occlusion, fluid and protein release
*occurs over 1-2 hours
T3HS reaction caused by _____
Clinical Sx depend on ____ and ____
Inflammation is induced by ____ and ______
Immune complexes (IgG + Ag)
Size and localization of IC’s
Complement activation and PMN’s
3 Types and examples of systemic immune complex diseases (T3HS)
Serum sickness (repeated foreign protein injection)
Chronic infections (subacute bacterial endocarditis)
Chronic Autoimmune disease (RA, SLE)
Results of IV, subQ, inhaled routes of T3HS reactions
IV = vasculitis, nephritis, arthritis
SubQ = arthus reaction in the perivascular area
Inhaled = Farmer’s lung
