Flashcards in L55 Hypersensitivity reactions Deck (103):
Name the 4 types of hypersensitivity reactions?
a) I – Immediate hypersensitivity
b) II – Antibody-mediated hypersensitivity
c) III – Immune complex mediated hypersensitivity
d) IV – Delayed (T cell-mediated) hypersensitivity
5 classes of antibodies>?
IgG, IgM, IgD, IgA1, IgE
What receptor is expressed by macrophage to recognize which antibody?
Fcγ receptor to recognize IgG
What are 3 outcomes of the activation of classical complement system?
Complement fragments (e.g. C3b receptor)
osponize microbes >> phagocytosed
Is classical complement activation complement specific?
What are the key/ signature cytokines produced by:
Th1 = IFN-γ (does not secrete IL-4)
Th2 = IL-4 (does not secrete IFN-γ)
Th17 = IL-17
Treg = IL-10
What is the role of Treg?
Immune tolerance and regulation
What is the difference in the pathogens that activate Th1, Th2 and Th17?
Th1 = Viral and INTRAcellular bacteria
Th2 = Extracellular parasite
Th17 = Extracellular bacteria and Fungal
In autoimmunity, which T helper cells are expressed?
In Humoral immunity, which T helper is expressed?
What is the nature of Hypersensitivity reaction?
What is the result?
Normal antigen-driven adaptive immune process, but exaggerated in
response magnitude / inappropriate form
Cause host tissue damage
Can be life-threatening
Compare the corresponding antibody/ mediator to type of hypersensitivity reaction?
I = IgE
II = IgM/IgG + complement
III = Antigen-antibody immune complexes (IC)
IV = Th1 T helper cells
Compare the speed of hypersensitivity reactions?
II = fast
III = slow
IV = delayed
What WBC detects allergen by responding to IgE in Type I hypersensitivity rxn?
What is the receptor on mast cell for Ab?
high affinity receptor for Fc portion of IgE antibody (FcεRI)
What are some symptoms of Rhinitis in Type I hypersensitivity?
Rhinitis: itchy nose, mouth, eyes, throat, skin
Sneezing, runny nose, nasal congestion
Tearing eyes, coughing
Where are mast cells located? Are they in the blood stream?
tissues exposed to environment (e.g. skin, mucosal lining of respiratory tract, digestive tract, conjunctiva)
Do not circulate in blood
What is contained in mast cells?
Pre-formed granules containing histamines and proteases
What are some allergens for Type I hyp. reaction?
Faecal pellets of housemold mites (Der P1 protein from Dermatophagoides pteryonyssinus)
What are the 2 routes of action in Type I hyp. rxn?
1) IgE mediated mast cell degranulation
2) Th2 response - sensitization and activation for RE-EXPOSURE to allergen
Explain the action of IgE mediated mast cell degranulation ?
1) allergen binds to IgE on mast cell surface
2) Cross link of IgE receptor (FcεRI) >> Influx of Ca2+ intracellularly >> Initiation of intracellular signalling events
3) Induce rapid degranulation
What is the immediate response of mast cell after stimulation by allergen?
Exocytose pre-formed granules > release:
1) Vasoactive amines (e.g. histamine, serotonin)
2) Inflammatory mediators, heparin
3) Proteases (e.g. typtase, chymase)
What is the role of Vasoactive amines (e.g. histamine, serotonin) and Inflammatory mediators, heparin?
-smooth muscle contraction, -Increase glandular / mucus
-Increase vascular permeability
-Increase sensory neural
What is the role of proteases (e.g. tryptase, chymase)?
Proteolysis of damaged tissue
What is the response of mast cell within hours of being stimulated by allergen?
activate enzymatic modification of arachidonic acid >> secrete lipid mediators
What lipid mediators are secreted by mast cells?
What is the role of prostaglandin?
Vascular dilatation, pulmonary smooth muscle contraction, platelet
What is the role of Leukotrienes?
Increase vascular permeability
What is the role of BRADYKININ?
Increase vascular permeability, smooth muscle contraction
What is the response of mast cells within days of being stimulated by allergen?
activate transcription of cytokine genes >> secrete pro-inflammatory cytokines
What is the role of pro-inflammatory cytokines?
Recruit inflammatory / immune cells
Link the following symptom of localized allergic reaction with physiological changes:
Watery eyes, Rhinitis (runny nose)?
Increased mucus secretion
Induced by vasoactive amines, proteases
Link the following symptom of localized allergic reaction with physiological changes: Angioedema, Hives (skin flush, itching)?
Vasodilation and increased vascular permeability
Induced by Vasoactive amines, prostaglandins, leukotrienes, bradykinins:
Link the following symptom of localized allergic reaction with physiological changes: Wheezing, shortness of breath, chest tightness?
Bronco-constriction due to smooth muscle contraction
Induced by: Vasoactive amines, prostaglandins, leukotrienes, bradykinins, platelet-activating factors
Link the following symptom of localized allergic reaction with physiological changes:
Coughing, sneezing, itchy sensation?
Sensory neural stimulation
Induced by Vasoactive amines
Name the two localized allergic reactions in type I hyp. rxn?
Describe the sensitization phase in Th2 reaction in type I hyp. rxn?
Allergen binds to naive B cell receptor > recognized by CD4 on Th2
Th2 secrete IL-4,5,13 to induce B cell differentiation>> plasma cells to make allergen specific IgE
IgE binds to IgE receptors (FcεRI) on mast cells >. mast cells are sensitized
Describe the activation phase in Th2 reaction in Type 1 hyp rxn?
UPON RE-EXPOSURE OF ALLERGEN
IgE receptors (FcεRI) crosslink >> intracellular Ca2+ flux >> initiate intracellular signaling
events >> induce rapid mast cell degranulation
What type of hyp rxn is anaphlaxis? What is the difference in symptoms compared to normal type 1 HS?
Severe form of Type 1 HS
Difference: Anaphylaxis causes systemic reactions rapidly
Normal type 1 HS causes localized symptoms (rhinitis, asthma)
Name some allergens causing anaphylaxis?
bee stings, medication (antibiotics), food
compare the mast cell degranulation in anaphylaxis vs normal type 1 HS?
Anaphylaxis = IgE-mediated mast cell degranulation in MULTIPLE tissues
Normal Type 1 HS = '' in localized tissue
What are 4 main symptoms of anaphylaxis?
1) bronco-constriction > shortness of breath
2) Swelling of larynx > airway obstruction
3) Extensive vasodilation of blood capillaries > rapid hypotension > Shock
4) Coronary spasm > cardiac arrest
What is the treatment for anaphylaxis?
Apart from systemic anaphylaxis, allergic rhinitis and asthma, what are 2 other IgE mediated allergic reaction?
Food allergy (e.g. to shellfish, milk, eggs, fish, wheat) >> causes vomiting, diarrhea, pruritis, hives
Wheal and flare (e.g to insect bites or allergy testing) >> causes local vasodilation and edema
What blood cell works with IgE to fight blood borne helminths?
IgE-mediated allergic reaction have different consequences depending on?
1) Dose of allergen
2) Route of entry
How are " high risk" people to type I allergic reaction different to low risk individuals?
High risk = Genetically susceptible to Type 1 HS >> have much high levels of IgE than low risk individuals
What is hygiene hypothesis?
Microbial exposure in early life has protective influence in the development of allergy and asthma
What allergy tests can be done for Type 1 HS?
a) Patch test
b) Prick/ scratch test
c) Intradermal test
Blood test> ELISA to test for allergen-specific IgE
How do skin tests for allergic reaction work?
Delivery tiny and controlled amount of extracts from potential allergens
Look for reaction over time:
Red, itchiness, swelling, hives
What are 3 treatment options for allergy?
1) Avoidance of allergens
What are 4 groups of drugs for treating allergy?
A C C ISE
A Cute Cat Eats Icky Shellfish *allergy*
-B agonists: Epinephrine, Isoproterenol, Salbutamol
Name some antihistamines?
histamine receptor blockers (H1 and H2)
What is the role of corticosteroid and cromolyn sodium?
- Corticosteroid: immune suppression
- Cromolyn sodium: prevents mast cell degranulation
What are the effects of Salbutamol, Epinephrine, Isoproterenol?
Adrenaline-like substances: reverse effect of histamine
Epinephrine (β agonist >> potent cardiac stimulant)
Salbutamol (β2 agonist >> treat asthma)
Isoproterenol (β agonist>> increase HR, increase SBP, lower DBP)
How is de-sensitization done to treat allergy?
immunization of small, increasing amount of allergen over a long period of time
What are the 2 possible mechanisms of de-sensitization in treating allergy?
Develop allergen-specific IgG for antigen competition (less IgE binding)
Develop allergen-specific regulatory T cells (Treg) >> suppress effector T cell responses
What are the risks of de-sensitization in treating allergy?
Effectiveness not universal
Risk of triggering the hypersensitivity reaction
What is the mediator of Type II HS?
IgM/ IgG + Complement system
What is the effector of Type II Hs?
Complement mediated Cytotoxicity/ cell lysis/ dysfunction
*Not mast cells*
Explain the action of type II HS?
antigen -antibody immune reaction > activate complement > Complement mediated Cytotoxicity > cell lysis
What is a problem of type II HS?
Targets normal cells
Give two possible causes of Type II HS?
Incompatible blood transfusion
Haemolytic disease of newborn
Explain the cause and outcome of incompatible blood transfusion?
Haemolytic reaction of the donor's red cells by antibody of the recipient (e.g. Group O recepient receives Group A blood > donor's group A blood reacts with the Anti-A antibodies in recipients plasma)
>> complement - mediated lysis of RBC
Majority of people are Rh +ve or -ve?
If one is Rhesus -ve, what antibody does the person have?
Majority = Rh+ve
If Rh-ve: have anti-Rh IgG
What is the baby Rh if mother is Rh -ve and father is Rh +ve?
Baby = Rh +ve
Explain how anti-Rh IgM doesn't develop during 1st pregnancy of a Rh-ve mother bearing a Rh+ve baby?
During 1st pregnancy: fetal RBCs are sheltered from maternal circulation by the placenta
Explain how anti-Rh IgM develops in Rh-ve mother during 1st delivery of a Rh+ve baby?
Deliver > Placenta separates from uterine wall >
**Rh antigen on fetal RBC meets with Rh-specific B cell in maternal circulation**
> Mother B cells differentiate into:
1) memory cell**
2) plasma cells which produce anti-Rh IgM**
What does the anti-Rh IgM do in the blood stream contaminated with Rh+ve blood?
Secreted IgM clears Rh+
How come a Rh-ve mother causes haemolytic disease during her 2nd pregnancy?
Mother already acquired anti-Rh IgM plasma and memory cells from first pregnancy
Maternal blood can diffuse across placenta to attach fetal RBC during 2nd pregnancy > haemolytic disease
What is the name of the fetal haemolytic disease caused by Type II HS?
(IgG-mediated attack of fetal RBC >> ADCC, phagocytosis... etc)
Compare the type of immune response between the 2nd and 3rd pregnancy of a Rh-ve mother baring Rh+ve children?
2nd preg = primary immune response
3rd preg = secondary immune response
Explain the process of Myasthenia gravis? (type II)
anti-acetylcholine auto-antibodies cause blockage of Ach receptors >> block neurotransmitter signaling at neuromuscular junction
>> cause muscle weakness
What are the mediators and effectors of Type III HS?
Immune complex mediated HS
Mediator: antigen-antibody immune complexes
Effector: IC-mediated inflammatory responses
Explain the action of Type III HS?
antigen-antibody immune complexes (IC): form aggregates in circulation >> deposit in small vessels in tissues
>> activate complement, IC-mediated inflammatory
What are the two immune complex mediated inflammatory responses in type III HS?
1. Complement-, Fc receptor-mediated inflammation
2. Osponization, phagocytosis
IC complexes circulate and deposit at which tissues?
Small vessels in joints, kidneys, skin ...
Explain the action of Complement- and Fc receptor-mediated inflammation?
complement by-products C5a, C3a >> attract and activate neutrophils >> chemotaxis to injured tissue > release enzymes, reactive oxygen intermediates at site
Explain the action of Osponization, phagocytosis?
C3b osponizes cell >> cell recognized by C3b receptor + Fc receptor on phagocyte>> phagocytosis
List 4 consequences of Type III HS?
Neutrophil attraction and activation
Platelet aggregation and microthrombus formation
Systemic Vasculitis and inflammation
What are the results of systemic vasculitis at joints, kidneys?
Joints : arthritis
Kidneys : Glomerulonephritis
What is serum sickness?
Transient allergic reaction to foreign serum proteins in
anti-serum of foreign / non-human sources
(e.g. as treatment to snakebite)
How are foreign serum proteins resolved in the body?
Day 5-8 after foreign serum injection: form antigen:antibody
complexes >> fever, vasculitis, arthritis, nephritis
By Day 9: high level of antibody against foreign serum proteins >> clear
What is SLE? which gender predominate?
Systemic lupus erythematosus
What causes SLE?
Loss of tolerance to self-antigens >> pathogenic antinuclear autoantibodies >> IC -mediated tissue / organ inflammation
What are some symptoms of SLE?
What are the effectors and mediators of Type IV HS?
Delayed -type hypersensitivity
Mediator = Th1
Effectors= Cell-mediated inflammatory responses (CMI), involving macrophages and CD8 T cells
Onset of Type IV DTH ? What is this HS against?
1-2 days after antigen exposure
Against facultative intracellular micro-organisms (e.g Mycobacterium tuberculosis)
Explain the sensitization phase of Type IV DTH to produce CD4+ T cells?
APC (e.g. macrophages, Langerhans cells) take up antigen / allergen >> migrate to lymph node to activate T, B cells towards site of infection
>> differentiate T cells to mostly CD4+ Th1 (sometimes CD8)
what cytokines and chemokines are secreted by Th1, and what are the results of the secretion?
Cytokines: IFN-γ , IL-12 , TNF-β ... etc
Chemokines: IL-8, CXCL8, MCP-1 ... etc
rapidly recruit, activate macrophages, CD8+ T cells, neutrophils
After macrophages are activated in Type IV DTH, what are the cell-mediated inflammatory responses of macrophages?
Increase production of:
Class II MHC
In type IV DTH, what is the result of re-exposure?
Rapid recruitment of macrophages that produce TNF- a + CD8+ T cells
> inflammatory infiltration, local edema and erythema
In contact hypersensitivity, allergens are taken up by which cells?
Dendritic cells and APCs
>> migrate to lymph nodes for T cell activation and Th1 development
Explain how TB causes granulomatous hypersensitivity?
Intracellular pathogen initially infects and activates alveolar macrophages to phagocytose > but ****cannot clear the infection****
continue to present Mtb antigens to TH1 cells >>
cause endless acitvation of macrophages, migration of B, T cells
>> TB granuloma
What is the structure of Tb granuloma?
Center = persistent antigen
Surrounded by necrotic tissue, multinucleated giant cells / epitheloid / foamy
macrophages, lymphocytes and granulocytes
What is the cytokine used by Th1 to stimulate macrophages?
What is the cytokine used by dendritic cells to stimulate Th1 differentiation?
What is the role of TB granuloma formation?
Fence off infectious agents and prevent dissemination
Apart from TB, what are some other diseases associated with granuloma formation?
Leprosy, Shistosomiasis, Sarcoidosis, Crohn's disease
What is the test for TB infection?
Tuberculin skin test
Subcutaneous inject of purified protein derivative (PPD) from infectious TB strain
Tuberculin skin test gives positive results under which 2 situations?
response in 48-72 hours if
1) Exposed to Mtb
2) Patient is vaccinated with BCG > gives false +ve result
Compare the manifestations of HS?
I = Allergy, anaphylaxis
II = Cytotoxicity/ abnormalities in cell function
III = systemic immune complex deposition
IV = systemic and local inflammation, granuloma