Allergy and Immune Response to Parasites Flashcards
1
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*Explain why multicellular parasites are difficult to eradicate
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2
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*Describe when and how IgE is synthesized
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3
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*Discuss the role of IL-4 and IL-13 in the development of immunity against parasites
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4
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*Describe how Ig E participates in protective immunity against parasites
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5
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*Compare and Contrast FceRI and FCeRII receptors
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6
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*Compare and Contrast the function of mast cells, basophils, and eosinophils against parasites (include their distribution, life span and mediators released)
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7
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*Define the term allergy and describe the hygiene hypothesis
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8
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*explain the factors which predispose an individual to allergies
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9
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*Discuss how an individual becomes sensitized to type I hypersensitivity
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10
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*Explain why type I hypersensitivity is referred to as “immediate”
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11
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*Describe the consequences of mast cell degranulation
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12
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*Distinguish between the early and late phases of type I hypersensitivity (clinical presentation, cell types, and mediators involved)
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13
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*Describe how the dose and route of antigen entry influence clinical presentation.
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14
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*Discuss treatment options for type I allergies
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15
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*Describe the mechanism underlying type II, type III, type IV hypersensitivity
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16
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*Discuss the two common examples of type II hypersensitivity. Explain how each arises and can be prevented
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17
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*Recognize how the form of antigen differs between type II and type III hypersensitivity
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18
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*Compare and contrast local vs systemic type III hypersensitivity reactions giving examples of each
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19
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*Explain the mechanism leading to contact dermatitis; include the types of compounds that cause it
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20
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*Examine how a drug can cause type I, Type II, Type III hypersensitivity
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21
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*List the main cytokine mediators of each hypersensitivity reaction
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22
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*Compare and contrast 4 types of hypersensitivity reactions; list the antibody class, cell types and mechanisms( effector functions) involved with each
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23
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why are multicellular parasites difficult to eradicate?
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Multicellular parasites are difficult to eradicate because they are LESS antigenic (more alike with humans, epitopes similar), they CANNOT be engulfed (too big for phagocytosis) and they have a LONG life span.
24
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How do IgE- mediated immune response help defend the body against multicellular parasites?
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Ig E defend the body against multicellular parasites (helminth worms) through:
-innate immune mechanisms and TH2 arm of adaptive immunity
Ig E is involved in TH2 mediated immunity to eliminate parasites from the body (by coughing, sneezing, vomiting, diarrhea).
25
What are the components of a typical adaptive immune system against helminth worms?
components: of adaptive immunes system against helminths:
T cells (cd4 TH2 cells)
Cytokines- IL-3, IL-4, IL-5, IL-9, IL-10, IL-13
Antibodies (IgE, IgG1, IgG4)
Effector cells (expanded populations of eosinophils, basophils, mast cells)
26
What are the functions of IL-4?
IL-4 functions:
1. induce differentiation of Th2 cells
2. cause class switching to IgE.
Basophils secrete IL-4.
27
Describe the properties of IgE.
IgE properties:
- IG E antibodies arise because of class switching
- Role of TH2 cells to make IL-4 and cause B cells to switch to Ig E.
- Ig E have serum levels: 5x10 ^-5 mg/ml
- Diffuses across endothelium which then binds Ig E R1 receptors of mast cells, basophils, and activated eosinophils
- IgE has unique structural conformation (4 constant heavy chains, bent configuration; asymmetrical) , unique CH2 domain
28
Differentiate between the two types of Fc receptors. Which one is high affinity vs low affinity?
-FcERI- HIGH affinity
-Tetramer
-alpha chain- that binds ig E
(single igE binding polypeptide)
-Beta, gamma, gamma- signaling function
-HYDROPHOBIC interaction between ChE2/3 and alpha chain (Ch2, ch3 )
-Mediates Effector functions of Ig E
2. FcERII- LOW affinity
-Homotroimer- CD23 on B CELLS
can bind up to 3 Ig E molecules.
-*Regulates the production of Ig E
-cell surface and soluble forms
*remember that Ig E binds to high affinity fcERI receptors on mast cells, basophils, and activated eosinophils, monocytes, platelets.
29
compare and contrast the specificity for B cells vs mast cells.
B cells:
-have 50,000-100,000 BCRS (b-cell receptors)
-They have the SAME specificity for all receptors .
Mast cells:
-mast cells maintain the depot of antigen-specific igE
- > 500,000 FcERI receptors
-Represent a type of memory (hence, they allow longer life Ig E)
-hold DIVERSITY of antigen-SPECIFIC Ig E
-they can respond to many different antigens
30
Why are mast cells so important?
Mast cells can respond/bind to thousands of different antigens, which make them versatile and different
they are also fast responders since their granules contain inflammatory mediators that are secreted immediately after antigen binds to cell surface IgE.
31
compare and contrast the essential cell types of Ig E mediated immunity (basophils, eosinophils, mast cells)
Ig E mediated immunity: Essential cell types
1. Mast cells- resident in tissues lining the body surfaces/organs
-present in all vascularize tissues (except CNS)
-cytoplasm contains abundant granules
-LONG LIVED
express FcERI
-have 2 different types of Mast cells (based on location):
Mucosal (GI and respiratory tract); expressing tryptase and Connective tissue (skin, surrounding blood vessels); express chymotryptase
2. Basophils
-start with BASIC dyes (hematoxylin) present in blood
-express FcERI
-SHORT LIVED
-Function similarly to mast cells
3. Eosinophils
-small #s in blood; most in tissues
-express FcERI when ACTIVATED
(they migrate into tissue, due to chemokines)
32
Describe the protective functions of mast cells and basophils
Protective functions of mast cells and basophils:
Innate and Adaptive immunity:
*1. Toll like receptors : secrete cytokines
*IL-4 and Il-13 which AMPLIFY TH2 response
IL-5 which leads to Eosinophil activation/production
2.* FcERI on mast/basophils, bind Ig E against parasites leading to Quick and efficient response (Degranulation)
3. Fc gamma and Fc Alpha receptors form cytokines.
basophils produce IL-4 and Il-13.
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What are the mediators of the Mast cell?
Mast cell mediators:
preformed mediators:
-Enzyme (tryptase, chmyase, cathephin G, carboxypeptidase)- that remodel Connective Tissue Matrix
-Toxic mediators: histamine and heparin poison parasites, increase vascular permeability, increase smooth muscle contraction
-Cytokine- TNF alpha will promote inflammation, stimulate cytokine production and activate endothelium
Newly synthesized mediators:
cytokines: IL-4, IL-13 that stimulate/amplify TH2 response; IL-3, IL-5 and GM-CSF promote eosinophil production/activation
Chemokine: CCL3 attracts monocytes, macs, neutrophils
Lipid mediator: Leukotrienes C4, D4, E4 that cause smooth muscle contraction, increase vascular permeability and cause mucus secretion
platelets-activating factor also attracts leukocytes, amplifies production of lipid mediators, activates platelets, neutrophils, eosinophils.
34
Further elaborate on the preformed mediators of Mast cells.
Preformed Mediators (Mast cells)
1.Histamine- increased blood flow
H1 receptors- in vascular endothelial cells- cause vasodilation (increased permeability)
Smooth muscle cells ; where bronchoconstriction occurs
Heart and brain
H2 receptors- vascular endothelial and GI
H3 and H4 receptors- CNS and bone marrow,
2. Serotonin- similar to histamine
3. Proteases- tryptase, chymotryptase,- break down Extra cellular matrix (ECM)
4. TNF-alpha- cytokine that increases expression of ADHESION molecules, activate endothelium and promotes inflammation
5. Chemokines (CCL3)- chemotactic factor (activate macs, neutros, monocytes)
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Describe the Newly synthesized mediators of Mast cells
Newly synthesized mediators (mast cells):
-cause sustained effects (late phase reaction)
1. Prostaglandins
-in smooth muscle cells- cause constriction
-Endothelial cells in blood vessels- cause vasodilation
Chemotactic for neutrophils.
2. Leukotrienes (SRS; Slow Reactive Substance)
-cause smooth muscle contraction, increase vascular permeability, mucus secretion
Leukotriene- SUPERMAN of Histamine (more potent)
3. Cytokines (IL-4, IL-13 stimulate TH2; IL-3, IL-5, GM-CSF promote eosinophil production/activation)
36
Differentiate between the appearance of resting mast cell vs an activated mast cell
Resting mast cell: have granules intact, containing its contents, inflammatory mediators.
Activated mast cell: contents in granules have been released, a lot of membrane left.
37
Describe the mechanism of how arachadonic acid can be converted into other compounds
Arachadonic acid can be converted through Cyclooxygenase pathway to form Prostaglandins
Arachadonic acid can also be converted through 5-Lipooxygenase pathway- forming Leukotriene
38
How does aspirin affect prostaglandins? which is more powerful (leukotrienes or prostaglandins?)
Aspirin will inhibit the formation of prostaglandins
| Leukotrienes are more powerful than prostaglandins.
39
What are the protective functions of Eosinophils in the late response?
Protective functions of Eosinophils (late response)
- Resident in connective tissue underlying the respiratory, GI, urogential tracts.
- have IL-5 receptors (which increase production of eosinophils), TLRs (toll-like receptors) and FcER1 (when activated)
- They release highly toxic mediators- for direct killing
- Release cytokines to amplify inflammatory response
40
discuss the important preformed mediators vs newly synthesized mediators for Eosinophils
Eosinophil preformed mediators:
1. Eosinophil peroxidase- poisons parasites and mammalian cells by catalyzing halogenation; triggers histamine release from mast cells
2. Major basic protein- poisons parasites, and does same function as eosin peroxidase.
3. Eosionophil cationic protein- poisons parasites, neurotoxin
All three of these mediators are TOXIC and cause damage to parasites
Eosinophil Newly synthesized mediator;
* 1. Leukotrienes (C4, D4, E4) that cause smooth muscle contraction, increase vascular permeability, cause mucus secretion
Leukotrienes and prostaglandins are lipid mediators.
also cytokines (Amplify eosinophil production/activation), chemokines (CXCL8) and platelet activating factor(attracts leukocytes, amplifies production of lipid mediators) all part of newly synthesized mediators
41
Define what an allergen/hypersensitivity is. provide examples of allergens.
Allergy/hypersensitivity- damaging immune response to innocuous (harmless) antigens
human come into daily contact with harmless macromolecules.
Environmental antigens= allergens
ex: plant pollen and dust mite feces (inhaled materials), insect venom and drugs (injected materials), peanuts and shellfish (ingested materials) and plant oil or metal (contact materials)
42
What are the 4 types of hypersensitivities and when do they occur?
The 4 types of Hypersensitivities:
Type I hypersensitivity
Type II hypersensitivity
Type III hypersensitivity
These three are all ANTIBODY-mediated
Type IV hypersensitivity- T cell mediated
These hypersensitivity reactions occur when an already immune or SENSITIZED individual is re-exposed to initiating substance (antigen)
-antibody will be directed against allergen already present.
43
How can you differentiate the types of hypersensitivity?
The types of hypersensitivity are differentiated by:
1. Time required to produce clinical symptoms
2. Antibody class involved
3. Cell types involved.
44
Describe the features of Type I hypersensitivity
Type I Hypersensitivity
- IMMEDIATE hypersensitivity (symptoms appear in 10-15 mins with exposure to antigen)
- mediated by Ig E in response to allergens
ex: pollen, pets?
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Where are type I allergies prevalent?
Type I allergies are prevalent in countries where parasite infections have been eliminated.
46
Describe the concept behind Hygiene hypothesis.
Hygiene Hypothesis- when excessive hygiene reduces childhood exposure to commensal and pathogenic microorganisms as well as to humans and to animals.
-Also, vaccination reduces immune system's experience to face natural infections and fight them successfully.
-Overreliance on antibiotics to terminate infection reduces use of immune system and its education in discrimination of self from foreign pathogens
and all of these factors lead to development of child's immune system being held back (poorly, educated, inexperienced, in fighting infections.
47
What are allergens?
Allergens - are protein antigens, that resemble parasite antigens.
48
What are the features of inhaled allergens that promote the priming of the TH2 cells that drive Ig E response?
Features of inhaled allergens:
1. they are protein antigens
2. Many of allergens are PROTEASES
3. Low dose of allergens that favor activation of IL-4-producing CD4 T cells
4. Low molecular mass (allergen diffuses out of particle into mucus)
5. High Solubility- allergen is readily eluted from particle
6. High Stability- allergens can survive in dessicated particles.
7. contains peptides that bind host MHC Class II.
49
What allergen is responsible for > 20% of allergens in North America?
The Cysteine Protease from D. Pteronyssinus (DUST MITE) is responsible for . 20 % of allergens in North America.
50
What factors can predispose an individual to type I hypersensitivity? Elaborate on these factors.
GENETIC and ENVIRONMENTAL factors can predispose an individual to Type I hypersensitivity
Genes:
MHC class II genes- lead to enhanced presentation of particular allergen-derived peptides
T-cell receptor alpha locus- enhanced T-cell recognition of certain allergen-derived peptides.
IL4 gene (IL-4) - cause variation in expression of IL-4 (cause high hypersensitivity responses)
MHC does not hold antigens (causing allergies ?)
51
What are the three main stages of type I hypersensitivity?
3 stages of Type I hypersensitivity:
1. Sensitization: allergen-specific Ig E binds to mast cells
2. Immediate reaction (10 mins) - allergen triggers cross linking of Ig E on mast cell surface, leading to degranulation
3. Late-phase rxn (1 hour) - synthesis of prostaglandins (vasodilators) and leukotrienes
52
Can a person experience clinical signs/symptoms of allergy the first time they encounter the allergen/antigen? Explain why or why not.
NO, a person cannot have signs/symptoms of allergy first time encountering antigen, because the person must be SENSITIZED first.
53
What is sensitization? Describe the process.
Sensitization:
when person has made primary response to allergen and tissue mast cells are heavily armed with allergen-specific Ig E
process occurs upon FIRST exposure to allergen
Process of sensitization:
1. First exposure to pollen or other allergen (inhale pollen)
2. The pollen particles are then trapped in mucosal surface of airways and allergen is taken up by mucosal antigen-presenting cells
3. The APC's travel down the lymph node, where MHC II present allegen-derived peptides to antigen-specific naive T-cells and*later activates pollen allergen-specific naive B cells (by TFH 2 cells)
4. IL-4 secreted by TFH 2 cells bind to IL-4 receptor and *production of Ig E and its binding to mast cell.
54
Describe the features of immediate and Late-phase reactions
Sensitization first occurs, and alleregen later cross links Ig E on surface of mast cells to trigger mast cell to degranulate.
Immediate Rxn (10 -15 mins) have preformed mediators (Histamine, serotonin, neutrophil/eosinophil and chemotactic factor, cytokines)
These mediators that cause inflammation, swelling, smooth muscle contraction and mucus secretion
Late-phase Rxn (8-10 hours) have Newly synthesized mediators (like leukotrienes, prostaglandins), that bring in eosinophils, basophils, cytokines to cause tissue damage.
55
Describe the clinical appearance present in immediate response followed by late-phase response. (discuss visible signs).
In Immediate reaction: substances that produce sensitivity to injection site will have WHEAL and FLARE reaction at site in a few minutes (15 mins up to 30). This is a consequence of Ig E mast cells being degranulated and HISTAMINE being released;
released histamine and other mediators increase permeability of blood vessels, and cause swelling (edema).
WHEAL- swelling at injection site
FLARE- caused by increased blood flow to surrounding area.
Late phase reaction-
-occurs 6-8 hours later (after immediate reaction)
-leads to widespread edematous (swelling) reaction caused by leukotrienes, prostaglandins, chemokines and cytokines.
56
How can one be tested for allergies?
Allergists can test a person's sensitivity to allergens by injecting small quantities of common allergens into the skin or back of forearm
57
What is the role of eosinophils during late phase reaction? What promotes and activated eosinophils?
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In the late phase reaction:
Eosinophils:
1. Release toxic granular proteins
-tissue injury
2. Amplify the inflammatory response
-chemokines
-prostaglandins
-leukotrienes.
IL-5 promotes activation, differentiation and survival of eosinophils.
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58
Explain how the dose route of allergen administration determines its outcome
The route of exposure to allergen can influence how you exhibit symptoms.
ingestion, inhalation or injection of allergen into skin or blood will all lead to mast cell activation and degranulation
1. Ingestion: will lead to increased fluid secretion, increased peristalsis in GI (gastrointestinal) tract; which leads to expulsion of GI tract contents by
diarrhea/vomiting
2. Inhalation: lead to decreased diameter of Airways and Increased mucus secretion in airways; which leads to expulsion of airway contents through coughing, sneezing and expulsion of phlegm.
3. Injection of allergen into blood or skin, leads to increased blood flow and increased permeability in blood vessels: causing EDEMA and INFLAMMATION; also increased flow of antigens in lymph to lymph nodes.
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*What happens when allergens are in blood?
Allergens in the blood trigger Systemic anaphylaxis (systemic response to allergen).
Anaphylactic shock- itchy rash, nausea/vomiting, rapid drop in blood pressure, difficulty breathing, organ damage
Causes of anaphylactic shock: INJECTED allergen (stings from insects or bees; drugs): INGESTED allergen (ate from food)
60
Further elaborate on what occurs when an antigen is in blood stream and discuss clinical symptoms associated with it.
1. Antigen in bloodstream enters tissues and activates connective tissue mast cells throughout the body
- (blood capillary will diffuse outward, and bind Ig E)
2. This will lead to mast cell degranulation and release of inflammatory mediators.
- In heart and vascular system: have increased capillary permeability, and entry of fluid into tissues; swelling of tissues (including tongue), Loss of blood pressure, reduced oxygen to tissues, irregular heart beat, anaphylactic shock and loss of consciousness
- Respiratory tract- get contraction of smooth muscle, constriction of throat and airways, difficulty swallowing and breathing, wheezing
- GI tract (Gastrointestinal tract)- contraction of smooth muscle, stomach cramps, vomiting, fluid outflow into gut, diarrhea.
61
Discuss the systemic anaphylaxis that occurs following a bee sting? Describe what occurs and clinical symptoms present. How can this be treated.
Systemic anaphylaxis following Bee sting
1. Bee venom penetrates skin and enters bloodstream.
-Then circulatory system spreads venom throughout the body
2. Bee venom encounters mast cells within tissues.
-Bee venom cross-links Ig E antibodies. The cross-linking triggers the release of various biologically active substances
many symptoms may occur:
dizziness, seizures, loss of consciousness (due to drop in blood pressure) , lips/tongue/throat swell making breathing and swallowing difficult. Also irregular heartbeat, or heart attack can occur (due to low bp),
skin may be reddened, rashes, severe itching may develop.
Treatment: EPINEPHRINE (as it will reverse vasodilation, reform Tight junctions in endothelium, reduce permeability, loss of fluid and cause rapid increase in blood pressure, relax smooth muscle (easier to breathe)
62
Explain how antibiotics can cause systemic anaphylaxis
Antibiotics can cause systemic anaphylaxis (most severe form, common cause of system anaphy.)
1. complement-coated penicillin modified erythrocytes are phagocytosed by macrophages.
2. Macrophages will present peptides from the penicillin protein conjugate and activate specific CD4 T cells to become TH2 cells.
3. B cells are activated by antigen and by help from activated TH2 cells.
4. Plasma cells secrete penicillin specific IgE which arms mast cell.
5. penicillin modified erythrocytes activate armed mast cells, causing anaphylaxis.
63
Describe the special features of penicillin
Penicillin- a HAPTEN and therefore NOT able to induce the production of antibodies
Penicillin is cleaved by Beta-Lactamase- reactive groups covalently bonded with proteins on host-cell surfaces.
remember an allergic reaction to penicilin (example of Type I hypersensitivity).
64
Describe the type I Hypersensitivity in the SKIN.
Type I hypersensitivity in SKIN: cause Urticaria and Angioedema
allergens that activate mast cells in the skin will cause histamine to be released and cause Urticaria(Raised, itchy swellings. Urticaria is also known as HIVES (less severe hypersensitivity in skin)
Urticaria- has same allergic reaction of immediate part of wheal and flare reaction (reproduced when injecting histamine on its own on skin).
Angioedema- occurs when there is an activation of mast cells in deeper SUBCUTANEOUS tissue in skin, causing more diffuse SWELLING.
insect bits also cause urticaria.
65
Further elaborate on mechanism of allergic reaction induced by mast cell activation in skin.
process:
1. subcutaneous antigen (low dose) present causes armed connective tissue mast cells to be activated and degranulate.
2. histamine will be released and will dilate blood vessels and cause rapid swelling due to leakage of fluid and proteins in tissues.
urticaria and angioedema are effects of systemic anaphylaxis.
66
Describe the type I hypersensitivity in respiratory tract
Type I hypersensitivity in Respiratory Tract:
1. Inhaled allergens -> affect Upper airways
cause Allergic rhinitis ( violent bursts of sneezing and runny nose)
-Nasal passages- where allergens will diffuse across mucous membrane and and activate mucosal mast cells.
-Conjuctiva- inflammation in the conjunctiva of the eye (causing itching and tears) due to exposure to same antigen/allergen (that caused allergic rhinits)
2. Inhaled allergies-> also affect Lower airways
- ASTHMA
67
Explain what occurs in asthma, including the mechanism and components involved. Differentiate between an acute response and chronic response of asthma.
Asthma:
-Lower airways of respiratory tract
Bronchiole constriction, contraction of smooth muscle surrounding airways
Increased mucus secretion
Chronic inflammation of airways occur; leukocyte infiltration -(like TH2, eosinophils)
Acute response:
- Mucosal mast cell captures antigen (causing mast cell degranulation, release of histamine)
-inflammatory mediators contract smooth muscle, increase mucus secretion by airway epithelium, and increase blood permeability.
Chronic response- will be mediated by cytokines and eosinophil products (eosinophil release granular contents augment eosinophil production)
effect of asthma attack: trap air in lungs, make breathing more difficult.
68
How does chronic asthma differ from asthma (allergen)?
Allergic asthma: allergic reaction cause chronic shortness of breath and wheezing
-driven by response to specific allergen, and chronic inflammation will still develop (in absence of re-exposure to antigen)
-caused by Ig E hypersensitivity reaction to inhaled antigen, causing bronchi to constrict and difficulty breathing
Chronic asthma:
entire airway filled with mucus.
chronic inflammation
hyperreactivity or hyperresponsiveness in the airway develops and environmental factors (smoke, cigarettes, sulfur dioxide) can trigger asthmatic attacks
additional leukocytes present in bronchial wall.
chronic asthma considered type IV hypersensitivity caused by T cells.
asthma can be alleviated by anti-IL-5 therapy.
69
Describe the type I hypersensitivity that occurs in GI tract and explain the process.
Type I hypersensitivity in Gastrointestinal tract
-ingested allergens, will cause Local and systemic effects
process:
ingestion of antigen activates mucosal mast cells.
-activated mast cells release histamine, which acts on epithelium, blood vessels and smooth muscle
-Antigen then diffuses into blood vessel and be disseminated, causing urticaria, smooth muscle contraction induces vomiting and diarrhea. Also fluid outflow into gut lumen.
70
What are the three main approached to clinical intervention for type I hypersensitivity?
Clinical intervention for Type I hypersensitivity:
3 approaches:
1. Prevention/Avoidance- avoid allergens (in food, move furniture, avoid dust mites).
2. Pharmacologic- have mast cell stabilizers(taking drugs) that prevent degranulation (ex: antihistamines, corticosteroids, epinephrine)
3. Immunologic- (modulate immune response, switch Ig E to Ig G)
-Desensitization- blocking antibodies ( triggering production of Ig G that binds to allergen; prevents allergen from contacting Ig E)
-another form of desensitization- introduce helminth worms into gut of people (with asthma or allergy)
-biologics: Omalizumab (Zolair) neutralizes/ against Ig E
Mepolizumab- neutralize/against IL-5 (eliminate eosinophil)
Omalizumab (monoclonal antibody, that is anti Ig E)
71
Explain what allergic rhinitis is characterized by
Allergic rhinitis is characterized by local edema (swelling )and obstruction of nasal airways and nasal discharge of mucus rich in eosinophils.
process;
inhaled antigen will enter mucosa and activate mast cells. Mast cell activation will cause blood vessel permeability and activation of epithelium. This causes eosinophils to be recruited from blood and enter nasal passages with mucus.
72
Describe the type II hypersensitivity reaction and all components involved. What are the type of antigens that cause type II hypersensitivity?
Type II Hypersensitivity Reactions- (CYTOTOXIC)
-Ig G or Ig M
-antibodies targeted against cell structures (proteins)
Ig G will be formed against new epitopes formed on cell surface and bind to antigen
-This results in Destruction of cell via
-Complement
-Opsonization
-ADCC (antibody-dependent cellular cytotoxicity)
-(cell mediated immune defense where an effector cell lyses a target cell whose surface antigens have been bound by antibodies (Ig G)
BLOOD GROUP ANTIGENS
-ABO antigen system- transfusion reactions
-Rh antigen- that causes hemolytic disease of the new born.
for these type II reactions to occur, a person must be SENSITIZED first.
73
What processes occur in type II hypersensitivity?
Cytotoxic process:
- sensitization (forming Ig G antibodies against new eptiope (antigen)
- Lysis- effector cells lyse the Ig G coated target cell and kill the cell.
74
Elaborate on the the Blood group antigens and the different genotypes. What are isohemagglutins?
Blood group antigens differ based on the Carbohydrate structures (antigen) present on blood:
Blood type O: has simplest structure of all blood types (regular chain, genotype OO)
Blood type A: has N-acetly galactosamine transferase); genotype AA, AO
Blood type B; has Galactose transferase; Genotype BB, BO
Blood type AB: have co dominant A and B alleles (AB)
Isohemagglutinins: Ig M antibodies that are directed against blood group antigens
Type O- have anti A,B antibodies
Type A -have anti B, antibodies
Type B- have anti A antibodies
Type AB- No isohemagglutinin (or antibodies)
75
What are the type II hypersensitivity Transfusion reactions?
Type II Hypersensitivity: Transfusion Reactions
-Blood Type O: Universal donor, but CAN only receive blood type O. When blood type O is Donor: NO agglutination for all blood types. When Type O is recipient: it has agglutination for type A, B, AB (it has anti A and Anti B antibodies).
-Blood Type A: Recipient: has agglutination for type B, and type AB. (can only receive from O and A). A can donate to type A and Type AB; Donor- agglutination for type O, B) has anti B antibodies.
-Blood type B: has anti-A antibodies.
Recipient (agglutination for type A and AB); can only receive from B and O
Donor: (agglutination for type O and type A) it can only donate to type B and AB
-Blood type AB: Universal recipient; Has no antibodies against A or B; Recipient (No agglutination)
-Donor (agglutination for type O, A, B) it can only donate to AB (itself)
76
Describe agglutination and its mechanism. What does an agglutinated cell look like vs non-agglutinated cell?
Agglutination: describes the reaction when antibody binds with antigen and forms clumps or aggregates. This results in a cytotoxic reaction as the cells become lysed (mediated by Ig M)
An agglutinated cell- will look like a lot of blood cells clumped together
a non-agglutinated cell- solid shape, no clumping
77
What are the consequences of transfusion reactions mismatched blood? What clinical symptoms occur?
Consequences of Transfusion Rxn with mismatched blood:
-Takes hours to days
-Cells become coated with antibody (Ig M) and are DESTROYED (by complement, opsonization and ADCC)
Clinical symptoms:
-Nausea
-Fever
-Chills
-Renal failure
-Nullifies beneficial effects of transfusion
78
Describe the Rh Blood group antigens and components involved.
Rh Blood group antigens:
-second major antigenic system- D antigen
-Encoded by the D gene
-Dominant Mendelian Inheritance: DD, Dd= Rh+
dd= Rh-
-If you have one dominant allele you will be Rh+, but if recessive alleles- Rh-
-NO ISOHEMMAGLUTININ production
-Clinical significance- when Rh- mother has Rh+ child(erythroblastosis fetalis)
The child must be treated or they will develop the hemolytic disease of newborn.
79
Describe the mechanism of Hemolytic disease of newborn and include how it prevent it.
Hemolytic Disease of the Newborn:
due to type II hypersensitivity
Mechanism:
1. Sensitization:
first pregnancy of RhD- mother carrying a RhD+ fetus,
will cause primary immune response, IgM and low amounts of LOW-affinity IgG. This will lead to minor destruction of fetal erythrocytes by anti-RhD IgG and healthy new born baby
Mom sensitized during first pregnancy.
2. HDN:
-Second and subsequent pregnancies of RhD- and RhD+ fetus will cause secondary immune response, an ABUNDANCE of HIGH-AFFINITY IgG transcytosed (transferred) to fetal circulation. This leads to MASSIVE destruction of fetal erythrocytes triggered by anti-RhD Ig G. You will have ANEMIC newborn babies
3. Treatment:
First and subsequent pregnancies of RhD- mother carrying a RhD+ fetus and infused with anti-Rh IgG will cause primary immune response to RhD and is inhibited by presence of RhD-specific IgG. So fetal erythrocytes are NOT destroyed and HEALTHY Newborn babies.
80
Describe what occurs in Type III hypersensitivity for Localized (Arthus reaction) and its components
Type III hypersensitivity- 1-2 hours for Localized (arthus reaction)- when inhale spores (antigens) in Lung
Immune Complex Hypersensitivity- Ig G
Mech:
1. Sensitized: Ig G is formed against spores (after inhaling spores)
2. spores diffuse from mucosal into tissue
3. Zone of Equivalence(equal concentration of antibodies and spores) leads to Immune complexes being formed. Immune complex is formed when there is a cross link between antibody and antigen (complex PRECIPITATE)
4. Complement activation (triggered by complex precipitate)
adverse effects are direct result of complement activation and accumulation of neutrophils/platelets.
-*C3a and C5a: cause Increased Vascular permeability-> EDEMA
-Anaphylatoxins
-Chemotaxins
*Influx of NEUTROPHILS/PLATELETS- cause Tissue Damage
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What is zone of equivalence?
Zone of equivalence- period where there is EQUAL concentration of spores(antigens) and antibodies
This occurs during type III hypersensitivity (when immune complex formed)
82
Differentiate what happens in Type III hypersensitivity for Systemic Reaction.
Type III Hypersensitivity- Systemic Reaction
-occurs when antigen is in bloodstream
-you develop serum sickness: results from injection of large quantities of foreign protein.
-Results from deposition of circulating immune complexes in:
-Blood vessels --> cause Vasculitis
-Basement membrane of kidneys- Glomerulonephritis
-Basement membrane of joints- arthritis
-Skin- Urticaria
Within 7-12 days, Antigen/antibody complex forms = clinical symptoms appear.
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What are the two skin conditions that result from type III hypersensitivity (systemic reaction)?
Type III hypersensitivity III (Systemic Reaction)
-lead to Hemorrhaging (Accumulation of neutrophils and platelets that cause bleeding from broken blood vessels) and URTICARIA
this occurs due to IV antibiotics (injection) being administered.
84
Explain the timeline of when type III hypersensitivity occurs
Type III Hypersensitivity Time period:
1. Serum injection of foreign protein occurs- which leads to increase or excess of antigen
2. 7-12 days, antigen/antibody complex forms (equal amount of antigen/antibody), develop symptoms of fever, vasculitis, arthritis, nephritis.
- immune complex activates complement to destroy antigen
3. After a while, you have higher amount of antibody against foreign serum.
85
Describe what occurs in type IV hypersensitivity and its components
Type IV Hypersensitivity:
DELAYED Type Hypersensitivity (T-cell mediated)
Prototype: Tuberculin reaction
T cell directed against TB antigen
Injection of TB antigen--> cause skin lesion in 1-3 DAYS
"ERYTHEMA and INDURATION"- redness in skin and thickening or hardening of skin (induration)
"Delayed onset"
This is TH1 cell mediated:
*IFN-gamma --> cause macrophage activation
*TNF-Beta--> cause tissue destruction and macrophage activation
-Monocyte/macrophage chemotactic factor
cytokines mediate reaction.
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What is the mechanism behind Type IV Hypersensitivity?
Mechanism of Type IV Hypersensitivity:
1.PRIOR sensitization to expand T cell clones: T cell directed against TB antigen
2. TH1 cell activation and release cytokines
3. recruitment of T cells, macrophages and fluid
4. Macrophage pick up TB antigen process and present antigen to T cells?
Clinical- Erythema and induration (redness; thickening of skin)
Histopathology- predominantly MACROPHAGE infiltrate (T-cells); may have GRAULOMA formation (macrophage in center, surrounded by T cells)
Normal response to Mycobacterium, varicella Zoster and herpes.
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What are steps in the mechanism of type IV hypersensitivity?
1. Need prior sensitization (first immune response to antigen to form antibodies)
2. second exposure to antigen: introduction of foreign substance to subcutaneous (skin)
3. Dendritic cells and Macrophages (mainly) release chemo-attractants
4. CD4+ T cells enter site, recognize foreign substance and release bioactive molecules (chemokines, cytokines)
5. Macrophages and other phagocytes enter site to cause cause inflammation
88
Describe what contact dermatitis is? What type of Hypersensitivity is it?
Contact Dermatitis: (type IV hypersentivity)
-antigen is HAPTEN
2 properties:
antigen has to penetrate skin,
-covalently couple with host proteins
-Occurs most frequently with ORGANIC chemicals, metals, *NICKEL, topically applied drugs, cosmetics and plant materials
-Certain lipid-like haptens, can also trigger activation of CD8+ T cells.
- also done through patch testing?
89
Discuss which antigens cause contact dermatitis
Contact Dermatitis (type IV Hypersensitivity)
Hapten: Pentadecacatechol
Paraphenylenediamine (HENNA tattoo) causes erythema and induration.
90
Compare and contrasts the 4 main types of Hypersensitivity?
Hypersensitivity:
1. Type I-
- IMMEDIATE takes 10-15 mins; involved IgE antibody; cell types/effector functions: mast cells; basophils;
- LATE PHASE- takes 6-8 hours, involves Ig E antibody, and cell types/effector: macrophages; basophils; eosinophils
2. Type II- CYTOTOXIC takes hrs to days; involved IgG/IgM antibodies; cell types/effector functions: Opsonization/Complement (C3a and C5a)
3. Type III- IMMUNE COMPLEX
- Local reaction takes 1-2 hours; involves IgG antibody: cell types/effector functions: Complement; neutrophils/platelets
4. Type IV- DELAYED Type takes 48-72 hrs; NO antibodies involved; cell types/effector functions: TH1/(CD8 + T cells)
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When can hypersensitivity reactions occur?
Hypersensitivity reactions ONLY occur When an already immune or SENSITIZED individual is re-exposed to the initiating substance (ALLERGEN).
92
Which blood type antigens have similar carb structure to that on bacterial surface?
Antigen A and B have carbohydrate structure that resemble bacterial surface.
