Hypersensitivities Flashcards
What is a hypersensitivity ?
an exaggerated and inappropriate reaction to an otherwise ‘harmless’ antigen
What does hypersensitivity lead to?
damaging rather than protective pathology
hypersensitivity can be the product of what mechanism(s)?
Humoral and cellular
What is the general definition for type I hypersensitivity?
Mediated by IgE, immediate type hypersensitivity
What response is responsible for IgE production upon first exposure to the antigen (Type I)?
Th2 response
What does the antigen become following the first exposure?
An allergen
Where does the IgE bind following first exposure?
to the high affinity FcεRI on mast cells, basophils and eosinophils, “sensitizing” the cells
What is the second exposure also called?
The challenge
What stimulates degranulation during the second exposure?
allergen crosslinking the IgE bound to the FcεRI
What is thought to be the functional use of a type I response?
rejection of parasites
What is atopy?
hereditary tendency to make IgE in response to common environmental antigens
What are the two possible expressions of atopy?
systemic (systemic anaphylaxis) or tissue localized
How many chains are in the FcεRI receptor?
4
What family of receptors is the FcεRI part of?
the immunoglobulin superfamily
what is the role of the alpha chain in the FcεRI ?
interacting with IgE
what is the role of the ß chain in the FcεRI receptor ?
links the alpha chain to the disulphide linked gamma chain homodimer
which chains of the FcεRI have ITAMs? what is the purpose?
each ß and gamma chain
- in the cytoplasm and it interacts with protein tyrosine kinases to transduce an activating signal
What is the second, lower affinity IgE receptor called?
FcεRII/CD23
What is the structure of FcεRII?
single polypeptide chain
what else can FcεRII bind?
binds CD21 on B cells
How does FcεRII contribute to a range of IgE control effects?
By being able to be solubilized
What are mast cells? what are they derived from?
Large granulated mononuclear cells
Derived from bone marrow
What are the two kinds of mast cells and where are they found?
- Tissue mast cells in connective tissue near nerves and blood vessels
- Mucosal mast cells in the mucosa lining the gut and lungs
what do mast cells secrete?
synthesize and secrete allergic mediators and a large number of cytokines
what % of circulating WBCs are basophils?
0.5-1%
what is the role of basophils?
recruited from the blood into inflamed tissue and synthesize and secrete allergic mediators
both the mast cells and the basophils express?
FcεRI
what are the three stages of the Type I response?
- Sensitization
- Activation
- Effector (early and late stages)
Sensitization phase: following antigenic presentation, ___ cells make __, ___, and ___. B cells switch to ___
Th2 cells make IL-4, IL-5, and IL-13
B cells switch to IgE
Sensitization phase: the IgE produced binds to….
FcεRI receptor on basophils and mast cells
When is the IgE more stable?
When bound to a receptor
Sensitization can also occur via …?
passive transfer of IgE
- ex: PCA reaction - passive cutaneous anaphylaxis
What is the first step in the activation phase?
Cross linking of at least two FcεRI
(and bound IgE) by multivalent allergen, anti-IgE antibody, anti-Fc receptor antibody or aggregated IgE
What is triggered following crosslinking of the FcεRI receptors?
mast cell and basophil degranulation
What are 5 non IgE activators of mast cells?
- C3a and C5a (anaphylatoxins),
- some drugs (codeine and morphine),
- cold,
- exercise,
- certain neuropeptides
What type of mediators are involved in the early effector phase?
Primary (preformed) mediators and secondary (synthesized) mediators
What are 4 preformed mediators?
histamine, eosinophil chemotactic factor, neutrophil chemotactic factor, proteases
Where are preformed mediators stored?
Cytoplasmic granules
What receptors does histamine bind to ?
H1, H2, H3 and H4 receptors
What is caused by histamine binding to H1 receptor? (3 symptoms)
1. intestinal and bronchial smooth muscle contraction 2. increased vascular permeability 3. increased mucus secretion by goblet cells
What is the result of histamine binding to H2 receptors?
- vasodilation
- increases vascular permeability
- stimulates exocrine glands
- causes acid release in the stomach
Binding to which histamine receptor acts as a negative feedback control mechanism? on what cells? How?
H2 on mast cells and basophils. Suppresses further degranulation
What is true about secondary effectors?
they must be synthesized
What are 5 types of secondary activators?
- leukotrienes
- prostaglandins
- Platelet activating factor
- Bradykinin
- Cytokines
What are leukotrienes and prostaglandins?
lipid mediators synthesized from arachidonic acid precursors
- occurs minutes after mast cell/basophil degranulation
What are the 3 roles of leukotrienes?
cause prolonged smooth muscle constriction, vascular permeability and mucus production
What are the 3 roles of prostaglandins?
cause platelet aggregation, vasodilation, and bronchoconstriction
What is the role of platelet activating factor? what is the result?
causes platelets to aggregate and degranulate, releasing additional histamine that causes vasodilation and bronchoconstriction
What are the 2 roles of Bradykinin?
increases vascular permeability, smooth muscle contraction
What are 5 cytokines involved in the effector phase?
IL-4, IL-5, IL-6, IL-13, and TNF
What is the hallmark of the late phase reactions?
localized inflammatory reactions within 4-6 hours of the initial allergic response that may persist for 1-2 days
What causes the late phase reactions?
infiltration of neutrophils, eosinophils, basophils, macrophages, and Th2 cells
- in response to activated mast cells releasing cytokines
What cell type plays a major role in the late phase reactions?
Eosinophils
What inflammatory mediator is released by eosinophils? what does it cause?
Major basic protein. Causes tissue damage
what 3 cytokines are released by activated mast cells that promote eosinophil growth and differentiation? `
IL-3, IL-5, and GM-CSF
What two chemotactic factors attract neutrophils to the site of infection?
NCF and IL- 8
What is systemic anaphylaxis?
life-threatening impaired breathing due to airway swelling
- caused by smooth muscle contraction
What other symptoms are indicative of systemic anaphylaxis?
Uterine cramps, involuntary defecation and urination
Hives and edema can occur
What causes anaphylactic SHOCK?
Sudden drop in blood pressure
What 2 cytokines secreted by mast cells during the late phase response increase the expression of cell adhesion molecules on the venular epithelial cells?
IL-1 and TNF-alpha
what is localized anaphylaxis?
reaction in a specific tissue or organ
What are 2 characteristics of cutaneous anaphylaxis?
erythema (redness, blood vessel dilation)
edema (swelling due
to release of serum into tissue)
What is the wheal and flare reaction?
The peak of the localized anaphylaxis reaction, 10-15 minutes after the antigen challenge
What are allergic rhinitis (hay fever) and asthma both examples of?
localized hypersensitivity reactions
What is RIST and what does it measure? is it antigen specific or not?
Radioimmunosorbent test 1. Anti IgE is coupled to a solid phase 2. Exposed to patient IgE in serum 3 Add radiolabelled anti-IgE 4. Count bound labels
non antigen specific
tells you total amount of IgE when you compare to a standard curve
doesn’t tell you what kinds of IgE it is
What is RAST? what does it measure? Is is antigen specific or non-specific?
Radioallergosorbent test
- Allergen coupled to solid phase
- Patient IgE in serum added
- Non specific IgE washed away
- Anti-IgE radiolabel added
- Count bound labels
Antigen specific
Tells you how much there is of a certain IgE
What are the 3 medical modes of treating Type I hypersensitivities?
1) Environmental: avoid the allergen
2) Pharmacologic
3) Immunological
What are 4 types of pharmacologic treatments for TIHSS?
- Antihistamines
- Leukotriene antagonists
- Cortisone
- Epinepherine
What do antihistamines do?
block H1 and H2 receptors
What does cortisone do? (2 things)
blocks degranulation through cAMP production and reduces
histamine production
What 2 things does Epinepherine do?
reverses effects of histamine on smooth muscle and
vascular endothelial cells.
Stimulates cAMP levels in mast cells and
basophils blocking degranulation
What is hyposensitization therapy?
repeated subcutaneous injections of the
allergen to induce the production of circulating allergen-specific IgG
What is hoped to be achieved through hyposensitization therapy?
To remove the allergen before it can trigger IgE sensitized mast cells and basophils
What might be caused by doing hyposensitization therapy?
May cause a shift to a Th1 response
What is Type II hypersensitivity?
Antibody-mediated cytotoxic hypersensitivity
What two classes of antibody are involved in a type 2 response
IgG and IgM
What is the general pathology of a type II response?
IgG or IgM antibody-mediated destruction of cells by complement- induced lysis, ADCC and/or phagocytosis (opsonization by Ab, C3b)
What are two examples of Type II hypersensitivity?
- Transfusion reaction
2. Erythroblastosis fetalis
What occurs during a transfusion reaction?
massive intravascular hemolysis of transfused red blood cells, primarily from complement-mediated lysis
What are the symptoms of a transfusion reaction?
fever, chills, nausea, clotting within blood vessels, and hemoglobin in the urine
What causes erythroblastosis fetalis?
When an Rh- mother makes anti Rh antibodies during her first pregnancy. Then, when she is pregnant with a second Rh+ fetus, the Rh-specific IgG crosses the placenta and damages fetal red blood cells during gestation
How can Hemolytic disease of the newborn (erythroblastosis fetalis) be prevented?
administering anti- Rh antibodies (Rhogam) soon after delivery of first child
eliminates fetal red blood cells from maternal circulation by phagocytosis before B cell activation occurs
What is Type III hypersensitivity ?
Immune complex-mediated hypersensitivity
What is the main feature of a type III response?
Reaction of Ab with Ag generates immune complexes
What do these immune complexes cause?
Large amounts of complexes can lead to tissue damage, depending on quantity and distribution in the body
Where are complexes usually deposited?
typically on blood vessel walls, in joint synovia, on the glomerular basement membrane
What is an Arthus reaction? When does it occur? Where?
When the effect of the antigen is localized to the site of antigen entry
occurs following subcutaneous or intradermal injection of antigen into an individual with high levels of pre-existing circulating antibody to the antigen
Aka. Localized type III hypersensitivity reaction
How long can an Arthus reaction take to develop?
4-8 hours
What is the range in severity for Arthus reactions?
mild swelling (edema and erythema) to tissue necrosis.
What is serum sickeness?
When large amounts of Ag enter the blood and bind Ab and with Ag in excess, small complexes form, not easily cleared by phagocytic cells, and cause damage in multiple tissue sites
What is type IV hypersensitivity?
Delayed type hypersensitivity (DTH)
What is the first phase of the DTH response?
Sensitization phase - initial exposure to antigen
What do macrophages and DCs secrete during the sensitization phase of DTH? What does it do?
IL-12 and Il-18, which induce the development and expansion of Th1 cells in regional lymph nodes
What occurs to the Th1 cells after they have been activated in the regional lymph nodes?
The home to the tissues with the antigen
What happens during the challenge exposure?
the response develops over 48-72 hours, this time with antigen presentation by a tissue macrophage, again with IL-12 and IL-18 secretion activating sensitized Th1 cells in the tissue
What secretions by activated Th1 cells act to recruit and activate additional macrophages? Which cytokine in particular is key for inducing a DTH response?
Chemokines (IL-8, MCP-1) and cytokines (IL-2, IFNy, MIF and LT)
IFNy is critical for the induction of DTH responses
What are the principle effector cells in a DTH response?
activated macrophages
What do activated macrophages show increased expression of?
class II MHC molecules, TNF receptors, oxygen radicals, and nitric oxide
What do leaked lytic enzymes from macrophages cause?
local tissue destruction
What else can participate in tissue destruction?
CTL induced by Th1 cells
What perpetuates a DTH reaction?
Recruited macrophages continuing to present antigen
Why are DTH reaction important?
defend against intracellular pathogens
What is contact dematitis?
e.g., skin reaction to poison oak and poison ivy
an oil from the plant complexes with skin proteins that are then presented by skin dendritic cells to Th1 cells.
A subsequent exposure and antigen presentation by tissue macrophages will activate the sensitized Th1 cells in the skin, leading to a localized delayed-type hypersensitive reaction
