Term
| How do Hypersensitivity Reactions arise? |
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Definition
| Over-sensitivity to antigens caused by either deregulated responses to foreign antigens, or direct attack of autologous antigens |
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Term
| What are the defining features of a Type 1 hypersensitivity reaction? |
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Definition
Allergic response of vasculature and smooth muscle that occurs WITHIN SECONDS
1)B-cells encounter antigen and bind to Th2 cells which release IgE and co-stimulate with IL-4 and CD40L (class switching).
2) IgE released from B-cells binds to mast cells or basophils via FceR1 ("sensitized") in response to antigen
2) Secondary antigen presentation leads to IgE cross-linkeing, which causes degranulation (histamine release) and IgE release. |
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Term
What are the defining features of a Type 2 hypersensitivity reaction?
Describe how penicillin reactions fit under this category. |
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Definition
ADCC that takes minutes-hours and is caused by ABO rejection in transfusions and Drug-induced hemolytic anemia (hapten-like binding to RBC).
Penicillin binds to RBC and is recognized by IgM or IgG, leading to NK-mediated ADCC or macrophage-mediated phagocytosis. |
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Term
What is Hemolytic disease of the newborn?
How can it be prevented? |
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Definition
Erythroblastosis Fetalis (type 2 reaction)
1) RhD- mother has a first RhD+ child
In a second pregnancy, the IgG ntibodies that the mother has developed can cross the placenta and attack an RhD- fetus.
2) If the mother is treated with RHOGAM during the first pregnancy, she will not form anti-RhD antibodies because the drug prevents B-cell activation and memory. |
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Term
What are the defining features of a Type III hypersensitivity reaction?
Provide 3 examples. |
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Definition
Ab-Ag complex issue (8-10 days)
1) Ab-Ag (IgG & IgM) complexes are not cleared and become trapped
2) When deposited in tissues, these cause complement activation leading to intense inflammation and recruitment of neutrophils (C5a and C3a)
1) Arthus reaction (serum sickness from passive immunization to a sensitized individual leading to vasculitis)
2) Acute glomerulonephritis (renal failure)
3) SLE in women (connective tissue inflammation) |
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Term
| What are the defining features of a Type IV hypersensitivity reaction? |
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Definition
T-cell mediated response with Th1, CTLs and macrophages (72h post exposure)
Response to Poison Ivy, tuberculin (PPD) skin test
1) "Sensitization" occurs with APC presentation to CD4+ cells, causing Th1 differentiation and occasional CTL cells
2) "Effector" phase occurs when sensitized Th1 cells interact with resting macrophages
Th1 cells secrete cytokines (IFN-y, TNF-b, IL-2, IL-3, GM-CSF) and chemokines (IL-8, MCAF, MIF)
Macrophages increase MHC-II, TNF receptors, Oxygen radicals and NO |
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Term
True or False
For an allergic (atopic) response to occur, more than one exposure to an allergin is necessary |
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Definition
| True! Sensitization is necessary |
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Term
| What 2 allergic responses can occur via inhalation? |
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Definition
1) Rhinitis- mast cell activation beneath nasal epithelium leading to local edema, histamine release (hay fever)
2) Asthma- mast cell activation in submucosal lower airways leading to bronchial constriction, mucus/fluid secretion and chronic inflammation (Th2 and eosinophil) |
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Term
| Explain the "immediate" and "late-phase" responses in allergic reactions. |
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Definition
1) Immediate- occurs within seconds and lasts up to 30 min (wheal and flare).
IgE-mediated mast cell activation with histamine and prostaglandin release, increasing vascular permeability and smooth muscle contraction.
2) Late phase- widespread edematous response after 8h that persists for several hours |
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Term
| What are some properties of common allergens? |
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Definition
1) Protein Proteases (T-cell specific)
2) Low dose (Favors activation of IL-4 producing CD4 T cells)
3) Low MW (Diffuse out of particle into mucus)
4) Soluble and Stable (survive in desiccated particle and easily elute out)
5) MHC-II binding (Required for T-cell priming) |
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Term
| What are the major effects of Mast cell activation? How are they blocked? |
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Definition
1) Smooth muscle contraction (vasoactive amine)
2) Eosinophil recruitment (IL-5 mediated)
3) Mucus secretion
4) Platelet activation
5) Vessel dilation
Use antihistamines, epinephrine (contraction) and steroids (anti-inflammatory) |
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Term
| What mast cell mediators are released from preformed granules in response to IgE cross-linking? |
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Definition
1) Cathepsin enzyme (and others) for remodeling of connective tissue
2) Histamine and Heparin (toxic mediators) that increase vascular permeability, smooth muscle contraction, and parasite killing |
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Term
| What mast cell mediators are synthesized following their activation? |
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Definition
1) Cytokines
IL-4 and IL-13 (Th2 amplification)
IL-3, IL-5 and GM-CSF (eosinophil production and activation),
TNF-a (inflammation and activates endothelium)
2) Chemokines (CCL3/MIP1-alpha) to attract monocytes, macrophages and neutrophils
3) Lipid mediators
Leukotrienes (smooth muscle contraction and increase vascular permeability and mucus secretion)
PAF (attracts leukocytes, amplifies lipid mediator production and activates neutrophils, eosinophils and platelets) |
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Term
What is "Systemic Anaphylaxis"?
What types of compounds can cause this? |
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Definition
1) Allergen in blood stream leads to connective tissue Mast Cell activation
2) Increased vascular permeability lowers BP
3) Airway constriction, Epiglottis swelling (leads to Shock)
Penicillin, venom, peanuts (treat with Epinephrine) |
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Term
| What is the "Late-phase" reaction of Anaphylaxis? |
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Definition
1) Synthesis of prostaglandins, leukotrienes, chemokines, cytokines from activated mast cells
2) Th2 cells and eosinophils cause chronic inflammation
3) Smooth muscle contraction
4) Sustained edema and tissue remodeling (hypertophy and hyperplasia)
5) Chronic illness- allergic asthma |
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Term
| Explain the pathogenesis of Asthma |
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Definition
Chronic Inflammatory disorder characterized by IgE production, Eosinophilia, Mucus production and Fibroblast proliferation
1) Environmental antigens/Genetics lead to atopic sensitization
2) Secondary exposures lead to mucosal inflammation and structural changes (hypertrophy and hyperplasia) |
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Term
| Where are most Eosinophils found and what do they do? |
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Definition
1) Most in connective tissues beneath respiratory, gut, urogenital epithelium (few circulating)
2) Once activated, they release toxic granule proteins and free radicals, as well as prostaglandins, leukotrienes and cytokines. |
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Term
| How is Eosinophil activation regulated? |
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Definition
1) Produced in bone marrow in response to IL-5 released from Th2 cells
2) Migration from circulation to tissues mediated by eotaxin-binding
3) Expression of FCeR1 increases by cytokine and chemokine activation. |
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Term
| How is allergy testing performed? |
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Definition
| Intraepidermal infection and measure levels of allergen specific IgE. |
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Term
| How do you treat Allergies? What are the risks with each approach? |
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Definition
1) Desensitization- Inject with escalating doses of allergen to shift Th2 to Th1 (IgE to IgG).
This down-regulates mast ell activation but has the risk of induced more IgE-mediated response.
2) Blocking effector pathways-
Epinephrine for anaphylactic reactions
Antihistamines
Topical corticosteroids
Bronchodilators
Leukotriene receptor antagonists (monteleukast) |
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Term
| Why might you target IL-4Ra in asthma? |
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Definition
This receptor binds IL-4, which would lead to IgE production. Blocking it would prevent IgE-mediated mast cell and eosinophil activation.
Might also inhibit IL-13 |
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