(16) Immunohypersensitivities Flashcards
What are some common inhaled substances that initiate hypersensitivity reactions?
Do not memorize
Plant Pollens
Dander of domesticated animals
Mold Spores
Feces of microscopic animals (e.g. dust mites)
What are some common injected materials that cause hypersensitivity reactions?
Do not memorize
- Insect Venoms
- Vaccines
- Drugs
- Therapeutic Proteins
What are some common ingested materials that cause hypersensitivity reactions?
Do not memorize
- Food (peanuts and shellfish)
- Orally ingested drugs
What are some common material that trigger hypersensitivity reactions on contact?
Do not memorize
- Plant Leaves
- Industrial Products made from Plants
- Synthetic chemicals in industrial products
- Metals
What are the 4 types of hypersensitivity reactions?
Type 1: Immediate-Type Hypersensitivity Reactions
Type 2: Altered self Hypersensitivity Reactions
Type 3: Immune Complex Hypersensitivity Reactions
Type 4: Delayed Type hypersensitivity Reactions
Type I: Immediate-Type Hypersensitivity reactions
- Time Scale
- Immune Reactant(s) / Effector Mech
- Antigen(s)
Time Scale:
Minutes
Immune Reactant(s) / Effector Mech: IgE that is bound to FcepsilonRI on mast cells
Antigen(s):
Soluble Antigen
Type II: Altered Self Hypersensitivity Reactions
- Time Scale
- Immune Reactant(s) / Effector Mech
- Antigen(s)
Time Scale:
4-12 hours typically
Immune Reactant(s) / Effector Mech: a. Complement, FcR+ receptors on Phagocytes and NK cells that use IgG
OR
b. Antibody alters Signaling
Antigen(s):
a. Cell- or Matrix-associated Antigen
b. Cell-surface Receptor
Type III: Immune Complex Complex Hypersensitivity Reactions
- Time Scale
- Immune Reactant(s) / Effector Mech
- Antigen(s)
Immune Reactant(s) / Effector Mech: Are the result of IMMUNE COMPLEXES deposited on host tissues and the PHAGOCYTE response as they encounter these complexes
Antigen(s):
Soluble Antigen
Type IV: Delayed Type Hypersensitivity Reactions
- Time Scale
- Immune Reactant(s)
- Antigen(s)
Time Scale:
24-72 hours
Immune Reactant(s) / Effector Mech:
a. TH1 cells can activate Macrophages
b. TH2 cells can activate eosinophils (via IL-4 and IL-5)
c. CTL kill shit with perforins, granzymes, and Fas
Antigen(s):
a/b. soluble antigens
c. Cell-associated antigen
Serum Sickness and Arthus Reaction:
- Immune Reactant?
- Antigen Type?
- Effector Mechanism?
Reactant:
- IgG
Antigen:
- SOLUBLE
Effector Mech.:
Complement Phagocytes
Allergic Rhinitis, Asthma, Systemic Anaphylaxis:
- Immune Reactant?
- Antigen Type?
- Effector Mechanism?
Reactant:
- IgE
Antigen:
- Soluble Antigen
Effector Mech:
- Systemic Anaphylaxis (Mast-Cell Activation)
Some Drug allergies (e.g. Penicillin).
- Immune Reactant?
- Antigen type?
- Effector Mechanism?
Reactant:
- IgG
Antigen:
- Cell- or Matrix-associated antigen
Effector Mech:
- Complement, FcR+ cells (Phagocytes, NK cells)
Contact Dermatitis
- Immune Reactant?
- Antigen Type?
- Effector Mechanism?
Reactant:
- CTL
Antigen:
- Cell-associated antigen
Effector Mech:
- Cytotoxicity
Chronic uriticaria (antibody to FalphaRIalpha)
- Immune Reactant?
- Antigen Type?
- Effector Mechanism?
Reactant:
IgG
Antigen Type:
- Cell-surface Receptor
Effector Mech:
- Antibody Alters Signalling
Chronic Asthma, Chronic allergic Rhinitis
- Immune Reactant?
- Antigen Type?
- Effector Mechanism?
Reactant:
- TH2 Cells
Antigen:
- Soluble antigen
Effector Mech:
- Eosinophil Activation
Contact Dermatitis and Tuberculin Reaction
- Immune Reactant?
- Antigen Type?
- Effector Mechanism?
Reactant:
- TH1
Antigen:
- Soluble antigen
Effector Mech:
- Macrophage Activation
Graft Rejection
- Immune Reactant?
- Antigen Type?
- Effector Mechanism?
Reactant:
- CTL
Antigen:
- Cell-associated antigen
Effector Mech:
- Cytotoxicity
What accounts for the length of time that it takes for a hypersensitivity reaction to become apparent in people with Contact Dermatitis, or Chronic allergic Rhinitis, or Organ Rejection?
Responses here rely on T cells which take longer to initiate symptomatic inflammatory Responses, so they are Delayed-type Hypersensitivity Reactions
What is the FIRST event that must occur for anyone to become allergic to anything?
- what happens here?
- Primary Exposure to the Antigen must happen and a Primary Immune response will be generated
- On subsequent exposure the Allergen will elicit a response and the Patient will be symptomatic
For a type I hypersensitivity reaction, what characteristics are we looking for in the antigen, explain why?
- Molecular Type and Mol. Wt.
- Allergen Function
- Dosage
- Solubility
- Stability?
***Overall Basis: We need TH2 so that we can get the cytokines (IL-4) to make IgE so it can bind to MAST cells and Degranulate
Molecular Type and Mol. Wt.
- MUST be a PROTEIN that bind MHC class II because at the root of this response is the need to activate TH2
- Must also be LOW molecular weight so it can diffuse out of the allergen into mucus
Function:
- These allergens are often PROTEASES (commonly from parasites because they like to remodel tissues)
Dose:
- LOW dose - remember the goal is to illicit TH2 response, this response is most reactive to low [MHC II - Antigen]
Stability/Solubility:
- It needs to be SOLUBLE and STABLE so that it can elute away from whatever it was packaged in (parasite) easily and without be destroyed
- WHAT ARE THE ENZYME, TOXIC MEDIATORS, CYTOKINES AND LIPID MEDIATORS OF MAST CELLS THAT WE MUST KNOW found in mast cell granules???
- Biological Effects??**
Enzyme:
- M = Trypstase, Chymase, Cathepsin G, Carboxypeptidase
- A = Remodeling or Connective Tissue Matrix
Toxic Mediators:
- M = Histamine, Heparin
- A = Toxic to parasites, Increase Vascular Permeability, Cause Smooth muscle contraction
Cytokines:
- M = TNF-alpha
- A = Promotes inflammation, Stimulates Cytokine Production by many cell types, Activates Endothelium
- M = IL-4 and IL-13
- A = Stimulate and Amplify TH2-cell response
Lipid Mediators:
- M = Leukotrienes C4, D4, and E4
- A = Smooth muscle contraction, Increased Vascular Perm, Mucus Secretion
What is the hallmark of a type I reaction?
Urticaria (hives)
What effect do mast cells have on the GI system, Airways, and Blood Vessels?
- How/Why?
- What is the advantage?
G.I:
- Increased Inflammation, Fluid, and Peristalsis results in Diarrhea and Vomitting
- Both of these could help to get pathogens out of upper and lower GI tract
Airways:
- Mucus Secretion in the Airways and Constriction or the Airways leads to violent sneezing and coughing that can help expel the organism
Blood Vessels:
- Dilate and become leaky Promoating diapedisis, this leads to inflammation which pushes antigens towards APCs in 2˚ lymph tissue
When are anaphylatic responses generated?
- If something like Bee venom is injected directly into circulation, this allows for the allergen to disseminate throughout the body and activate many B cells
Suppose an allergen disseminates into the bloodstream, what are the responses that follow in the:
- Heart and Vascular System
- Respiratory Tract
- GI tract
Heart and Vascular System:
- Dilation and Permeability - Systemic Tissue swelling (tongue), LOSS of Blood Pressure (irregular heartbeat)
Respiratory Tract:
- Contraction of Smooth mm. (airway constriction, inability to swallow or breathe)
GI Tract:
- Contract of Smooth mm. (stomach cramps and vomiting)
**Collectively this = ANAPHYLACTIC SHOCK
What’s the treatment of Anaphylactic shock?
Epinephrine
What is the common response to allergens like Drugs, Serum, Venoms, Peanuts?
- route of entry?
Systemic Anaphylaxis
- Intravenous is the route of entry either directly or after rapid absorption.
What is the common response to insect bites and Allergy testing?
- route of entry?
Wheal and flare - from local increases in blood flow and vascular permeability
- Subcutaneous Route
What is the common response to Shellfish, Milk, Egg, Fish, and Wheat allergies?
- route of entry
Vomiting, Diarrhea, Pruritis (itching), Urticaria (hives), Anaphylaxis
- Oral route
What are some common triggers of bronchial asthma?
Pollens, Dust-Mite Feces
**Feces of these things have a lot of proteolytic enzymes in it which triggers the allergic response
T or F: while IgG is the primary antibody responsible for type II hypersensitivity responses, IgM can also participate.
True
How does penicillin induce a type II hypersensitivity??
- Penicillin Binds to RBC’s causing a change in surface determinants
- Infection is present so complement is active and C3b is deposited onto RBC’s - APCs phagocytose RBC’s because they have C3b on their surface and present penicillin-RBC surface antigens to Naive T cells on MHC class II, APCs can do this because B7 is up-regulated in the presence of active infection
- T cells activate B cells that also recognize the Penicillin-RBC surface antigen
- Abs bind to Penicillin bound RBCs in the periphery and trigger opsonization and fix complement causing MAC destruction of RBCs
What is the Arthus Reaction?
- what are the steps leading to its development?
- How long does it take to develop?
Type III hypersensitivity Reaction
- Allergen is introduced to tissues underlying the epithelium
- Ab specific for the allergen bind it and then activate the classical complement pathway
- Anaphylatoxins mediate inflammation cascade directly as well as binding to C5a receptors on Mast Cells, this triggers Mast Cell Degranulation
- Macrophages and Neutrophils also recognize opsonized antigens and release their inflammatory mediators.
**This typically takes an hour or 2
What causes immune complex disease?
- what are the steps in the pathogensis of immune complex disease?
Formed in Response to a Systemic Allergen
- Allergen (penicillin) gets access to vasculature and preformed IgG binds to the allergen
- If enough of the allergen is present it results in too many immune complexes to be cleared efficiently (by the spleen)
- Multiple effects:
a. Immune complexes deposit along the vasculature ESPECIALLY in the Kidney Glomeruli
b. Systemic inflammation from complement anaphylatoxins (C5a => mast cell degranulation)
c. Phagocyte mediated inflammation
What are the outcomes of immune complex disease?
- Clogged Kidney Glomeruli =Nephritis
- Vascularitis
- Neurological Damage
- Arthritis
What is the difference in the administration method that triggers Arthus Reaction vs. Immune complex disease?
Subcutaneous Administration is typically associated with Arthus Reaction
Intravenous administration is typically associated with Immune Complex disease - Localized to the perivascular area
What is Farmer’s Lung?
Inhaled Allergen leading to immune complex deposition at the alveolar/capillary interface
What causes Farmer’s Lung?
Inhaled mold spores and other allergens from hay create a chronic inflammatory response in the lower respiratory tract that is clinically relevant.
What causes Pigeon Breeder’s Disease/Poultry Worker’s Lung/Bird Breeders disease?
Inhaled allergens from bird droppings
What type or reaction is generated by the TB skin test?
- cells involved?
Type IV Delayed Type Hypersensitivity
- Cells involved are TH1 CD4 cells
What 3 general steps happen in delayed type hypersensitivity reactions?
- Antigen is introduced Subcutaneously and processed by local APCs
- TH1 effector cell recognizes antigen and releases cytokines which act on vascular endothelium
- T cell are recruited as well as fluid and phagocytes and inflammation becomes apparent
How does Poison Ivy generate a delayed type hypersensitivity?
- what chemical is responsible?
- cells involved?
- how long does the reaction last?
Pentadecatechol penetrates the skin and causes ALTERATION OF NORMAL SELF DETERMINANTS in the underlying endothelial tissues
- Both TH1’s and CTL’s are involved and the reaction will continue for about a week after exposure (must wait for recycling of cell proteins)
T or F: on first exposure to poison ivy or nickel you body will elicit an immune response
False, this is an acquired response meaning that you must have been exposed at a prior time to be sensitive to this
What is atopy?
Predisposed state to producing IgE responses because these people have higher levels of circulating IgE and Eosinophils than normal individuals
What genetic basis is there for explaining why some individuals are atopic?
- Atopic people have an inherited difference in the PROMOTER region of the IL-4 gene
- HLA class II polymorphism also may explain it (ppl. with HLA DRB1*1501)
- these people are more likely to make an HLA class II:peptide combo. that elicits a TH2 response
What factors mediate the 2nd step of the Type I hypersensitivity reaction?
- how does the inflammation differ
Leukotrienes, Chemokines, and Cytokines
Specifically:
TNF-alpha and LTB4 - these induce cellular infiltration that will persist for 6-8 hours
How does it differ:
- Inflammation here differs by being more widespread
Why is it necessary that an allergen be in the blood for an anaphylactic reaction to occur?
- Mast Cell degranulation requires DIRECT contact with ANTIGEN to to happen
What are anaphylactoid reactions?
- how is it treated?
- why this treatment?
- Reactions that resemble anaphylactic reactions but does not involve IgE
How:
- Epinephrine is used just like anaphylactic reaction
Why:
- Stimulates reformation of tight junctions (reduced perm), the net affect is reduced swelling, and raised blood pressure
- Relaxes constricted bronchial smooth muscle
- Stimulates the heart
What is the difference in effect of a hypersensitivity that affects the lower respiratory tract vs. the upper respiratory tract?
Lower Respiratory Tract = Asthma
Upper Respiratory Tract = Rhinitis
Would you expect a bacteria that was intracellular or extracellular to have the greatest effect on an asthma patient?
Extracellular infections would be worse for these patients because they trigger TH2 responses allowing for more formation of IgE
T or F: chronic asthma is a T cell mediated type IV hypersensitivity
True
What type of allergies are coriticosteroids typically used to form?
Typically for Chronic Allergic conditions because it prevents leukocyte proliferation
What are two methods used to desensitize people to an allergen in immunological treatment?
- start with low doses of the allergen and gradually increase the dose to change a TH2 response to a TH1 response
- Vaccinate patients with allergen-derived peptides that are presented on HLA class II molecules in an attempt to induce anergy.
Why are people who live in regions were parasitic infections are common, often have low incidence of allergies?
- Parasites elicit NON-SPECIFIC POLYCLONAL B and T cell activation.
- Random IgE ultimately out competes the parasite specific IgE
- With this constant exposure happening there is a high IgE turnover rate in Mast Cells and no long standing allergy could ever be maintained because the IgE bound will never have a homogenous specificity
What drugs are known to induce type II hypersensitivity reactions?
- Penicillin
- Quinidine (cardiac arrythmia medicine)
- Methyldopa (used to treat HBP)
Why is farmer’s lung and pigeon breeder’s lung considered a type III hypersensitivity rather than Type I?
- Over time the exposure changes the response from IgE mediated to IgG
- Immune complexes then accumulate in the alveoli of the lungs
T or F: type IV hypersensitivity reactions require the lowest amount of allergen to trigger a reaction
False, they require 100 - 1000 times as much antigen as other types
How does pentadecatechol work?
- Penetrates the outer layers of the skin and indiscriminately forms covalent bonds with extracellular proteins, skin cell surface proteins, AND INTRACELLULAR protein that will now be recognized as Non-self
- Extracellular Proteins will be be loaded onto MHC class II of Macs and Landerhan’s cells and go to 2˚ lymph = CD4 response => TH1 cells cause inflammation
- Intracellular Proteins will be loaded onto the cell’s MHC class I and the APC’s class I triggering CTLs => CTLs cause sloughing of skin
