APPP 21: Hypersensitivity Reactions Flashcards
What are hypersensitivity reactions?
altered immunological response to an antigen that results in disease or damage to host
What are the 2 ways that hypersensitivity reactions can be classified by?
- mechanisms that cause the disease (Gell and Coombs classification – type I-IV)
- source of antigens
What are the 3 sources of antigens that can cause hypersensitivity reactions?
- allergy: over-reactivity to otherwise unharmful environmental antigens or chemicals
- autoimmunity: disturbance of immunological tolerance of self-antigens
- alloimmunity: immunological reactions against tissues of another individual (blood transfusion, organ transplant, fetus during pregnancy)
Type I Hypersensitivity
- IgE mediated
- classic allergy
- onset in minutes
Type II Hypersensitivity
- IgG/IgM mediated
- cytotoxic reactions
- onset in hours to days
Type III Hypersensitivity
- IgG/IgM
- immune-complex diseases
- onset in hours to weeks (1st encounter)
Type IV Hypersensitivity
- T cell
- delayed type hypersensitivity
- onset in 2-3 days
Mechanism of Allergic Response
How does degranulation occur?
- allergen binds IgE/FceR1 on mast cell surface
- cross-links of two IgE to activate degranulation signal with tyrosine phosphorylation
- Ca2+ influx
- degranulation and release of inflammation mediators
- granule contents include histamine, proteases, chemotactic factors (ECF, NCF)
What is an immediate phase event?
- release of histamine and cytokines by mast cells
- occurs within minutes following exposure to allergens
What is a late phase event?
- induction and continuing synthesis of eicosanoids, cytokines, and chemokines
- immune cell infiltrate (eosinophils and others)
- smooth muscle contraction, edema
- may last hours to days, and lead to chronic inflammatory reaction
Mechanism of Allergic Response
What is sensitization?
- first antibodies made following antigen presentation are from IgM or IgG classes
- repeated exposure is needed for switching (to IgE) in the presence of correct cytokines (IL-4)
Mechanism of Allergic Response
What is the effector stage?
- high affinity IgE receptor (FceR1) found on mast cells, basophils, and activated eosinophils
- subsequent to sensitization, increasing number of mast cells are primed with (already binding to) IgE on surface
How are we exposed to allergens?
commonly though mucosal exposure
- airway
- gastrointestinal
- urogenital
Type I Hypersensitivity Reactions
What is localized anaphylaxis?
target organ responds to direct contact with allergens
Type I Hypersensitivity Reactions – Localized Anaphylaxis
Lung
- disease
- major symptoms
- common allergens
- route
- asthma
- wheezing, dyspnea
- pollens, dust, danders
- inhalation
Type I Hypersensitivity Reactions – Localized Anaphylaxis
Nose/Eyes
- disease
- major symptoms
- common allergens
- route
- rhinitis (hay fever)
- running nose, itchiness
- pollens
- mucous membrane
Type I Hypersensitivity Reactions – Localized Anaphylaxis
Skin
- disease
- major symptoms
- common allergens
- route
- urticaria (hives)
- itchiness and blisters
- foods, medications
- ingestion
Type I Hypersensitivity Reactions – Localized Anaphylaxis
GI Tract
- disease
- major symptoms
- common allergens
- route
- allergic gastroenteropathy
- vomiting, diarrhea
- foods
- ingestion
Type I Hypersensitivity Reactions
What is systemic anaphylaxis?
systemic vasodilation and smooth muscle contraction leading to severe bronchiole constriction, edema, and hypotension (shock)
- tachycardia, arrhythmia, cyanosis, and cardiac arrest can occur
- anaphylactic shock requires immediate medical interventions
- biphasic presentations up to 30% of cases
Type I Hypersensitivity Reactions
What is atopy?
associated with genetic predisposition for localized anaphylaxis
- atopic individuals have higher levels of IgE and eosinophils
Type I Hypersensitivity Reactions – Genetic Predisposition
What are the candidate polymorphic genes related to atopy? (5)
- IL-4 receptor
- IL-4 cytokine (promoter region)
- FceRI: high affinity IgE receptor
- class II MHC (present peptides promoting Th2 response)
- inflammation genes
Type I Hypersensitivity Reactions – Genetic Predisposition
What is the allergic triangle?
people who have one atopic condition are more likely to develop another atopic condition, and the trigger factors for each may be the same
Type II: Cytotoxic Hypersensitivity
What is this hypersensitivity mediated by?
inappropriate binding of antibodies (IgG or IgM) to a tissue cell surface antigen, including:
- extrinsic antigens presented on a cell surface following an infection
- chemical that modified a cell surface component (ie. penicillin binding to RBC and quinine binding to platelet)
- self antigen (auto-immune disease)
Type II: Cytotoxic Hypersensitivity
Antibody binding directs cellular toxicity of target cells through ____________. (2)
- classical complement pathway MAC
- immune cell mediated ADCC
Type II: Cytotoxic Hypersensitivity
What are some examples of type II hypersensitivity reactions? (3)
- ABO hemolytic anemia (clinical mistakes in blood transfusions)
- auto-immune hemolytic anemia (autoimmune disease)
- Guillain Barre Syndrome (autoimmune reaction following viral infections)
Type II: Cytotoxic Hypersensitivity
What are the special type II reactions?
- known as type V in the UK
- associated with cell surface receptors targeting antibodies
Type II: Cytotoxic Hypersensitivity
What does mixing wrong blood types result in?
agglutination (clumping) and MAC
Type III Hypersensitivity: Immune Complex Disease
What occurs in the 3 phases?
phase 1:
- antigen presentation and antibody (IgG or IgM) production
- formation of antigen-antibody complexes in circulation (soluble)
phase 2:
- deposition of antigen-antibody complexes in tissues
- frustrated phagocytes unable to clear these complexes
phase 3:
- inflammation and tissue injury where antigen-antibody complexes are deposited (kidney, endothelial cells, joints)
Type III Hypersensitivity: Immune Complex Disease
When are immune complexes (IC) formed?
when clusters of antibodies (mostly IgG, but also IgM) interlock after binding to soluble (not cell surface) foreign or tissue antigen (self antigen = autoimmune disease)
Type III Hypersensitivity: Immune Complex Disease
Where are immune complexes (IC) found?
- in circulation
- in body fluids
- deposited in tissue (ie. glomerular basement membrane)
Type III Hypersensitivity: Immune Complex Disease
How are immune complexes normally removed and what happens if they aren’t?
- normally rapidly removed through actions of phagocytic cells
- when not effectively removed, they could become trapped in local tissues and cause degranulation of phagocytes
- activation of complement system is also implicated in tissue injury caused by precipitated/trapped IC
Type III Hypersensitivity: Immune Complex Disease
What are some common immune complex conditions? (3)
- glomerulonephritis following streptococcal infection
- rheumatoid arthritis (autoimmune)
- systemic lupus erythematosus (autoimmune)
Type III Hypersensitivity: Immune Complex Disease
What is systemic lupus erythematosus?
- antibodies against dsDNA from apoptotic cells form immune complexes
- these complexes are deposited in kidney’s glomerular structures and in blood vessels
- immune complex deposition/formation eventually leads to immune-mediated tissue inflammation and damage
Type IV Hypersensitivity: Delayed Type Hypersensitivity (DTH)
What are the 2 phases?
- sensitization phase: initial contact with antigen
- effector phase: secondary contact with antigen
Type IV Hypersensitivity: Delayed Type Hypersensitivity (DTH)
What is DTH?
type of immune response classified by macrophage APC and T cell activation that results in tissue damage
- can be the result of chronic infection or exposure to antigens
Type IV Hypersensitivity: Delayed Type Hypersensitivity (DTH)
What is contact dermatitis?
(example: response to poison ivy)
- small molecules act as haptens and complex with skin proteins to be taken up by APCs and presented to Th1 cells to get sensitization
- during secondary exposure, Th1 memory cells become activated by cytotoxic T cells to cause DTH
Type IV Hypersensitivity: Delayed Type Hypersensitivity (DTH)
What are some other haptens? (2)
- heavy metals (nickel, cobalt, chromium, and zinc)
- latex
Type IV Hypersensitivity: Delayed Type Hypersensitivity (DTH)
What are DTHs?
- T-cell mediated inflammatory conditions
- also implicated in some autoimmune diseases (type IV cell-mediated vs. type II and III antibody-mediated)
Type IV Hypersensitivity: Delayed Type Hypersensitivity (DTH)
How do DTHs occur?
- soluble protein antigens are presented by macrophages or dendritic cells to TH1 helper T-cells
- in the classical TH1-macrophage feedback, TH1 cells secrete cytokines to recruit mononuclear cells and form granulomas
- at the epidermis, Langerhans cells (dendritic cells specific to skin and mucosa) act as APC – small molecules bind to normal cellular proteins following skin contact, and present as modified epidermal antigens to elicit immune activation of cytotoxic T cells
Type IV Hypersensitivity: Delayed Type Hypersensitivity (DTH)
What are some examples of type IV hypersensitivity disorders? (2)
- contact dermatitis (effector phase is cytotoxic T cell mediated)
- tuberculin formation in tuberculosis (effector phase is TH1- macrophage)
What are the causes of autoimmune disorders? (3)
- breakdown in immune tolerance against self antigens
- molecular mimicry of infectious microbe’s antigens resembling self-antigen
- neo-antigen creation through hapten binding to cellular proteins, as well as somatic mutations that altered protein structures
What are the risk factors in autoimmune disease? (4)
- genetics: polymorphic forms of MHC II allotypes
- sex: hormonal, X-inactivation, and micro-chimerism roles
- infections in susceptible individuals (see mimicry above)
- age: immunosenescence and loss of immune system self-regulatory capacity
What hypersensitivity type is Guillain Barre disease?
II
What hypersensitivity type is Graves Disease?
II
What hypersensitivity type is Myasthenia Gravis?
II
What hypersensitivity type is rheumatoid arthritis?
III
What hypersensitivity type is systemic lupus erythematosus?
III
What hypersensitivity type is celiac disease?
IV
What hypersensitivity type is multiple sclerosis?
IV
What hypersensitivity type is type I diabetes?
IV
