Microbiology - Hypersensitivity Flashcards
What are 3 factors that contribute the complexity of allergic diseases?
Same disease in different ethnic groups is associated with different genes Allergic disease is modulated by balance between Th1 and Th2 responses – but BOTH gene polymorphisms and environmental factors can affect this balance Allergic diseases are associated with abnormal MHC genes AND non-MHC related genes
What is the hygiene hypothesis and what is thought to mediate it?
incidence of allergies has doubled over the past 10-15 years, possibly due to better and increased hygiene less exposure to pathogens skews the balance towards Th2 rather than Th1 responses – Th2 cells produce IL-4 which is important for production of IgE
Excessive hygiene reduces childhood exposures to microorganisms
Vaccination reduces immune system experience with “natural” infection
Overuse of antibiotics reduces immune system experience and ability to discriminate self from foreign
Immune system perception of foreign “danger” is affected
What countries are most susceptible to high incidence of allergies?
countries where parasite infections have been eliminated
What are allergies?
Adaptive immune responses develop to a foreign substances that is not associated with infection. In genetically susceptible individuals, these are manifested as allergies or hypersensitivities.
When do hypersensitivity reactions occur?
after secondary exposure to an antigen, due to its interaction with previously formed antibodies or as a consequence of the activation of antigen-specific memory T cells.
What defines the different types of hypersensitivity reactions?
the effector mechanisms that are involved
What type of Hypersensitivity Rxn involves IgE binding to its FcR on mast cells leading to their activation/degranulation?
Type I
What type of Hypersensitivity Rxn is mediated by antigen-specific effector T cells
Type IV
What type of Hypersensitivity involves IgG binding to FcR on phagocytes, NK cells, followed by complement activation or binding of IgG raised against new epitopes of cell-surface proteins cell-surface receptor leading to altered signaling
Type II
What type of Hypersensitivity Rxn involves the formation of immune complexes which bind to FcR and fix complement.
Type III
What anitbodies are associated with H. Rxn Type I
IgE against soluble antigen leading to mast cell activation
Occurs when preformed IgE binds irreversibly to FcRε principally on mast cells, basophils and
eosinophils.
What antibodies are associated with Type II H Rxns?
Where are the antigens?
What are the effectors?
IgG against cell surface antigens or receptors or matrix associated antigen
Effectors for cell surface or matrix associated antigens are compliment, FcR+ cells (e.g. NK cells and other phagocytes)
Effectors for cell surface receptors are altered intracellular signalling pathways
What antibodies are associated with Type III H Rxns?
Where are the antigens?
What are the effectors?
IgG against soluble antigen leading to complement and phagocytosis
What cell types are involved in Type IV H Rxns?
Where are the antigens?
What does each cell type do?
Th1, Th2, Cytotoxic T Lymphocytes (CTLs)
Th1 + Th2 ==> soluble antigens
CTLs ==> cell associated antigens
Th1: macrophage activation
Th2: eosinophil activation
CTLs: cytotoxicity
What type of H Rxn does penicillin alergy cause?
What is the immune reactant?
Type II
IgG
What type of H Rxn is chronic urticaria?
What is the immune reactant?
Type II
IgG
What type of H Rxn is asthma?
What is the immune reactant?
Type I
IgE
What type of H Rxn is allergic rhinitis?
What is the immune reactant?
Type I
IgE
What type of H Rxn is syrum sickness?
What is the immune reactant?
Type III
IgG
What type of H Rxn is contact dermatitis?
What is the immune reactant?
Type IV
Th1 and CTLs - activates macrophages
What type of H Rxn is a tuberculin reaction?
What is the immune reactant?
Type IV
Th1
What type of H Rxn is chronic asthma?
What is the immune reactant?
Type IV
Th2 ==> eosinophil activation
What type of H Rxn is chronic allergic rhinitis?
What is the immune reactant?
Type IV
Th2 ==> eosinophil
Why would higher levels of Th2 cells (a shift in the balance of Th1 to Th2) favor an increased the incidence of allergies?
Th2 cells produce IL-4 which promotes B-cell class switching to IgE production
What is the most common way mast cells become activated during allergies?
Alergies require second exposure to antigen - first exposure results in IgE production and binding of IgE to Fc Recptors on mast cells. Second exposure binds antigen to mast cell - Fc - IgE complex and triggers degranulation
What are other ways (asside from IgE) that allow mast cell degranulation?
- IgG cross-linking (IgE KO still develop antigen-induced degranulation)
- C5a binds to complement receptors
Mast cells also express TLRs
What is the effect of serotonin in the acute phase of an alergic reaction?
TNF?
SRS-A?
5HT - increases vascular permeability
TNF - upregulates adhesion molecules on endothelial cells
SRS-A (slow releasing substance of anaphalaxis) - mix of leukotrienes
What are blood granulocytes with structural and functional properties similar to mast cells?
What activates/stimualtes them?
Basophils
-Reciprocally regulated with eosinophils- TGFb, IL-3 lead to increased basophils and decreased eosinophils, which are stimulated by IL-5 and GM-CSF
Usually low levels unless activated and must be activated to express IgE FcR
what are bone-marrow derived granulocytes found in the inflammatory infiltrates of late phase reactions?
How are they regulated? What stimulates them?
Eosinophils
-Reciprocally regulated with basophils - TGFb, IL-3 lead to increased basophils and decreased eosinophils, which are stimulated by IL-5 and GM-CSF
Usually low levels unless activated and must be activated to express IgE FcR
How does granulocyte response (basophil, eosinophil, mast cell) affect the GI tract?
Granulocyte response normally promotes expulsion of parasites by increased peristalsis and mucus production
What is a mechanism in skin-testing for allergies?
RAST assay for allergen-specific IgE
What is the response to a subcutaneous allergen?
Localized swelling -urticaria (hives); deeper, more diffuse swelling is angiodema. Also eczema
what is the sequence of events in response to an inhalled alergen in allergic rhinitis?
1) extraction of antigen from mucosal lining by antigen presenting cell
2) presentation of antigen on MHC II activates Th2 cells
3) activated Th2 cells activate B cells and secrete IL-4 which triggers class switching to IgE
4) Fc region of IgE (heavy chain) binds to Fc receptors on mast cells, priming them for secondary exposure
5) secondary exposure to antigen binds to IgE-Fc triggering degranulation of mast cell
6) mast cell degranulation results in changes in vascular permeability, cytokine expression, nasal mucus secretions, and increased expression of endothelial adhestion molecules that facilitate extravasation of eosinophols through nasal epithelium
7) eosinophils degranulate, release histamine, kill parasites
If eyes are infected - allergic conjunctivitis ensues - similar sequence of events
What causes allergic asthma?
What are the major cells/molecules involved in acute vs chronic response?
Th2 Cells that produce IL-13 - important for release of IgE by activated B cells
Immediate (within minutes) phase involves pre-formed mediators and late phase (6-8 hours)
involves cellular infiltration.
What are contained in mast cell granules? Are they preformed or formed upon expsure to allergen?
a. enzymes like tryptase, which contribute to tissue remodeling.
b. toxic mediators like histamine, which increase vascular permability and cause
smooth muscle contractions.
c. cytokines especially TNF alpha, which promote inflammation and stimulate other
cytokine production.
d. chemokines like CCL3, which promote influx of monocytes, macrophages and
neutrophils.
e. lipid activators like leukotrienes, which cause smooth muscle contraction, increase
vascular permeability and are involved in smooth muscle contraction.
what type of H Rxns are mistmatched blood transfusions, myasthenia gravis,
Grave’s disease (hyperthyroidism), Hashimoto’s thyroiditis (hypothyroidism) and insulin-resistant
diabetes?
What is the immune reactant?
Type II
IgG
Type III H rxns involve what immune reactant? What does it do? What factors influence the pathogenicity?
IgG
Forms immune complex with antigen that then binds to compliment and results in inflammatory responses that can damage self tissue
factors that influence pathogenicity of immune complex:
size, isotype, valency, charge, ability to fix
complement
In type III H Rxns what determines the clinical manifestation?
the site of deposition determines clinical manifestation:
a. intravenous- vasculitis if in blood vessels, nephritis if in renal glomeruli, arthritis if in
joints.
b. subcutaneous- Arthus reaction in perivascular area (local vasculitis due to deposition of IgG-based immune complexes in dermal blood vessels).
c. inhaled- Farmer’s lung in alveolar/capillary interface.
What is the Arthus reaction? What type of H Rxn? What is the immune reactant?
Type III Immune Complex - localized injected antigen binds to IgG, activates complement, triggers
mast cell degranulation resulting in localized inflammatory response with increased
fluid, protein and cells.
What is serum sickness? What type of H Rxn? What immune reactant?
Type III Immune Comlex Rxn – occurs after development of antibodies (IgG) to large amounts of foreign
protein such as anti-venom, mouse monoclonal antibody therapeutics, streptokinase.
what is Post-streptococcal glomerulonephritis? What type of H. Rxn? Immune reactant?
Type III - immune comlex of IgG forms
occurs several weeks after a group A β-
hemolytic
What are some treatments for Type II, III, IV H Rxns?
a. Avoidance of the antigen.
b. Reduction of the impact of the immune response to the antigen with antiinflammatories
and steroids.
c. Reduce the immune response in general (steroids, cytoxan) or specifically (targeting
pathogenic T and B cells).
d. Induce regulation of the response- Treg (peptide vaccination).
e. Block the effector mechanisms of allergic response-cytokines, co-stimulatory molecules.
f. Controlled and deliberate helminth infections are being explored as possible treatment.
What is the time course of a Type IV H. Rxn? Do they require more of less antigen than Type II (antibody mediated)?
- Occur 1-3 days after contact with antigen.
- Require 100-1000 times more antigen than an antibody-mediated hypersensitivity reaction.
What type of H. Rxn is a TB infection?
Type IV - Delayed-type hypersensitivity
Characterized by local skin swelling,
erythema and cellular infiltrate in response to tuberculin.
This is why PPDs are read 3 days later
What type of H Rxn is caused by poison Ivy exposure?
Type IV - Contact hypersensitivity caused by local epidermal reaction
including erythema, cellular infiltrate, vesicles and intra-epidermal abscesses in
response to pentadecatechol.
What type of H Rxn is Celiac disease
Type IV - Delayed (cell mediated) hypersensitivity rxn – (gluten-sensitive enteropathy), which manifests as villous atrophy in
the small bowel due to T cell response to gliadin.
What is the cause of uticaria (hives)?
absorbed antigen triggers degranulation of granulocytes which causes increases in vascular permeability - antigen diffuses into blood and becomes systemic eventually triggering degranulation of tissue granulocytes surrounding superficial capillary beds and resulting disseminated inflammatory responses
What type of H Rxn is caused by venom and peanuts?
Why would you treat with epinephrine?
Type I - IgE - anaphylaxis
promotes the formation of tight junctions, relaxes bronchial smooth muscle, stimulates the heart
Pt presents with rapid onset disseminated edema including swelling of the tounge, drop in BP, arrythmia, low O2 sat, constriction of throat and airways, difficulty swallowing, difficulty breathing, wheezing, stomach cramps, vomiting, diarrhea and loss of consiousness.
What is the Dx?
What is the pathogenic process that triggers the symptoms?
What is the treatment? Why does the treatment work?
Anaphylactic shock
antigen in blood stream (e.g. from peanuts or snake venom) extravasates into tissues througout the body activating connective tissue mast cells coated with IgE - caues degranulation and release of inflammatory mediators into all major organs.
Treatment is Epinepherine. Works because it promotes the formation of tight junctions, relaxes bronchial smooth muscle, stimulates the heart
Can IgE and antigen pass from mother to fetus during pregnancy?
Yes.
Child is more at risk for allergy if mother not father is atopic (allergic)
IgE complexed with allergen in amniotic fluid could be ingested by fetus
What is Omalizumab?
humanized anti-IgE used for treatment of type I hypersensitivity rxns
What is desensitization (as a treatment for Type I H Rxns)?
controlled exposure to increased dose of antigen over time leads to IgA and IgG antibodies which block binding of allergen to IgE on mast cells
What type of H rxn is hemolytic disease of the newborn?
type II - Rh- mother has Rh+ fetus, produces IgG for Rh+, second Rh+ fetus has anti-Rh-IgG enter fetal circulation and kill RBS
What is the risk of having a tetanus booster in less than 5 years?
Type III immunte complex hypersensitivity rxn - Arthus Reaction (localized reaction) - PMNs attracted to site, produce lysosomal enzymes, causing tissue damage
How does serum sickness present? What type of H. Rxn?
Type III - immune complex rxn
fever, vasculitis, arthritis, nephritis
doesn’t develop until 7-10 days after exposure to blood born antigen - occurs after development of antibody to the introduced blood born antigen
Symptoms are due to formation of antibody-antigen complex that are capable of depositing systemically in any of a variety of tissue sites (blood vessel walls, kidney glomeruli, joints) leading to cellular damage with many different clinical presentations
What type of H rxn do small metal ions (nickel, chromate) cause?
Type IV - contact hypersensitivity
What are the treatments for Type I H rxns?
- Avoid the allergen
- Treat symptoms with antihistamines, corticosteroids, cromolyn sodium, montelukast (Singulair) epinephrine, theophylline, albuterol
- Desensitization –controlled exposure to increased dose of antigen over time leads to IgA and IgG antibodies which block binding of allergen to IgE on mast cells
- Allergenic peptide vaccination to anergize allergen-specific T cells
- Omalizumab- humanized anti-IgE
- Block effector mechanisms of allergic response-eg. anti-cytokines
