page ‹#› dermatitis can be caused by poison ivy and mango sap some allergies and autoimmunity...
TRANSCRIPT
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Lecture 8:Immune Dysfunction - Immunopathology
Allergy and Asthma
Graft rejection and Lupus
Autoimmune disease
Immunodeficiency
Friend of Foe?
Four Types of Hypersensitivity
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Allergic Responses - Type I
Produces
antibodies with
unique constant
region (IgE)
IgE
antibodies
bind to
mast cells
Mast cells
release
histaminesAntigen
binds to
IgE on
mast cells
Antigen
binds to B
cell and
activates it
Type I hypersensitivity mediated by IgE on mast cells
Wheal and flare
Allergen Characteristics
• It is not fully understood how or
why, but these type of antigens
tend to stimulate IL-4 production
• IL-4 production tends to lead to
more IL-4 production.
• IL-4 favors class switching to IgE
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A CulpritDust Mite Fecal Protein
Mast Cell Activation
Compounds Released from Eosinophils
Cytokine-activated
Eosinophils have
Fce receptors
(FceR)
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Th2 mediated Chronic Airway Obstruction
Type I hypersensitivity because IgE-mediated Type IV hypersensitivity
because TH2 involvement
(asthma)
Allergy Treatments
make IgG response to
compete with IgE
desensitizationdesensitizationReverse TH1/TH2 balance
(2006)
Delayed-Type Hypersensitivity
TH1 from a previous
immunization
(memory)
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Chemical Mediators of DTH
A positive tuberculin
skin test is a DTH
reaction
Before the distinction
between TH1 and TH2
(circa 1990), there
was TH cell and TDTH.
TH is now TH2 and
TDTH is now TH1
DTH as a Result of Contact Sensitizing Agent
*a contact-sensitizing agent is usually a small
molecule that penetrates the skin then binds to self-
proteins, making the protein “look” foreign
Can be caused by poison ivy and mango sapContact Dermatitis
Some Allergies and Autoimmunity canbe Mapped to Specific Gene Loci
Many others cannot yet be mapped to specific loci
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Examples of Susceptibility Genes
Genetics AND Environement Play a Role
The “hygiene hypothesishygiene hypothesis” of
allergy induction contends that
too clean of an environment
and lack of infections during
childhood (along with a genetic
susceptibility) promote a bias
of the immune system toward
TH2 cells and IgE production
Atopy: a increased
tendency toward type
I hypersensitivity
(IgE allergies)
Autoimmunity(I added this slide after the lecture as a summary)
Estimated that 2-5%
of human population
suffers from
autoimmune disease
Autoimmunity results from a failure or breakdown of the mechanisms normally responsible formaintaining self-tolerance in B cells, T cells, or both.
The major factors that contribute to the development of autoimmunity are genetic susceptibility
and environmental triggers, such as infections.
Most autoimmune
diseases are
polygenic (many
genes involved),
and affectedindividuals inherit
multiple genetic
polymorphisms
that contribute to
disease
susceptibility.
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Autoimmunity(I added this slide after the lecture as a summary)
Covered
in the
book
Autoimmunity
• Book does a nice job of discussing several autoimmune diseases
Look at the various links on the webpage!
The red boxed diseases on this slide and the next are mentioned in the book
Autoimmunity
• Book does a nice job of discussing several autoimmune diseases
Look at the various links on the webpage!
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Summary of Abnormal Immune Responses
• Disorders caused by abnormal immune responses are called hypersensitivity
diseases. Pathologic immune responses may be autoimmune responses directed
against self antigens or uncontrolled and excessive responses to foreign antigens.
• Hypersensitivity diseases may result from antibodies that bind to cells or tissues,
circulating immune complexes that are deposited in tissues, or T lymphocytes reactive with antigens in tissues.
• The effector mechanisms of antibody-mediated tissue injury are complement activation and Fc receptor-mediated inflammation.
• The effector mechanisms of T cell-mediated tissue injury are DTH reactions and cell lysis by CTLs.
• Autoimmunity results from a failure of self-tolerance. Most autoimmune diseases are polygenic, and numerous susceptibility genes contribute to disease
development.
• Infections may predispose to autoimmunity through cross-reactions between
microbial antigens and self antigens and enhanced expression of costimulators.
TH1 cells promote cytotoxicity anddestruction of intracellular pathogens
• IL-12 drives T-cells to develop into TH1 cells
• TH1 cells orchestrate a response directed to inhibit intracellular pathogens likeviruses, certain bacteria (e.g. TB), or certain protozoan parasites (Leishmania)
• They secret Interferon gamma which activates intracellular killing mechanisms
• They activate macrophages and cytotoxic T-cells
TH2 cells promote neutralizing antibodiesand mast cell activity
• The ‘choice’ towards a TH2 response is driven by the cytokine IL-4
• TH2 cells suppress activation of macrophages and activate eosinophils and mast cells
• TH2 cells promote a strong antibody response based on neutralizing IgGs and IgEs
• A TH2 response is most effective to combat extracellular pathogens
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Immune modulation by worms can bedetrimental or beneficial
• Numerous recent epidemiological studies show that certainvaccines are less effective in children that are infected with wormsthan those that have been cured using drugs.(these are mostly vaccines that require a robust TH1 response)
• This is backed up by many studies in mice that use vaccination orco-infection.
• On the other hand worm infection can dampen autoimmunediseases and allergies (diseases due to an ‘over-active’ immunesystem.
The Hygiene Hypothesis
• There has been a considerable increase in the diagnosis ofautoimmune diseases and allergies over the second half ofthe 20th century.
• Prevalence of allergies in urban areas appears higher thanin rural environments.
• Environmental factors like pollution, nutrition etc. can beimportant for specific allergies but have shown littleconsistent overall association with allergies andautoimmunity.
• Childhood infections though show strong negativecorrelation with both autoimmune disease and allergies.
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Inverse correlation of type I diabetes andchronic infectious diseases
Red delineates areas which harbour six or more of the low mortality neglected diseases (filariasis, leprosy, onchocerciasis, schistosomiasis,
soil-transmitted helminths, and trachoma). Yellow delineates areas where there are relatively high incidences of T1D (> 8 per 100000/year).
Non coloured areas delineate where T1D < 8 per 100 000/year and where the ‘neglected diseases’ are not endemic.
From: Zaccone et al. Parasite Immunol. 2006 28:515–523.
Yellow - aTID
_ND
Red - _TID
aND
XX Th1 vs Th2 hypothesis
T1D - Th1 mediated
Inverse correlation of allergies with infections
• Among kids invarious studies indifferent areas ofthe world around30% haveantibodies againstdust mite allergen(suggesting they allare exposed)
• But whereas asthmais found in 12% ofkids from Europeand Australia, only3% have asthma inGambia and Nigeria
The Hygiene Hypothesis
• High pathogen burdenstimulates the immunesystem to develop arobust regulatorynetwork that keepsinflammation in check
• Worms set up longlasting chronicinfections, they inducestrong TH2 responsesand promote regulationof this process
• Understanding thisprocess in detail couldpoint to new allergyinterventions