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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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Mast Cell Activation

Biological Effects

Common Symptom

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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

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The You Ecosystem