1Hypersensitivity08 by akram.ppt - Mymensingh Medical College file/Hypersensitivity-1by akram.pdf · C’ products of C3a and C5a are very active in degranulating mast cells Compounds

Hypersensitivity

Prof. Md. Akram Hossain

1/1/20141Prof. Muhammad Akram Hossain,

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Working Definition of Working Definition of Hypersensitivity

Adverse clinical reaction to the antigen or,“when the immune system does something“when the immune system does something

bad to the host, i.e. tissue damage”


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Other definitions

� Classical definition� Inappropriate or excessive immune

response in pre-sensitized host leadingto tissue damage.

� But recent opinion-Hypersensitivity can also arise from direct

interaction of the inciting agent with elementsof the innate immune system withoutintervention by acquired responses. (Roitt2006 11th edition)1/1/20143

Prof. Muhammad Akram Hossain, Hypersensitivity-1

Historical background of hypersensitivity

� Charles Robert Richet & Paul Portier in 1902� Experiment

� Injected toxin to Dogs, when 2nd dose given after 1 week, instead of protection, dogs become ill (excessive salivation,defecation, difficulty respiration, (excessive salivation,defecation, difficulty respiration, death) within minutes.

� So they named this phenomenon as anaphylaxis, Greek ana- means away from, phylaxis means Protection

� This is first example that immune system can cause harm.


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Charles Robert Richet(August 25, 1850 – December4, 1935) was a Frenchphysiologistphysiologist

Won Nobel Prize forPhysiology or Medicine in1913.


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Classification

A. On the basis of onset of action

B. On the basis of mechanism of action B. On the basis of mechanism of action

C. Coomb’s and Gel classification

(Combined)


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Classification..

1. Based on onset of action

Immediate hypersensitivities

Delayed hypersensitivities

2. Based on mechanism of actionAntibody mediated: Type I, II, III & VCell mediated: Type IV


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Classification…

3. Coombs & Gel - - In the early 1970s, P.G.H. Gell and R.A.

Coombs proposed following method of classification

of hypersensitivity.

Type-1 or anaphylactic hypersensitivity

Type-II or cytotoxic hypersensitivity

Type-III or immune complex hypersensitivity

Type-IV or Delayed or Cell mediated hypersensitivity

Type-V or Stimulatory hypersensitivity (Later added)


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Coombs and Gell’s Classification of Hypersensitivity


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Type I Hypersensitivity

� Also known as:� Immediate

hypersensitivityhypersensitivity� Allergy� Anaphylaxis� IgE-associated

immune responses


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What is an Allergy?

� Allergy: a biological hypersensitivity in certainindividuals to substances which, in similar amountsand circumstances, do not have an effect on others.

In other words, an allergy is an unusual or exaggeratedresponse to certain substances.

� Allergen: a substance capable of producing an allergicreaction. (can be anything!)

� “One person’s food in another person’s poison.”-- Hippocrates (460–377 BC)


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Where does the term “allergy” come from?

� Term “allergy” was coined in 1906 byAustrian pediatrician Clements VonPirquet (1874-1929)

Clemens Peter Freiherr von Pirquet was an Austrian scientist In 1906 henoticed that patients who had previously received injections of horse serum orsmallpox vaccine had quicker, more severe reactions to a second injection. He,along with Bela Schick, coined the word allergy (from the Greek allos meaning"other" and ergon meaning "reaction") to describe this hypersensitivity reaction


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Two Types of Allergies

ACTIVE Allergies…

Cause very visible, uncomfortable allergic reactions includinghives, rashes, swelling, wheezing, runny eyes, runny nose, etc.

HIDDEN Allergies…

Cause few visible allergic reactions.

Patients complain of poor function of body and/or mind including fatigue, anxiety, nose, etc. including fatigue, anxiety, mental fogginess, back pain, arthritis, malaise, etc. and don’t know the reason why.

FACT: Most allergy sufferers have both types.1/1/201413


Allergen

� Allergen: are antigens that induce production of specific IgE AB

� Examples- protein- polypeptide- polysaccharide- nucleic acid- low M.W chemicals


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Charecteristic of Allergen

1. Low M.W : < 40 kD1. Low M.W : < 40 kD

2. Water soluble

3. Stability


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Route of Allergen Entry

- Skin

- Respiratory tract

- GI tract

- Eye


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Common Allergens :- House dust : mite

- Pollen

- Animal dander

- Microorganisms

- Serum protein/Animal protein

- Antibiotic ( penicillin, streptomycin )

- Insect poison1/1/201417



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Atopy

� Atopy: Describes individuals that produce IgEAb in response to various environmental Ag anddevelop immediate hypersensitivity (Type I)responses.(Asthma, eczema, hay fever, andresponses.(Asthma, eczema, hay fever, andurticaria)

� These individuals normally have a strong familyhistory (autosomal transmission of atopy)


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Atopy

� HLA vs. Allergen Responsiveness-Some allergens response have a relationship to HLA-HLA-DR2 and HLA-A2: high responder to low dos of ragweed-HLA-B8: high responder to ragweed and also associated to other forms of hyperimmunity (autoimmunity)


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Risk of Allergy

Parents – both = 50 %

one = 30 %

none = 15 % ( 30 % )


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IgE

� IgE blood concentrations are oftenincreased in allergic disease and aregrossly elevated in parasitic infectionsgrossly elevated in parasitic infections

� IL-4: promote B-cells to differentiate intoIgE-producing specific cells


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Fig 15.10 Risk factors for allergy


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Phases of Type -1Hypersensitivity Phases of Type -1Hypersensitivity


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Sensitization


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Triggering Phase


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Type-I Hypersensitivity: Animation IProduction of IgE in Response to an Allergen


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Type-I Hypersensitivity: Animation II

Allergen Interaction with IgE on the Surface of Mast Cells triggers the Release of Inflammatory Mediators


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Activation of mast cells in type I hypersensitivity and release of their mediators. ECF, eosinophil chemotactic factor; NCF, neutrophil

Slide 7.9

factor; NCF, neutrophil chemotactic factor; PAF, platelet-activating factor. ）


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IgE-mediated Activation


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Type I Mediators and Effects


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Granule proteinsMBP, ECP, EPO

CytokinesIL-3, IL-4, IL-5, GM -CSF,

IL-6, IL-12, TGF-β

Epithelial damage / loss Muscarinic M2 dysfunction/ AHR

Attract/activate eosinophilsAirway remodelling, IgE,

Products of Human Mast Cells

LTC4, PAF ChemokinesEotaxin, RANTES

Muscarinic M2 dysfunction/ AHR Airway remodelling, IgE, Th2 polarisation

Attract/activate eosinophils

Mucus hypersecretion,Airway narrowingAttract/activate pro-inflammatory cells


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1. Early phase: 2-3 min. to 6 hr.

- histamine

- eosinophil chemotactic facter ( ECF )

Time of Chemical Mediator Release

- neutrophil chemotactic factor ( NCF ) etc.

2. Late phase: > 6 hr. - 24 hr.

- SRS-A ( Leukotrienes )

- PAF ( platelet activating factor )

- vasoactive amine


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Spasmogens:

- Histamine -Bronchial smooth

- Prostaglandin muscle contraction

- Leukotriene-C4 -Mucosal edema

- Leukotriene-D4 - Mucus secretion


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• Bronchial asthma

• Allergic rhinitis

Example of Type -1diseases

• Urticaria

• Anaphylactic shock

• Food allergy

• Eczema• Hay fever


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IgE-Mediated Allergic Reactions


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Type I Mediators and Effects


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Vasculature

Skin

Upper respiratoryrespiratory

Lower respiratory

GI Tract


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1. Skin test ( Prick test )

2. Histamine determination

Laboratory Testing

3. IgElavel - RIA

4. Eosinophil count = 10-20 %


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Skin Prick TestIn this test a small needle is used togently prick the skin through a dropof fluid containing a known allergen.It is usually done on the forearm,although with young children it maybe done on the back so they don'tbe done on the back so they don'thave to see what is happening.A negative reaction means that youdo not have an allergy to thatparticular allergen.


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Roles of Mast Cells

� Part of connective tissue (contains granules ofhistamine and heparin)

� Allergic diseases (asthma,eczema,itch)� Anaphylaxis (systemic shock to allergens such� Anaphylaxis (systemic shock to allergens such

as bee sting,nuts,drugs)� Autoimmune disorders/Acute or chronic

inflammation (MS, Rheumatoid arthritis)� Wound healing� Innate response for clearing bacteria and

viruses


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BasophilMast Cell


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Mediator Release from Mast Cells1/1/201448


Two Types of Mast Cells

1) Connective tissue mast cells (CTMCs)2) Mucosal mast cells (MMC)2) Mucosal mast cells (MMC)


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Type I: Mast Cells� Type I reaction is dependent upon the specific

triggering of IgE-sensitized mast-cells byallergen (Ag)

� Ag enter via mucosal surfaces and are taken upby APCby APC

� Th2 cells release IL-4 to facilitate the B-cellproliferation and differentiation, producing IgEspecific for the allergen

� REMEMBER: THIS IS A TH2 RESPONSE!


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Connective Tissue Mass Cells

� CTMCs are found most in blood vesselsbut vary in size and number of granules atdifferent regions of the bodydifferent regions of the body

� Diseases such as Crohn’s disease,ulcerative colitis, and RA all present withincrease in CTMCs


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Mast-Cells: Cytokines

� IL-3: Promote mast cell proliferation� IL-4, IL-5: Promote Th2 differentiation and

IgE AB productionIgE AB production� TNF-α, MIP-1α : Enhance inflammatory

reaction


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Activation of Mast Cells

� IgE from B-cells binds to FcεRI on mast-cells-ε is the heavy chain responsible for IgE -ε is the heavy chain responsible for IgE isotype switching

� FcεRI on mast-cells cross-links with Ag-bounded IgE and induces degranulation of mediators


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Mast Cells Activation

� Cross-linking can be artificially inducedwith lectins such as PHA(Polyhydroxyaldehyde) and ConAThese carbohydrates cross-link with IgE� These carbohydrates cross-link with IgEand cause degranulation

� This explains urticaria in individualsallergic to fruits (ie strawberries-containlarge amt of lectin


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Degranulation

� C’ products of C3a and C5a are veryactive in degranulating mast cells

� Compounds that affect Ca+2 influx into� Compounds that affect Ca influx intomast cells can induce degranulation

� Drugs such as morphine, codeine,synthetic ACTH can create clinicalmanifestations related to mast cells


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Eosinophil

� Th2 produce IL-5: Promotes the synthesisand secretion of IgA from B-cells and alsoimportant in stimulating eosinophilimportant in stimulating eosinophildevelopment and activation

� IL-4 and IL-5 production by Th2 cells mayaccount for the eosinophilia seen in type Ihypersensitivity and parasitemia


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Products of Human Eosinophils


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Types of Fc Receptors for IgE

� There are two types of receptors for IgE1) FcεRI (high affinity): Expressed on mastcells and basophilscells and basophils2) FcεRII (low affinity): Expressed bylymphocytes


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Anaphylactic-type Degranulation of a Mast Cell


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vity Reaction

Type I Hypersensitivity


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Treatment & Prevention


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Fig 15.12 Atopic allergies and their treatment1/1/201462


Treatment & Prevention…1.Allergen avoidance

- Environmental control

2. IgE removement2. IgE removement

2.1 Hyposensitization ( Desensitization )

Allergen i.d Blocking IgG


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2.2 Remove IgE out of serum

Blood Plasmapheresis Plasma

Body Rbc AffinityBody Rbc Affinity

chromtography

Plasma without IgE (Anti-IgE)


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3. Inhibition of mediators release

3.1 Methylxanthines: theophylline

theophylline

cAMP 5 AMP

3.2 ß-Adrenergic receptor stimulators3.2 ß-Adrenergic receptor stimulators

epinephrine ß -adrenergic receptor

cAMP ATP adenyl cyclase


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4. Histamine antagonist (Anti-histamine)

Histamine Target

Anti-histamine cell

- sodium cromoglycate( cromolyn )- sodium cromoglycate( cromolyn )

5. Late phase inhibitor

steroid, indomethacin

SRS-A Target cell

steroid = anti-inflammation1/1/201466



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Immunological interventions

Desensitisation

� Acute desensitisation –

� Very small amounts of Ag at 15 min intervals to formAg-IgE complex on small scale which will notdegranulate mast cell.degranulate mast cell.

� Chronic desensitisation -

� Small doses of allergens are injected at weeklyintervals where IgG antibody is produced whichblocks the Ag by binding with it and does not allowthe Ag to reach the mast cell bound IgE .


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Desensitization..Severity may be reduced by desensitization shots (allergy

shots). It is thought that when very dilute allergen is given

by injection, it stimulates the production of IgG and IgA. IgG

and IgA then act as blocking antibodies to bind and

neutralize much of the allergen in secretions before it canneutralize much of the allergen in secretions before it can

bind to the deeper cell-bound IgE on the mast cells in the

connective tissue. The shots also appear to suppress

production of IgE by inducing tolerance and/or by activating

T8-suppressor cells.


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Desensitization…A new experimental approach to treating and preventing Type-I

hypersensitivity involves giving the person with allergies

injections of monoclonal antibodies that have been made

against the Fc portion of human IgE .

This, in turn, blocks the attachment of the IgE to the FcThis, in turn, blocks the attachment of the IgE to the Fc

receptors on mast cells and basophils and the subsequent

release of histamine by those cells upon exposure to

allergen.

In addition, the anti-IgE binds to IgE-producing B-lymphocytes

causing apoptosis .


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The monoclonal antibody is a humanizedhybrid molecule consisting of a mousebinding (Fab) portion attached to a humanbinding (Fab) portion attached to a humanconstant (Fc) portion and is known asrhuMab (recombinant human monoclonalantibody).


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Intervention for Type I Hypersensitivity

Animation: Treatment with monoclonal anti-IgE antibody1/1/201472


Documents

1Hypersensitivity08 by akram.ppt - Mymensingh Medical College file/Hypersensitivity-1by akram.pdf · C’ products of C3a and C5a are very active in degranulating mast cells Compounds