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HYPERSENSITIVITY

Presented by,
Dr. Nitha Willy
First year PG
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Department Of Oral Medicine And Radiology
CONTENTS

1.Introduction

2.Classification of hypersensitivity

3.Type 1 hypersensitivity

4.Type 2 hypersensitivity

5.Type 3 hypersensitivity

6.Type 4 hypersensitivity

7.References

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Hypersensitivity (allergy) is an inappropriate immune response that may develop in

the humoral or cell-mediated responses.

Gell and Coombs were the first scientists to define hypersensitivity reaction.

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There are several important general features of hypersensitivity disorders.

Both exogenous and endogenous antigens may elicit hypersensitivity reactions.

The development of hypersensitivity diseases is often associated with the

inheritance of particular susceptibility genes.

Hypersensitivity reflects an imbalance between the effector mechanisms of immune

responses and the control mechanisms that serve to normally limit such responses.

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An antigen is defined as a substance, usually protein in nature, which when introduced

into the tissues stimulates antibody production.

An antibody is a protein substance produced as a result of antigenic stimulations.

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T cell, also called T lymphocyte, type of leukocyte (white blood cell) that is an

essential part of the immune system.

T cells originate in the bone marrow and mature in the thymus.

In the thymus, T cells multiply and differentiate into helper, regulatory, or cytotoxic T

cells or become memory T cells.

Once stimulated by the appropriate antigen, helper T cells secrete chemical messengers

called cytokines

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B-cell : A type of white blood cell that makes antibodies.

B-cell production in humans is a lifelong process that starts in the fetal liver intrauterine

and bone marrow after birth.

Their development is from hematopoietic stem cells.

B-cell development constitutes of all the stages

I. early differentiation in the absence of antigen interaction until the maturation

II. antigen interaction, and, ultimately,

III. antibodies synthesis.

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By this process, B cells acquire two important features of adaptive immunity:

(1) discrimination between self and non-self (the ability of B-cell to recognize foreign

antigens rather than self-antigens)

(2) memory (the ability to recall the previous contact with antigens, therefore, subsequent

interaction leads to a more effective and quicker response).

B-cell is a key regulatory cell in the immune system; it acts by producing antibodies,

antigen-presenting cells, supporting other mononuclear cells, and contributing to

inflammatory pathways directly

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Immunoglobulins (Ig) or circulating antibodies are glycoproteins produced by plasma cells.

 Immunoglobulins have two light chains and two heavy chains in a light-heavy-heavy-light

structure arrangement.

The following are five types of immunoglobulins in humans:

1) IgM

2) IgG

3) IgA

4) IgE

5) IgD
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Classification Of Hypersensitivity Reactions

Hypersensitivity reactions are classified traditionally into :

Immediate hypersensitivity (B cell or Antibodies mediated)

Delayed type (T cell mediated or Cell mediated reaction)

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Immediate hypersensitivity Delayed hypersensitivity

Appears and recedes rapidly Appear slowly, lasts longer

Antigen or haptens intradermally or with Freud's

Induced by antigen or haptens by any route
reagent or by skin contact.

Antibody mediated reaction: In this type of Cell mediated reaction: Here circulating

hypersensitivity circulating Antibodies are present Antibodies are absent and they are not

and they are responsible for Reactions. responsible for the Reactions.

Passive transfer is possible with the serum Can’t be able to transfer with the serum

Desensitization easy but short lived Difficult but it is long lasting 13

Microbiology Chapter 16
Hypersensitivity reactions can be

classified on the basis of the

immunologic mechanism that

mediates the diseases.

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Type of Reaction Immune Mechanisms
Immediate (type I) hypersensitivity Production of IgE antibody → immediate release of vasoactive
amines and other mediators from mast cells; later recruitment of
inflammatory cells
Antibody-mediated (type II) hypersensitivity Production of IgG, IgM → binds to antigen on target cell or
tissue → phagocytosis or lysis of target cell by activated
complement or Fc receptors; recruitment of leukocytes
Immune complex– mediated (type III) Deposition of antigen-antibody complexes → complement
hypersensitivity activation → recruitment of leukocytes by complement
products and Fc receptors → release of enzymes and other
toxic molecules
Cell-mediated(type IV) hypersensitivity
Activated T lymphocytes →
(i) release of cytokines →inflammation and macrophage activation;
(ii) T cell–mediated cytotoxicity
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Immediate (Type I) Hypersensitivity

Immediate, or type I, hypersensitivity is a rapid immunologic reaction occurring within

minutes after the combination of an antigen with antibody bound to mast cells in individuals

previously sensitized to the antigen.

Immediate hypersensitivity may occur

as a systemic disorder or

as a local reaction.

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The systemic reaction usually follows injection of an antigen into a sensitized individual.

Sometimes, within minutes the patient goes into a state of shock, which may be fatal.

Local reactions are diverse and vary depending on the portal of entry of the allergen.

 They may take the form of localized cutaneous swellings (skin allergy, hives), nasal and

conjunctival discharge (allergic rhinitis and conjunctivitis), hay fever, bronchial asthma, or

allergic gastroenteritis (food allergy).

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The symptoms resulting from allergic responses are

known as anaphylaxis.

Allergens are nonparasite antigens that can

stimulate a type hypersensitivity response.

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Common allergens associated with type I hypersensitivity

Proteins Drugs Insect products

Foreign serum Penicillin Bee venom
Vaccines Sulfonamides Wasp venom
Local anesthetics Ant venom
Plant pollens Salicylates Cockroach calyx
Rye grass Dust mites
Ragweed Foods
Timothy grass Nuts Mold spores
Birch trees Seafood
Eggs Animal hair and dander
Peas,beans
Milk
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Examples of systemic anaphylaxis:
I. Administration of anti sera
II. Administration of drugs
III. Sting by wasp or bee

Examples of local anaphylaxis:

IV. Hay fever
V. Food allergy
VI. Bronchial asthma due to allergy to inhaled allergens

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ATOPY

Atopy is the term for the genetic trait to have a predisposition for localized anaphylaxis.

Candidate polymorphic genes include:

 IL-4 Receptor.
IL-4 cytokine (promoter region).
FcεRI. High affinity IgE receptor.
Class II MHC (present peptides promoting Th2 response).
Inflammation genes.

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Type I hypersensitivity reactions have two well-defined phases:

Immediate reaction Late-phase Reaction

evident within 5 to 30 minutes, subside in 60 sets in 2 to 24 hours, may last for several

minutes days

Vasodilation, Vascular leakage, Smooth Leukocyte infiltration, Epithelial damage,

muscle spasm Bronchospasm

Mediators : Histamine, Leukotrienes,

Prostaglandins
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Sequence of events in immediate (type I)
hypersensitivity.

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Mediators responsible for the initial, symptoms of immediate hypersensitivity, and also set

into motion the events that lead to the late-phase reaction are:

Preformed Mediators : Vasoactive amines, Enzymes, Proteoglycans

Lipid Mediators: Leukotrienes, Prostaglandin D2, Platelet-activating factor (PAF)

Cytokines: TNF, IL-1, and chemokines

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The development of immediate hypersensitivity reactions is dependent on the coordinated
actions of a variety of chemotactic, vasoactive, and spasmogenic compounds

Action Mediators
Vasodilatation, increased vascular Histamine
permeability PAF
Leukotrienes C4, D4, E4
Neutral proteases that activate complement and kinins
Prostaglandin D2
Smooth muscle spasm Leukotrienes C4, D4, E4
Histamine
Prostaglandins
PAF
Cellular infiltration Cytokines (e.g., chemokines, TNF)
Leukotriene B4
Eosinophil and neutrophil chemotactic factors (not defined
biochemically)
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Examples of IgE-mediated disease

Systemic anaphylaxis : characterized by vascular shock, widespread edema, and difficulty

in breathing

Local Immediate Hypersensitivity Reactions: allergies involving localized reactions to

common environmental allergens, such as pollen, animal dander, house dust, foods, and the

like. Specific diseases include urticaria, angioedema, allergic rhinitis (hay fever), and

bronchial asthma

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Testing

In-Vivo Tests - Skin tests

1. Small amount of allergen injected into skin
2. Look for wheal formation of 3mm or
greater in diameter
3. Simple, inexpensive, can screen for
multiple allergens.
4. Stop anti-histamines 24-72 hours before
test.
5. Danger of systemic reaction
6. Not for children under 3
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PRAUSNITZ-KUSTNER(P-K) TEST

 A test for detecting antibodies responsible for anaphylactic reaction

 In this test ,serum from allergic individual is injected into the skin of a normal person

 After 1-2 days(lag period)the site of injection is sensitized and would respond with

hive reaction when injected with that antigen to which donor was allergic

 Such a passively sensitised animals is called passive cutaneous anaphylaxis

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TREATMENT

Acute management:

The first and most important treatment in anaphylaxis is epinephrine. There are NO

absolute contraindications to epinephrine in the setting of anaphylaxis.

Airway – Immediate intubation if evidence of impending airway obstruction from

angioedema. Delay may lead to complete obstruction. Intubation can be difficult and

should be performed by the most experienced clinician available. Cricothyrotomy may be

necessary.

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Promptly and simultaneously, give:

IM epinephrine (1 mg/mL preparation) – Give epinephrine 0.3 to 0.5 mg IM, preferably in the
mid-outer thigh. Can repeat every 5 to 15 minutes (or more frequently), as needed. If epinephrine is
injected promptly IM, most patients respond to 1, 2, or at most, 3 doses. If symptoms are not
responding to epinephrine injections, prepare IV epinephrine for infusion.

Place patient in recumbent position, if tolerated, and elevate lower extremities.

Oxygen – Give 8 to 10 L/minute via facemask or up to 100% oxygen, as needed.

Normal saline rapid bolus – Treat hypotension with rapid infusion of 1 to 2 liters IV. Repeat, as
needed. Massive fluid shifts with severe loss of intravascular volume can occur.

Albuterol (salbutamol) – For bronchospasm resistant to IM epinephrine, give 2.5 to 5 mg in 3 mL

saline via nebulizer, or 2 to 3 puffs by metered dose inhaler. Repeat, as needed. 31
Adjunctive therapies:

H1 antihistamine – Consider giving cetirizine 10 mg IV (given over 2 minutes) or

diphenhydramine 25 to 50 mg IV (given over 5 minutes) – for relief of urticaria and itching
only.

H2 antihistamine – Consider giving famotidine 20 mg IV (given over 2 minutes).

Glucocorticoid – Consider giving methylprednisolone 125 mg IV.

Monitoring – Continuous noninvasive hemodynamic monitoring and pulse oximetry

monitoring should be performed. Urine output should be monitored in patients receiving IV
fluid resuscitation for severe hypotension or shock.

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Treatment of refractory symptoms:

Epinephrine infusion – For patients with inadequate response to IM epinephrine and IV saline, give

epinephrine continuous infusion, beginning at 0.1 mcg/kg/minute by infusion pump. Titrate the dose

continuously according to blood pressure, cardiac rate and function, and oxygenation.

Vasopressors – Some patients may require a second vasopressor (in addition to epinephrine). All

vasopressors should be given by infusion pump, with the doses titrated continuously according to

blood pressure and cardiac rate/function and oxygenation monitored by pulse oximetry.

Glucagon – Patients on beta blockers may not respond to epinephrine and can be given glucagon 1 to

5 mg IV over 5 minutes, followed by infusion of 5 to 15 mcg/minute. Rapid administration of

glucagon can cause vomiting. 33

Immunotherapy

Desensitization (hyposensitization) also known as allergy shots.

Repeated injections of allergen to reduce the IgE on Mast cells and produce IgG.

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Antibody-Mediated (Type II) Hypersensitivity

This type of hypersensitivity is caused by antibodies that react with antigens present

on cell surfaces or in the extracellular matrix.

The antigenic determinants may be intrinsic to the cell membrane or matrix, or they

may take the form of an exogenous antigen adsorbed on a cell surface or matrix.

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Mechanisms of Antibody-
Mediated Injury

A. Opsonization of cells by
antibodies and complement
components and ingestion by
phagocytes.
B. Inflammation induced by
antibody binding to Fc receptors of
leukocytes and by complement
breakdown products.
C. Anti-receptor antibodies disturb
the normal function of receptors.

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Opsonization and phagocytosis :

Phagocytosis is largely responsible

for depletion of cells coated with

antibodies.

Antibody-dependent cellular

cytotoxicity: Antibody-mediated

destruction of cells may occur by

another process called antibody-

dependent cellular cytotoxicity

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Inflammation

When antibodies deposit in fixed tissues, such as basement membranes and extracellular

matrix, the resultant injury is due to inflammation.

Inflammation in antibody-mediated (and immune complex–mediated) diseases is due to both

complement and Fc receptor–dependent reactions.

Cellular Dysfunction

In some cases, antibodies directed against cell surface receptors impair or dysregulate

function without causing cell injury or inflammation. 38

Clinically,

antibody-mediated cell destruction and phagocytosis occur in the following situations:

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Certain drug reactions, in which a drug acts as a

“hapten” by attaching to surface molecules of red

cells and antibodies are produced against the drug–

membrane protein complex.

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Transfusion reactions, in which cells from an

incompatible donor react with and are opsonized

by preformed antibody in the host

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Hemolytic disease of the

newborn (erythroblastosis

fetalis), in which there is an

antigenic difference

between the mother and the

fetus, and antibodies (of the

IgG class) from the mother

cross the placenta and cause

destruction of fetal red42cells

Autoimmune hemolytic

anemia, agranulocytosis, and

thrombocytopenia, in which

individuals produce antibodies

to their own blood cells, which

are then destroyed

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Examples of Antibody-Mediated Diseases (Type II Hypersensitivity)

1. Autoimmune hemolytic anemia

TARGET ANTIGEN: Red cell membrane proteins (Rh blood group antigens, I antigen)

MECHANISM OF DISEASE: Opsonization and phagocytosis of red cells

CLINICOPATHOLOGIC MANIFESTATION: Hemolysis, anemia

2. Autoimmune thrombocytopenic purpura

TARGET ANTIGEN : Platelet membrane proteins (Gpllb : Illa integrin)

MECHANISM OF DISEASE : Opsonization and phagocytosis of platelets

CLINICOPATHOLOGIC MANIFESTATION :Bleeding 44

3. Graves disease (hyperthyroidism)

TARGET ANTIGEN : TSH receptor Antibody-mediated

MECHANISM OF DISEASE : Stimulation of TSH receptors

CLINICOPATHOLOGIC MANIFESTATION : Hyperthyroidism

4.Insulin-resistant diabetes

TARGET ANTIGEN : Insulin receptor

MECHANISM OF DISEASE : Antibody inhibits binding of insulin

CLINICOPATHOLOGIC MANIFESTATION :Hyperglycemia, ketoacidosis 45

5. Pernicious anemia

TARGET ANTIGEN: Intrinsic factor of gastric parietal cells

MECHANISM OF DISEASE : Neutralization of intrinsic factor, decreased absorption of

vitamin B12

CLINICOPATHOLOGIC MANIFESTATION :Abnormal erythropoiesis, anemia

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Immune Complex–Mediated (Type III) Hypersensitivity

Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the

sites of deposition.

Immune complex– mediated diseases can be

 Systemic, if immune complexes are formed in the circulation and are deposited in many

organs

Localized to particular organs, such as the kidney (glomerulonephritis), joints (arthritis), or

the small blood vessels of the skin if the complexes are deposited or formed in these tissues. 47
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1. Antibody combines with excess soluble antigen, forming large

quantities of Ag-Ab complexes.

2. Circulating immune complexes become lodged in the basement

membrane of epithelia in sites such as kidneys, lungs, joints,skin.

3. Fragments of complement cause release of histamine and other

mediator substances.

4. Neutrophils migrate to the site of immune complex deposition

and release enzymes that cause severe damege in the tissues and

organs involved
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Systemic Immune Complex Disease

ACUTE SERUM SICKNESS is the prototype of a systemic immune complex disease

The pathogenesis of systemic immune complex disease can be divided into three phases:

(1) formation of antigen-antibody complexes in the circulation

(2) deposition of the immune complexes in various tissues, thus initiating

(3) An inflammatory reaction at the sites of immune complex deposition

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The pathogenesis of systemic immune complex disease

can be divided into three phases:

(1) formation of antigen-antibody complexes in the

circulation

(2) deposition of the immune complexes in various

tissues, thus initiating

(3) An inflammatory reaction at the sites of immune

complex deposition
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Local Immune Complex Disease

ARTHUS REACTION

The arthus reaction is a localized area of tissue necrosis resulting from acute immune

complex vasculitis, usually elicited in the skin.

Localized inflammatory response that typically occurs after vaccination.

The reaction usually presents at the site of injection after a vaccination (e.g., Tetanus-

diphteria booster).

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Examples of Immune Complex–Mediated Diseases

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T Cell–Mediated (Type IV) Hypersensitivity

The cell-mediated type of hypersensitivity is initiated by antigen-activated (sensitized) T

lymphocytes, including CD4+ and CD8+ T cells.

CD4+ T cell–mediated hypersensitivity induced by environmental and self-antigens can be

a cause of chronic inflammatory disease.

Many auto immune diseases are now known to be caused by inflammatory reactions

driven by CD4+ T cells.

In certain forms of t cell–mediated reactions, especially those that follow viral infections,

CD8+ cells may be the dominant effector cells. 55

Inducers of Type IV Hypersensitivity

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Reactions of CD4+ T Cells

Delayed-Type Hypersensitivity and Immune Inflammation

Inflammatory reactions caused by CD4+ T cells were initially characterized on the basis of

delayed-type hypersensitivity (DTH) to exogenously administered antigens.

The cellular events in T cell–mediated hypersensitivity consist of a series of reactions in

which cytokines play important roles.

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The reactions can be divided into the following stages.

I. Proliferation and Differentiation of CD4+ T Cells

II. Responses of Differentiated Effector T Cells

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Reactions of CD8+ T Cells

Cell-Mediated Cytotoxicity

In this type of T cell–mediated reaction, CD8+ CTLs kill antigen-bearing target cells.

Tissue destruction by CTLs may be an important component of many T cell–mediated

diseases, such as type 1 diabetes.

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Phases of the DTH Response

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Sensitization phase:

occurs 1-2 weeks after primary contact with Ag

What happens during this phase?

 TH cells are activated and clonally expanded by Ag presented together with class

II MHC on an appropriate APC, such as macrophages or Langerhan cell

(dendritic epidermal cell)

 Generally CD4+ cells of the TH1 subtype are activated during sensitization and

designated as TDTH cells

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Effector phase

occurs upon subsequent exposure to the Ag

What happens during this phase?

TDTH cells secrete a variety of cytokines and chemokines, which recruit and activate

macrophages

Macrophage activation promotes phagocytic activity and increased concentration of lytic

enzymes for more effective killing

Activated macrophages are also more effective in presenting Ag and function as the primary

effector cell 63
WHAT HAPPENS IF THE DTH RESPONSE IS PROLONGED?

A granuloma develops

Continuous activation of macrophages

induces the macrophages to adhere

closely to one another, assuming an

epithelioid shape and sometimes fusing

together to form giant, multinucleated

cells. 64
The principal mechanism of T cell–mediated killing of targets involves

Perforins and granzymes , preformed mediators contained in the lysosome-like granules of

cytotoxic T lymphocytes (CTLs)

CTLs that recognize the target cells secrete a complex consisting of perforin, granzymes, and

a protein called serglycin, which enters target cells by endocytosis.

In the target cell cytoplasm, perforin facilitates the release of the granzymes from the

complex.

Granzymes are proteases that cleave and activate caspases, which induce apoptosis of the
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target cells.
Protective Role of DTH Response

Intracellular bacteria Intracellular viruses Contact Antigens

Mycobacterium tuberculosis Herpes simplex virus Hair dyes

Mycobacterium leprae Measles virus Poison ivy

 A variety of intracellular pathogens and contact antigens can induce a DTH response.

 Cells harboring intracellular pathogens are rapidly destroyed by lytic enzymes released

by activated macrophages
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DETRIMENTAL EFFECTS OF DTH RESPONSE

 The initial response of the DTH is nonspecific and often results in significant damage

to healthy tissue

 In some cases, a DTH response can cause such extensive tissue damage that the

response itself is pathogenic

 Example: Mycobacterium tuberculosis – an accumulation of activated macrophages

whose lysosomal enzymes destroy healthy lung tissue

 In this case, tissue damage far outweighs any beneficial effects.

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HOW IMPORTANT IS THE DTH RESPONSE?

 The AIDS virus illustrates the vitally important role of the DTH response in protecting

against various intracellular pathogens.

 The disease cause severe depletion of CD4+ T cells, which results in a loss of the DTH

response.

 AIDS patients develop life-threatening infections from intracellular pathogens that

normally would not occur in individuals with intact DTH responses.

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Examples of T Cell–Mediated (Type IV) Hypersensitivity

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CONCLUSION

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REFERENCES

1. Robbins & Cotran Pathologic Basis of Disease

2. Hypersensitivity, M.G.Rajanandh

3. Essential pathology for dental students by Harsh Mohan

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