Differentiate between the mechanisms of the four hypersensitivity reactions.

1. Mechanism of Type I hypersensitivity

2. Understand the principle of chronic desensitization

3. Examples of Type I

4. Know the role of ADCC in Type II hypersensitivity

5. Foreign antigen versus self‐antigen in Type II hypersensitivity

6. Drug‐induced hypersensitivity

7. Examples of Type II

8. Mechanism of Type III

9. Foreign antigen verses self antigen in Type III hypersensitivity

10. Examples of Type III

11. Mechanism of Type IV

12. Foreign antigen verses self antigen in Type IV hypersensitivity

13. Examples of Type IV

Learning objectives:

BIG QUESTION:

What happens when immune system overreacts?

Although immune responses may cause some damage

to the body during antigen removal (such as swelling

and pain), the damage is usually mild.

However, when the damage is too great,

the injury can become very serious, even life-

threatening.

This undesirable reaction done to the body by an

immune response is called a hypersensitivity

reaction.

Hypersensitivities are classified into four types based

on the mechanism of tissue damage.

Hypersensitivities

Type I Hypersensitivity

Most of what we call "allergy" is Type I hypersensitivity, in which

mast cells are activated by IgE produced in response to an allergen

ONE IN 5 PEOPLE HAVE ATOPY - a predisposition towards Type

I hypersensitivity

The risk of developing a Type I hypersensitivity is linked to family

history and IgE levels.

People with higher IgE levels tend to be atopic more often than

people with lower IgE levels, although the linkage is not absolute.

Allergens for Type I fall into groups of molecules, such as grasses,

pollens, animal, and foods that usually reach mucosal surfaces at

very low doses.

They are protein, since only protein molecules can be presented

to T cells and elicit T cell help.

Mast cells are common at sites in the

body exposed to the external

environment, such as the skin.

• Found in close proximity to

blood vessels, where they can

regulate vascular permeability

and effector-cell recruitment.

• No direct cell–cell contact with

local populations of APCs,

such as the Langerhans cells

in the skin.

• Modulate the behavior of

neighboring effector cells

through the release of

mediators.

Mast cells

Mast cells

Type I examples

Asthma- thick mucous

plug, inflammatory cells,

hypertrophy of smooth

muscle, thickened basal

membrane, increased

number of eosonophils

TYPE I mechanism:

Has two distinct phases:

1.Sensitization phase (the synthesis of IgE

upon initial exposure to Ag)

2. Activation phase (the stimulation of mast

cells upon re-exposure)

.

Sensitization phase

mucosal membranes

Low Ag dose

Low M.W, soluble

Activation phase

Mast cell

ACTIVATION PHASE: detailed

Initial/Early response – can occur immediately

1. Preformed molecules stored in cytoplasmic granules of mast cell are

rapidly released

• Histamine - causes smooth muscle contraction, mucus release,

vasodilatation, sensory nerve stimulation and increased capillary

permeability

• Proteolytic enzymes - break down tissue matrix proteins

2. Rresult: Increased blood flow and fluid released at the mucus membranes

and at the tissues washes away antigen

Late-phase response – usually occurs hours after initial binding

• Further tissue damage

• The chemokines released in early phase attract more leukocytes, such as eosinophils

to the inflammation.

• Cytokines from early and late phase stimulate white blood cell production in the marrow,

Skin test

Chronic desensitization – allergy immunotherapy

Injected administration of allergen beginning with very low doses that are

increased over many months.

Current hypotheses is that the immune response is switched from IgE

to IgG, which binds allergen before it can trigger mast cells

Desensitization is not effective for every allergen or for every individual, and

its mechanism of action is unresolved.

Type II Hypersensitivity Disease

• Antibody binds to a cell-surface antigen.

• The ensuing reaction causes damage by:

1. Activation of complementClassical complement activation by IgG releases

inflammation-promoting anaphylatoxins and leads to

formation of membrane attack complex (MAC) and lysis

of the antibody-coated cell.

2. Antibody-dependent cell-mediated cytotoxicity

(ADCC)

The binding of Ab-cell complex to FcgRI on cells such as NK

cells and macrophages.

Both processes can result in lysis of the target cell.

.

Activate complement and ADCC

If a cell is part of an organ, the result is inflammation

Clinical examples of Type II hypersensitivities:

Foreign antigen induced

Blood transfusion reaction

Drug induced reaction

(Hyperacute graft rejection)

Autoantigen induced

Myasthenia gravis

Graves disease

Hemolytic anemia

1. Blood transfusion can also result in Type II

Hypersensitivity to blood group antigens such as A, B

and Rh.

Foreign antigen-induced:

Foreign antigen-induced:

2. Drugs like aspirin and penicillin, which often complex with

erythrocyte membrane proteins, may induce synthesis of IgG antibodies

which then bind drug-coated erythrocytes and damage them.

Autoantigens induced: antibodies are produced to

membrane proteins

1. Myasthenia gravis

2. Graves' disease

3. Autoimmune hemolytic anemia

ACh Ab

Autoantigens induced

1. Myasthenia gravis – Ab against the acetylcholine receptor

• Myasthenia gravis is a neuromuscular

disorder.

• It effects skeletal muscles and is caused

by antibody binding to the ACh receptor

on skeletal muscle.

• The symptoms include:

• Weakness in muscles that control

eye movement

• Weakness in arms and legs,

• Difficulty swallowing

2. Graves' disease - thyroid hormone receptor Ab

Hyperthyroidism is the most common feature of Graves' disease, affecting nearly all patients

• Caused by agonistic autoantibodies to the TSH receptor

• Ab activates the TSH receptor, thereby stimulating thyroid hormones T3 and T4

synthesis and secretion

• Ab also stimulates thyroid growth (causing a diffuse goiter)

• People with Graves disease often have swelling around the eyes, redness, and bulging

eyes. This is due to an infiltration of the orbital connective tissue because it also contains

TSH receptor.

3. Autoimmune hemolytic anemia –

Ab against erythrocyte membrane protein

Type III hypersensitivity

Type III is caused by Immune complex deposition in the tissues, where the

complement cascade results in tissue damage.

When antigen persists in the body for long period or if high levels of antigen are

encountered at one time, immune complexes reach high levels and cause damage.

Common sites of deposition and tissue damage are blood vessel walls, kidney, and

joints.

Clinical examples of Type III hypersensitivities:

Foreign antigen induced

Arthus reaction

Serum sickness

Autoantigen induced

Lupus

Rheumatoid arthritis

1. Arthus reaction

Foreign antigen – local:

1. Serum sickness: A response to passive

immunization with foreign antiserum

Example: A person is bitten by Malayan pit viper

Anti–snake venom (ASV) immunoglobulins

are administered as therapy

• The person will develop a primary response to

the horse anti-venom IgG.

• After 7-10 days, enough anti-horse IgG antibody

has been produced to form immune complexes

that deposit in small vessels and activate

complement and macrophages.

• On second exposure to ASV, the patient would

begin experiencing serum sickness within hours

or days since isotype switching to IgG had

already occurred.

• Symptoms of serum sickness include fever,

chills, rash, arthritis, and sometimes kidney

damage.

Foreign antigen: systemic

1. Rheumatoid arthritis

Patients develop an auto-IgM antibody against their own IgG that

is thought to contribute to arthritic joint inflammation.

Autoimmune diseases:

2. Systemic Lupus Erythematosis autoantibodies are produced against the

patient’s own DNA and histones.

Autoimmune diseases:

Events

required

to trigger

lupus

Type III flow chart

Infection

Environment

Auto-Ag

Ag

Ab Immune complex

Clearance by

complement

Immune

complex disease

localized systemic

SLE

Serum sickness

Glomerulonephritis

Rheumatoid arthritis

Arthus rxn

Delayed-type hypersensitivity (DTH)

Occurs 48-72 hours after antigen contact

Mediated by antigen-specific Th1 cells and activated

macrophages or by CD8 T cells

Initial response is called sensitization and may not result

in symptoms but generated memory Th1 and CD8 cells

Second contact with antigen results in activation of

memory T cells which often causes the development of

the characteristic itchy rash.

Type IV hypersensitivity

Clinical examples of Type IV hypersensitivities:

Foreign antigen induced

Poison Ivy, nickel (and other

contact dermatitis)

PPD test

Acute and Chronic Graft vs Host

Autoantigen induced

Diabetes Type I

Multiple Sclerosis

Celiac disease

1. Poison ivy reaction.

Foreign antigen induced

2. Mycobacterial proteins used in TB skin testing (PPD test)

Sensitization during prior exposure to Mycobacterium tuberculosis

results in production of memory Th1 cells to Mycobacterial proteins.

When purified tuberculin is injected into intradermally into the skin,

memory Th1 cells secrete cytokines to attract macrophages and

granulocytes and visa versa and cause induration and erythema.

Foreign antigen induced

3. Acute and Chronic Allograft rejection

(NOT hyperacute)

Foreign antigen induced

Autoimmune reactions:

• Type I diabetes

• Multiple sclerosis

• Celiac disease

1. Type I diabetes

In type 1,

pancreatic beta

cells in the islets

of Langerhans

are destroyed,

decreasing

endogenous

insulin

production.

Autoimmune reactions

2. Multiple sclerosis

Demyelination of nerves in CNS, including the optic nerves

which control vision, so vision is affected, but the closure of

eyelid is fine.

Autoimmune reactions

3. Celiac diseaseAutoimmune reactions

Hapten

Binds cell

Type II

Binds soluble protein

Stimulate IgG

Type III

Stimulate IgE

Type I

Binds cytoplasmic

protein

Activates T cells

(Type IV)