Hypersensitivity: Disorders Caused by Immune Responses

Question 1

What are Hypersensitivity Reactions?

Answer 1

Immune responses that cause tissue injury are called HYPERSENSITIVITY REACTIONS. • Diseases caused by these reactions are called HYPERSENSITIVITY DISEASES or IMMUNE-MEDIATED INFLAMMATORY DISEASES. • Hypersensitivity reactions may arise from: » uncontrolled or ABNORMAL RESPONSES to foreign Ags or » AUTOIMMUNE RESPONSES against self Ags. • Hypersensitivity reactions are CLASSIFIED according to the mechanism of tissue injury: » Type I hypersensitivity (immediate) » Type II hypersensitivity » Type III hypersensitivity » Type IV hypersensitivity (delayed)

Question 2

What are the 4 mechanisms of hypersensitivity?

Answer 2

• Type I hypersensitivity is mediated by IgE and results from the actions of mediators secreted by mast cells.
• Type II hypersensitivity is mediated by Abs that bind tissue Ags and cause complement-dependent TISSUE INJURY and disease.
• Type III hypersensitivity is mediated by circulating Ag-Ab complexes which deposit in vessels and cause complement-dependent injury in the vessel wall (VASCULITIS).
• Type IV hypersensitivity is mediated by T cells and results from INFLAMMATION caused by cytokines produced by CD4+ Th1 and Th17 cells, macrophages, or killing of host cells by CD8+ CTLs.

Question 3

Describe Type I Hypersensitivity

Answer 3

• Type I hypersensitivity is an IMMEDIATE type of pathologic reaction that is caused by the release of mediators from mast cells.
• This reaction is most often triggered by ENVIRONMENTAL Ags which activate mast cells in an IgE-dependent manner.
• ATOPY refers to a genetic tendency to develop ALLERGIC DISEASES.
• INDIVIDUALS with a strong propensity to develop allergic reactions are said to be atopic.

Question 4

What is the unique property of IgE?

Answer 4

IgE enters circulation and is rapidly bound by FcR[E] (CD23) on mast cells in the tissues

Question 5

What is the sequence of events in the development of IMMEDIATE HYPERSENSITIVITY REACTIONS?

Answer 5

1. PRIMARY EXPOSURE to allergen causes activation of Th2 cells and production of IgE.
2. BINDING of the IgE to Fcε receptors of mast cells. - Patients is said to be SENSITIZED
3. Upon SECONDARY EXPOSURE, Agdependent cross-linking of the membrane-bound IgE causes ACTIVATION of mast cells that results in RELEASE of inflammatory mediators.

Question 6

What are the mediators of type I Hypersensitivity?

Answer 6

• MAST CELL MEDIATORS are responsible for acute reactions and inflammation, the hallmarks of immediate hypersensitivity.
• IMPORTANT :

– HISTAMINE is the major amine that causes dilation of small vessels and increases vascular permeability.

– PROTEASES may cause local tissue damage.

– PROSTAGLANDINS cause vascular dilation.

– LEUKOTRIENES stimulate prolonged smooth muscle contraction.

– CYTOKINES induce local inflammation (the LATE-PHASE REACTION).

Question 7

Describe the immediate and late phases of type I Hypersensitivity.

Answer 7

The IMMEDIATE vascular and smooth muscle REACTIONS develop within minutes after challenge with allergen.

• Morphology of the immediate reaction is characterized by VASODILATION, CONGESTION, and EDEMA.
• The LATE-PHASE REACTION develops 2 to 24 hours later.
• Late-phase reaction is characterized by an INFLAMMATORY INFILTRATE rich in eosinophils, neutrophils, and T cells.

Question 8

What are local asthma reactions?

Answer 8

Asthma is a reversible AIRWAY OBSTRUCTION often caused by LOCAL RELEASE of inflammatory mediators from mast cells upon encounter with allergen.

• These inflammatory mediators cause increased CAPILLARY PERMEABILITY (prostaglandins) and SPASMODIC CONTRACTION (leukotrienes) of smooth muscle surrounding the bronchi.
• This temporarily decreases the size of the bronchial lumen, resulting in SHORTNESS OF BREATH.
• NON-IMMUNOLOGIC STIMULI such as cold and exercise, also stimulate the same airway inflammation and BRONCHOSPASMS.

Question 9

Describe Systemic Reactions: Anaphylaxis

Answer 9

• Exposure to FOOD ALLERGEN may cause a massive release of VASOACTIVE AMINES and CYTOKINES from mast cells and basophils THROUGH OUT THE BODY resulting in the contraction of SMOOTH MUSCLE in the vasculature and VASODILATION of capillary endothelium.
• BLOOD PRESSURE drops that results in vascular shock.
• The release of mediators increases the contraction of smooth muscles in the bronchi and bronchioles of the respiratory tract, making BREATHING DIFFICULT.

Question 10

Describe Allergen Testing.

Answer 10

These tests assess type I HYPERSENSITIVITIES to various potential allergens.

• Testing is often performed on the ventral side of the ARM (adults) or BACK (children).
• A grid is marked and small quantities of STANDARDIZED ALLERGENS to be tested are injected into the dermis.
• POSITIVE REACTIONS are indicated as redness and swelling within 20 to 30 minutes after exposure to the allergen.

Question 11

Describe Allergen-Specific Immunotherapy.

Answer 11

• Allergen-SIT remains the SINGLE CURATIVE APPROACH to allergic diseases.
• Allergen-SIT is performed by the ADMINISTRATION of increasing doses of ALLERGEN.
• The AIMS of allergen-SIT are: • to induce peripheral T cell tolerance to allergens • to increase the thresholds for mast cell and basophil activation by allergens • to decrease IgE-mediated histamine release by mast cells
• The GENERATION of induced regulatory FOXP3+CD4+CD25+ Treg cells is the key mechanisms in allergen-SIT.

Question 12

What is Type II Hypersensitivity?

Answer 12

• Specific ANTIBODIES may interact in situ with tissue or cell ANTIGENS and cause injury by inducing local inflammation via activation of complement.
• IgG and IgM antibodies activate the complement system by the CP, resulting in the production of C3a and C5a complement byproducts that recruit leukocytes and induce INFLAMMATION.
• Abs OPSONIZE cells that leads to phagocytosis of the cells through FcRγ or CR1 receptors.
• Activated in a Fc RECEPTOR- and CR1-DEPENDENT manner neutrophil and macrophage release their inflammatory mediators: – ROS and LYSOSOMAL ENZYMES damage the adjacent tissues and cause inflammation.

Question 13

What are the 2 Effector Mechanisms (Type II Hypersensitivity)?

Answer 13

Complement-mediated Cytotoxicity and Ab-dependent Cellular Cytotoxity (ADCC)

Question 14

Describe Abnormal Physiological Responses Without Cell/Tissue Injury.

Answer 14

Abs specific for CELL RECEPTORS for hormones or neurotransmitters: • May stimulate the activity of the thyroid-stimulating hormone receptors even in the absence of the hormone causing hyperthyroidism (GRAVES’ DISEASES) • May inhibit binding of acetylcholine neurotransmitter to ACh receptor causing MYASTHENIA GRAVIS.

Question 15

Describe ABO Blood Transfusion Reactions.

Answer 15

ABO antibodies in the serum are formed naturally. Their production is stimulated when the immune system encounters the “missing” ABO blood group antigens in foods or in micro-organisms. This happens at an early age because sugars that are identical to, or very similar to, the ABO blood group antigens are found throughout nature.

Question 16

Describe Hemolytic Disease of Newborn.

Answer 16

During delivery, Rh antigens enter mother’s circulation thru breaks in placenta. Mother then makes anti-Rh antibodies. The anti-Rh antibodies cross the placenta and destroy fetal blood cells

Question 17

Describe Drug-Induced Hemolytic Anemias.

Answer 17

Drug-induced immune hemolytic anemia (DIIHA) is a RARE CONDITION with the incidence of 1-2 cases per million. 1. PENICILLIN-INDUCED anemias: • The drug binds directly to the erythrocyte surface and induces an anti-drug antibody. • These conditions improve when the drug is discontinued. 2. QUINIDINE-INDUCED anemia: • Autoantibodies form immune complexes with the drug. • The immune complexes can bind to the erythrocyte surface through CR1. • Treatment may require immunosuppression and/or plasmapheresis to remove the immune complexes. 3. METHYLDOPA-INDUCED anemias: • This drug induces an antidrug antibody that cross-reacts with an Rh antigen. • Treatment may require immunosuppression and/or plasmapheresis to remove the autoantibodies.

Question 18

Describe Type III Hypersensitivity

Answer 18

Ab-Ag IMMUNE COMPLEXES may be formed in the circulation and then deposited in blood vessels and other tissues, including the kidney and lungs. • These immune complexes induce VASCULAR INFLAMMATION, and subsequent ischemic damage to the tissues. • The MAJOR MECHANISM triggering tissue damage is the CP of complement activation and recruitment of leukocytes.

Question 19

What are some of the diseases that are mediated byb Type II Hypersensitivity?

Answer 19

Autoimmmune hemolytic anemia

Autoimmune (idiopathic) thrombocytopenic purpura

Goodpasture’s syndrome

Grave’s disease (Hyperthyroidism)

Myasthenia gravis

Pemphigus vulgaris

Pernicious anemia

Rheumatic fever

Question 20

What are some Diseases of Type III Hypersensitivity?

Answer 20

The diseases mediated by type III hypersensitivity, IMMUNE COMPLEXES are formed in the BLOOD and then are deposited in the TISSUES that are the sites of injury.

• In all the disorders, INJURY is caused by complement- mediated and Fc receptor– mediated inflammation.

The ARTHUS REACTION is induced by subcutaneous administration of a protein Ag to a previously immunized animal. It results in the formation of immune complexes at the site of Ag injection, and a local vasculitis (compare to the systemic vasculitis in serum sickness).

Diseases- Systemic lupus erthematosus, Polyarteritis nodosa, Post-streptococcal glomerulonephritis, Serum sickness (clinical and experimental, systemic), Arthus reaction (experimental, local)

Question 21

What is Type IV Hypersensitivity?

Answer 21

The MAJOR TRIGGERS of type IV hypersensitivity reactions are autoimmunity, exaggerated or persistent responses to environmental Ags and some microbial Ags (M. tuberculosis).

• TISSUE INJURY is caused by inflammation induced by cytokines that are produced mainly by CD4+ T cells (Th1 and Th17 cells), macrophages, and/or by killing of host cells by CD8 + CTLs.
• The classical T cell–mediated inflammatory reaction which is also called DELAYED-TYPE HYPERSENSITIVITY (DTH).
• In type IV hypersensitivity INFLAMMATION, Th1 and Th17 cells secrete cytokines which recruit and activate macrophages and neutrophils.
• TISSUE INJURY results from the products of the recruited and activated neutrophils and macrophages, such as lysosomal enzymes, reactive oxygen species, nitric oxide, and proinflammatory cytokines.
• Many organ-specific AUTOIMMUNE DISEASES are caused by interaction of autoreactive T cells with self Ags, leading to cytokine release and inflammation.
• T cell reactions specific for MICROBES (M. tuberculosis) and other foreign Ags may cause type IV hypersensitivity reactions which lead to inflammation and tissue injury.

Question 22

What are some Diseases of Type IV Hypersensitivity?

Answer 22

• AUTOIMMUNE DISEASES mediated by type IV hypersensitivity: – multiple sclerosis – rheumatoid arthritis – type 1 diabetes.
• INFLAMMATORY DISEASE with microbial component: – Crohn′s disease (Inflammatory Bowl Disease, IBD) is likely caused by the aberrant reactions to intestine microflora which have an autoimmunity component – The other diseases like tuberculosis are caused by reactions microbial Ags

ALSO, contact sensitivity (e.g. poison ivy) and chronic infections (e.g. tuberculosis)

Question 23

What is Delayed-Type Hypersensitivity?

Answer 23

Delayed-type hypersensitivity (DTH) is an injurious cytokine-mediated inflammatory reaction resulting from activation of T cells, particularly CD4+ T cells .

• The reactions are called delayed because it typically develops 24 to 48 hours after the Ag exposure.
• Humans may be sensitized for DTH reactions by microbial antigens (TB) or by contact sensitization with Poison Ivy, metals, or some chemicals.
• Purified protein derivative (PPD), a protein antigen of Mycobacterium tuberculosis, elicits a DTH reaction, called the TUBERCULIN REACTION.

Question 24

Describe Contact Dermatitis with Poison Ivy

Answer 24

Question 25

What is Allergic Contact Dermatitis (ACD)?

Answer 25

• ACD is caused by ENVIRONMENTAL EXPOSURE to external agents that in contact with the skin trigger an inflammatory reaction.
• ACD results from a DTH reactions (type IV hypersensitivity).
• METALS are the most common contact allergens: – Sensitization to metals can occur at any age, even in neonates. – Costumer jewelry, particularly earrings, is linked to increased sensitization to NICKEL and COBALT. – The most common source of sensitization to CHROMIUM is leather.