Hypersensitivity

Question 1

• hypersensitivity mediated by IgE and results from actions of mediators secreted by mast cells
• immediate
• most often trigger is environmental antigens
• atopy: genetic tendency to develop allergic dz

Answer 1

type 1 hypersensitivity

Question 2

• hypersensitivity mediated by antibodies that bind tissue antigens and cause complement-dependent tissue injury and disease
• IgG and IgM antibodies activate complement system by CP, results in prod of C3a and C5a comp byproducts that recruit leukocytes and induce inflammation
• antibodies opsonize cells that leads to phagocytosis of cells through FcRγ or CR1 receptors
• activated in Fc receptor or CR1 dependent manner: neutrophils and macrophages release inflammatory mediators (ROS and lysosomal enzymes that damage adjacent tissues and cause inflammation)

Answer 2

type II hypersensitivity

Question 3

• hypersensitivity mediated by circulating antigen-antibody complexes which deposit in vessels and cause complement-dependent injury in the vessel wall (vasculitis)
• IC’s induce vascular inflammation and subsequent ischemic damage to tissues
• major mechanism triggering damage is CP of complement activation and recruitment of leukocytes

Answer 3

type III hypersensitivity

Question 4

• hypersensitivity mediated by T cells and results from inflammation caused by cytokines produced by Th1 and Th17 cells, macrophages, or killing of host cells by CTLs
• major triggers are autoimmunity, exaggerated or persistent responses to environmental antigens and some microbial antigens (M. tuberculosis)
• tissue injury results from products of recruited neutrophils and macros: lysosomal enzymes, ROS, nitric oxide, and proinflammatory cytokines
• also called delayed-type hypersensitivity (DTH)

Answer 4

type IV hypersensitivity

Question 5

type I hypersensitivity

• pathologic immune mechanisms:
• mechanisms of tissue injury/dz:

Answer 5

• Th2 cells (IL4-), IgE antibodies, mast cells, eosinophils
• mast cell-derived mediators (vasoactive amines, lipid mediators, cytokines); cytokine-mediated inflammation (eosinophils, neutrophils)

Question 6

What is the unique property of IgE?

Answer 6

IgE enters circulation and is rapidly bound by FcRε (CD23) on mast cells in tissues

Question 7

What are the effects of subsequent allergen encounters in terms of mast cell function?

Answer 7

• cross-linking causes mast cell degranulation that releases: vasoactive amines, cytokines/chemokines, lipids
• physiological results: vascular smooth muscle contraction (SM appears on the tunica media of larger venules that drain the post-capillary venules), endothelial vasodilation, leukocyte chemotaxis and activation

Question 8

What are the general steps of type I hypersensitivity? (3)

Answer 8

1. primary exposure to allergen causes activation of Th2 cells and production of IgE
2. binding of IgE to FcεR of mast cells (patient is sensitized)
3. secondary exposure: antigen dependent cross-linking of membrane bound IgE causes activation of mast cells that results in release of inflammatory mediators

Question 9

What are the inflammatory mediators in type I hypersensitivity and their effects?

Answer 9

• vasoactive amines, lipid mediators: immediate hypersensitivity reaction (minutes after repeat exposure)
• cytokines: late phase reaction (6-24 hours after repeat exposure)

Question 10

What are the important mediator molecules of type I hypersensitivity? (5)

Answer 10

• histamines (vasoactive amines): come from the granule of mast cells; causes dilation of small vessels and increases vascular permeability
• proteases: come from the granule of mast cells; causes local tissue damage
• prostaglandins (lipid mediators): come from enzymatic mod of arachidonic acid; cause vascular dilation
• leukotrienes (lipid mediators): come from enzymatic mod of arachidonic acid; stimulate prolonged smooth muscle contraction
• cytokines (e.g. TNF): come from transcriptional activation of cyto genes; induce local inflammation (late phase reaction) by recruiting leukocytes

Question 11

Describe the immediate and late phase reactions in terms of timing and morphology

Answer 11

• immediate: develops within minutes after antigenic exposure; vascular and smooth muscle reactions causes vasodilation, congestion, and edema
• late phase: develops within 2-24 hours after antigenic exposure; causes inflammation rich in eosinophils, neutrophils, and T cells

Question 12

Describe asthma in terms of type I hypersensitivities

Answer 12

• asthma: reversible airway obstruction, often caused by local release of inflammatory mediators from mast cells
• inflammatory mediators: increased capillary perm (prostaglandins) and spasmodic contraction (leukotrienes) of smooth muscle surrounding bronchi
• causes decrease in size of bronchial lumen = shortness of breath
• non-immunologic stimuli (cold, exercise): stimulate same airway inflammation and bronchospasms

Question 13

Describe anaphylaxis in terms of type I hypersensitivity

Answer 13

• exposure to allergen (food) causes massive release of vasoactive amines and cytokines from mast cells/basophils throughout the body
• causes smooth muscle contraction in vasculature and vasodilation of capillary endothelium
• blood pressure drops = vascular shock
• mediators also increase smooth muscle contraction in bronchi and bronchioles, causing difficulty breathing

Question 14

What are allergen tests used for, how are they performed, and what are their results indicative of?

Answer 14

• tests assess type I hypersensitivities to various allergens
• often performed on ventral side of arm (adults) and backs (children)
• grid is marked, small quantities of standardized allergens are injected into dermis
• positive reactions are indicated as redness and swelling within 20-30 min after exposure

Question 15

• single curative approach to allergic diseases
• performed by administration of increasing doses of allergen
• aims: increase peripheral T cell tolerance, increase threshold for mast cell/basophil activation, decrease IgE mediated histamine release
• generation of induced regulatory FOXp3, CD4, CD25, and Treg cells is the mechanism of tx

Answer 15

allergen-specific immunotherapy (allergen-SIT)

Question 16

What are the 3 aims of allergen-SIT?

Answer 16

1. induce peripheral T cell tolerance to allergens
2. increase the threshold for mast cell/basophil activation by allergens
3. decrease IgE-mediated histamine release by mast cells

Question 17

type II hypersensitivity

• pathologic immune mechanisms:
• mechanisms of tissue injury/dz:

Answer 17

• IgM, IgG antibodies against cell surface or extraceullar matrix antigens
• complement and Fc receptor mediated recruitment and activation of leukocutes (neutrophils, macrophages); opsonization and phagocytosis of cells; abnormalities in cellular function (e.g. hormone receptor signaling)

Question 18

What is the mechanism of Graves’ disease in terms of type II hypersensitivity?

Answer 18

antibody against TSH receptor stimulates the activity of the thyroid-stimulating hormone receptors even in the absence of the hormone, causes increase in prod of thyroid hormones and hyperthyroidism

Question 19

What is the mechanism of myasthenia gravis in terms of type II hypersensitivity?

Answer 19

antibody inhibits binding of acetylcholine neurotransmitter to acetylcholine receptor

Question 20

What is the process of hemolytic disease in newborns and how does it occur?

Answer 20

• during first pregnancy, mother who is Rh- with Rh+ fetus will develop anti-Rh antibodies
• during subsequent pregnancies, mother who is Rh- with Rh+ fetus will have her anti-Rh antibodies cross the placenta and destroy fetal blood cells
• HDN can be prevented by immunotherapy with anti-(anti-Rh) at around 28 wk of pregnancy

Question 21

What are the 3 types of drug-induced hemolytic anemias and how do they work?

Answer 21

1. hapten model (penicillin): drug binds directly to RBC and acts as antigen, IgG’s form against drug = hemolysis by complement or phagocytosis

(conditions improve once drug is d/c’d)

2. immune complex formation (quinidine): drug binds antibody against drug, carrier protein, and C3b (immune complex), the C3b binds to C3bR (CR1) on RBC = hemolysis by complement
   (tx: immunosuppression and/or plasmapheresis to remove immune complexes)
3. autoimmune model (methyldopa): drug induces antidrug antibody that cross-reacts with Rh antigen on RBC’s = hemolysis by phagocytosis
   (tx: immunosuppression and/or plasmapheresis to remove autoantibodies)

Question 22

type III hypersensitivity

• pathologic immune mechanisms:
• mechanisms of tissue injury/dz:

Answer 22

• immune complexes of circulating antigens and IgM and IgG antibodies deposited in vascular basement membrane
• complement and Fc mediated recruitment and activation of leukocytes

Question 23

What is the difference between serum sickness and arthus reaction in type III hypersensitivities?

Answer 23

• serum sickness is a systemic reaction that causes systemic vasculitis, nephritis, and arthritis
• arthus reaction is experimental, it is induced by subcutaneous admin of protein antigen to a previously immunized animal, results in form of IC’s at site of antigen injection and local vasculitis

Question 24

type IV hypersensitivity

• pathologic immune mechanisms:
• mechanisms of tissue injury/dz:

Answer 24

• 1. CD4+ T cells (cytokine mediated inflammation), 2. CD8+ CTL’s (T cell mediated cytolysis)
• 1. macrophage activation, cytokine mediated inflammation, 2. direct target cell lysis, cytokine mediated inflammation

Question 26

What are the autoimmune diseases mediated by type IV hypersensitivity?

Answer 26

- multiple sclerosis - rheumatoid arthritis - type 1 diabetes

Question 27

What are the inflammatory diseases with microbial component mediated by type IV hypersensitivity?

Answer 27

- Crohn's disease (IBD): likely caused by aberrant rxn to intestine microflora which have an autoimmunity component - tuberculosis: caused by reactions to microbial antigens

Question 28

- an injurious cytokine mediated inflammatory reaction resulting from activation of T cells, particularly CD4+ T cells - rxn are delayed because it typically develops 24-48 hours after antigen exposure - humans may be sensitized to these rxns by microbial antigens (e.g. TB) or by contact sensitization (e.g. poison ivy, metals, chemicals) - purified protein derivative (PPD) is a protein antigen of M. tuberculosis that elicits this type of rxn, called the tuberculin rxn

Answer 28

delayed-type hypersensitivity

Question 29

How does contact dermatitis (type IV) with poison ivy occur?

Answer 29

- first exposure: pentadecacatechol (PI) combines with skin proteins, T cells sensitized within 7-10 days (no dermatitis) - second exposure: T memory cells elicit immune response within 1-2 days, active T cells = dermatitis

Question 30

- type IV hypersensitivity - caused by environmental exposure to external agents in contact with skin trigger inflammatory rxn - results from DTH rxns - metals are most common contact allergens - can occur at any age - costumer jewelry, earrings, are linked to increased sensitization to nickel and cobalt - most common source of sensitization to chromium is leather

Answer 30

allergic contact dermatitis (ACD)