03/09i Complement, Hypersensitivity I & II

Question 1

What are the three pathways of complement activation?

Answer 1

Classical
Lectin
Alternative/Spontaneous

Question 2

At what point does the complement system get amplified?

Answer 2

C3

Question 3

What are the functions of complement?

Answer 3

1) Opsonization and phagocytosis
2) Formation of the Membrane Attack Complex
3) Release of soluble inflammatory mediators C3a and C5a - chemoattractants, activate macrophages

Question 4

What distinguishes the lectin complement pathway from the classical pathway?

Answer 4

Instead of using antibodies, it used mannose-binding lectins or ficolins to bind carbohydrates on pathogen surfaces

Question 5

Why is the alternative pathway also considered the ‘spontaneous’ pathway?

Answer 5

C3 convertase can be activated spontaneously on cell surfaces
Does not require C1 or MBP

Question 6

If complement can be activated spontaneously, why don’t we do it all the time?

Answer 6

Endogenous complement inhibitors - Decay Accelerating Factor (DAF), Membrane Cofactor Protein (MCP), and C1 Inhibitor

Question 7

What are the anaphylatoxins?

Answer 7

C3a, C5a, and C4a - mediators of inflammation
Initiate inflammatory processes
Increase vascular permeability and smooth muscle contraction, histamine release from mast cells, chemotaxis, and cell activation

Question 8

What are the functions of C5a?

Answer 8

Mediator of inflammation

Activation of phagocytosis by macrophages

Question 9

What is the most common regulator of complement?

Answer 9

C1 inhibitor

Question 10

Why doesn’t the Membrane Attack Complex work on our cells?

Answer 10

We have CD59, which inhibits its formation

Question 11

What happens if you lack certain components of complement? List three complement deficiencies and their associated diseases

Answer 11

C1 Inhibitor deficiency - hereditary angioedema
C3 deficiency - recurrent infections, SLE
C2 and C4 deficiency - immune complex diseases

Question 12

What are the two phases of a hypersensitivity reaction?

Answer 12

Sensitization phase

Elicitation phase

Question 13

What are the four types of hypersensitivity reactions? By what antibodies or cells are they mediated?

Answer 13

Type 1 - immediate (IgE/mast cell)
Type 2 - antibody (IgG or IgM)
Type 3 - immune complex
Type 4 - T cell

Question 14

What are the hallmarks of a Type 1 hypersensitivity reaction?

Answer 14

Activation of Th2 cells and production of IgE - inappropriate anti-helminthic-like response
IgE binds to mast cells
Re-exposure to the antigen results in release of mediators from mast cells, and subsequent effects

Question 15

What are the mediators of Type 1 hypersensitivity? What are their effects?

Answer 15

Histamines - vasodilation, vascular permeability
Lipid mediators - bronchoconstriction, intestinal hypermotility, inflammation
Cytokines (TNF) - inflammation
Enzymes - tissue damage

Question 16

What are some possibly causes of Type 1 hypersensitivity reactions?

Answer 16

Genetic propensity
Nature of the antigen
Hygiene hypothesis - lack of exposure to bugs!

Question 17

What are the clinical manifestations of immediate hypersensitivity?

Answer 17

Rashes
Sinus congestion
Bronchial constriction
Abdominal pain, diarrhea
Systemic shock
Anaphylaxis

Question 18

What does the degree of immediate hypersensitivity reaction that develops depend upon?

Answer 18

Route of allergen exposure
Dose of allergen exposure
Frequency of allergen exposure

Question 19

What are the characteristics of the immediate phase of Type 1 hypersensitivity?

Answer 19

Mast cell degranulation
Vascular response
Edema

Question 20

What causes the immediate reaction of type 1 hypersensitivity?

Answer 20

Dependent on cross-linking of IgE and granule contents of mast cells

Question 21

What is the Wheal and Flare Reaction?

Answer 21

Immediate phase of a Type 1 hypersensitivity reaction
Caused by injection of an allergen under the skin
Wheal = bump of inflammation, flare = vasodilation

Question 22

What are the characteristics of the late phase of a type 1 hypersensitivity reaction?

Answer 22

Develops in 2-4 hours
Symptoms are due to the accumulation of inflammatory cells - neutrophils, eosinophils, basophils, and Th2 cells
May occur without a detectable immediate hypersensitivity reaction

Question 23

What are some common examples of allergic diseases in humans? List five

Answer 23

Systemic anaphylaxis
Bronchial asthma
Allergic rhinitis
Food allergies
Urticaria and atopic dermatitis

Question 24

What is anaphylaxis?

Answer 24

A systemic hypersensitivity reaction
Characterized by systemic edema, drop in blood pressure, vasodilation and increased permeability
Clinical symptoms - constriction of airways, laryngeal edema, hypermotility of the gut, outpouring of mucous, and hives

Question 25

How is anaphylaxis treated?

Answer 25

Systemic epinephrine - reverses bronchoconstriction, improves cardiac output Antihistamines Steroids - prevent a late-phase reaction

Question 26

What is bronchial asthma?

Answer 26

Intermittent and reversible airway obstruction caused by repeated immediate-phase hypersensitivity and late-phase allergic reactions in the lung

Question 27

What are the characteristics of bronchial asthma?

Answer 27

Chronic bronchial inflammation Bronchial smooth muscle cell hypertrophy and hyperreactivity Increased production of thick mucous

Question 28

What happens in the early phase of asthma?

Answer 28

Vasodilation Bronchoconstriction Mucous secretion

Question 29

What happens in the late phase of asthma?

Answer 29

Inflammation and leukocyte activation Tissue damage Fibrosis and repair

Question 30

How do you treat asthma?

Answer 30

Prevent mast cell degranulation Bronchial relaxers Leukotriene inhibitors Corticosteroids to inhibit inflammatory reaction

Question 31

What is urticaria?

Answer 31

An all-over acute wheal and flare reaction that occurs in response to direct contact with an allergen or when an allergen enters circulation

Question 32

What is atopic dermatitis?

Answer 32

A late-phase reaction to an allergen in the skin mediated by Th2 cytokines (TNF, IL-4), which promote inflammation Not inhibited by antihistamines Can be blocked by corticosteroids

Question 33

How are type I hypersensitivity reactions generally treated?

Answer 33

Avoidance Pharmacologic agents - antihistamines, epinephrine, corticosteroids Immunologic therapy - desensitization (allergy shots)

Question 34

What causes type 2 hypersensitivity reactions?

Answer 34

Antibodies (IgG or IgM) that bind to antigens on particular cells or in particular tissues Frequently involves self antibodies, due to a loss or lack of self-tolerance Can be due to cross-reactive antigens

Question 35

What are the two types of Type 2 hypersensitivity reactions? What mechanisms/cells are involved in each?

Answer 35

Non-cytolytic - involves antibody neutralization | Cytolytic - involves complement, macrophages, and NK cells

Question 36

How do antibodies against tissue antigen cause disease? List three ways

Answer 36

1) Antibodies bind to normal cellular receptors or other proteins, and interfere with their function (without causing inflammation or tissue damage) 2) Antibodies directly opsonize cells or activate complement, leading to phagocytosis 3) Antibodies recruit neutrophils and macrophages, which cause tissue injury

Question 37

What are four examples of non-cytolytic type 2 hypersensitivity reactions?

Answer 37

Myasthenia gravis Graves' disease Insulin-resistant diabetes Pernicious anemia

Question 38

What is myasthenia gravis?

Answer 38

Caused by autoantibodies against nicotinic acetylcholine receptors, which blocks muscle contraction Hallmark - progressive weakness and fatigue Treatment - acetylcholinesterase inhibitors, immunosuppression

Question 39

What is Graves' disease?

Answer 39

Caused by agonistic antibodies which activate the thyroid-stimulating hormone receptor Hallmark - hyperthyroidism, goiter, ophthalmopathy, and pretibial myxedema Treatment - thyroid ablation

Question 40

What is insulin resistant diabetes?

Answer 40

Caused by anti-insulin receptor autoantibodies, which inhibit insulin binding and cause severe insulin resistance Hallmark - diabetes and acanthosis nigricans (skin lesion)

Question 41

What is pernicious anemia?

Answer 41

Caused by autoantibodies against intrinsic factor, which is necessary for the absorption of vitamin B12 Hallmark - anemia that is unresponsive to B12 supplementation, often associated with chronic atrophic gastritis and autoimmune thyroid disease Treatment - vitamin B12 shots

Question 42

What are five examples of cytolytic type 2 hypersensitivities?

Answer 42

``` Autoimmune hemolytic anemia Autoimmune thrombocytopenia purpura Pemphigus vulgaris Goodpasture's syndrome Acute rheumatic fever ```

Question 43

What is autoimmune hemolytic anemia?

Answer 43

Caused by a variety antibodies against antigens on RBCs Response depends on the type of antibody - IgG leads to phagocytosis in the spleen, IgM leads to complement activation and RBC lysis Can be caused by infections, drugs, and autoimmune diseases

Question 44

What are the hallmarks of autoimmune hemolytic anemia?

Answer 44

``` Anemia Spherocytosis Reticulocytosis Elevated serum bilirubin and lactic dehydrogenase Increased urine hemoglobin ```

Question 45

What causes acute transfusion reactions?

Answer 45

Antibody-mediated hemolysis (IgG and IgM)

Question 46

What is Rh disease?

Answer 46

If an Rh- mother gives birth to an Rh+ fetus, the mother's B cells become sensitizes to Rh antigen at the time of birth During subsequent Rh+ pregnancies, the mother's IgG will cross the placenta and attack the fetus Treated with Rhogam