Hypersensitivity

Question 1

What are the types of hypersensitivity reactions (Gel and Coombs classification)

Answer 1

Type 1 Immediate hypersensitivity which is assocaited with mast cells Type 2 Antibody mediated cytotoxicity which is associated with IgG or IgM - against cell surface or ECM Type 3 Immune complex mediated - deposition of immune complexes in vascular basement membrane Type 4 is T cell mediated and associated with autoimmunity

Question 2

More details on Type 1

Answer 2

Type 1 is mediated by mast cells and IgE

1. Rapid Vascular leakage causing inflammation
2. Varying severity: hays fever, food allergies, asthma, drug allergies and anaphylaxis
3. Most frequent disorder of the immune system

Question 3

Mast cells

Answer 3

1. Important against parasitic infections
2. Associated with allergies
3. Has granules that contain histamine, leukotrines and prostagladins
4. Secrete cytokine such as TNF alpha

It is important to know how they look like

Question 4

Explain the immediate hypersensitivity reaction associated with Type 1

Answer 4

1. First exposure to allergen, B cell is induced by a TH2 cell to switch to IgE antibody. This is done by antigen presentation + IL4 +IL13
2. Production of IgE
3. IgE binds to the mast cells. AT THIS POINT, WITH THE FIRST EXPOSURE THERE IS NO CLINICAL MANIFESTATION
4. Second exposure, mast cells activate and release mediators. There are 2 types, vasoactive amines and lipid mediators cause immediate hypersensitivity and cytokines cause delayed reaction

Question 5

What cytokine activates a naive mature T cell (along with TCR and CD40 ligand, CD40L is present on the naive T cell)

Answer 5

IL-4

Question 6

Signaling pathway in mast cells that leads to hypersensitivity reactions

Answer 6

1. ITAMs lead signaling pathways
2. Granules are released
3. Arachidonic acid metabolism leading to lipid mediators
4. Release of cytokines

Question 7

Mechanism of action of signaling in mast cells

Answer 7

Question 8

Arachidonic Acid metabolism pathway

Answer 8

Question 9

What are the mast cell mediator effects

Answer 9

1. Chemotaxis
2. ICAM-1 upregualtion via TNFalpha and IL1
3. Platelet aggregation due to Platelet Activating Factor
4. Anti-coagulation since heparin is released in the granules
5. Complement activation: C3a and C5a causing inflammation and C4a is also released
6. Mast cells make IL3 and IL4
7. Th2 cell activation making IL4, IL5 and IL13

Question 10

Clinical effects of mediators

Answer 10

1. itching due to histamine release
2. Increased vascular permeability and vasodilation
3. Smooth muscle contraction if it is in the gut
4. Gut peristalsis
5. Tryptase in the granules and leukotrienes cause mucus secretion

Question 11

Biological phenomenas that happen immediately in hypersensitivity

Answer 11

Histamine causes

1, Dilation of small blood vessels

2. Increased vascular permeability
3. Transient contraction of smooth muscles

Proteases are released which cause tissue damage

Arachidonic acid metabolites are released (2): Prostaglandins which cause vascular dilation and leukotrienes which cause smooth muscle contraction

Question 12

Describe the late phase reaction in hypersensitivity

Answer 12

1. Mast cells release TNFalpha, IL4 and 5
2. Th2 cells release IL4,5 and 13
3. Leukocyte recruitment involving neutrophils, eosinophils (IL5) and production of proteases causing tissue damage

Question 13

What are the clinical syndrome associated with immediate hypersensitivity

Answer 13

1. Allergic rhinitus causing inflammation and mucus production
2. Food allergies
3. Asthma: bronchial smooth muscle hyperactivity, inflammation and tissue injury

Question 14

Anaphylaxis

Answer 14

1. Life threatening
2. Systemic reaction involving widespread mast cell degranulation
3. Edema, larynx airway obstruction
4. Dramatic fall in blood pressure due to vasodilation

Question 15

Diagnosis of hypersensitivity

Answer 15

1. Diagnosis of atopy involves skin test, looking for the wheel and flare reaction, intradermal test, more sensitivie and Epicutaneous test, skin prick/patch test
2. Food challenge
3. Immunocap which is ELISA

Question 16

Answer 16

C

Question 17

ELISA process

Answer 17

Question 18

How are Anaphylaxis and Asthma clinically treated

Answer 18

Anaphylaxis is treated by giving epinephrine: increases cardiac output and relaxes aiway muscles

Asthma is treated by giving

1. bronchodilators - beta2 adrenergic agonists
2. corticosteroids to reduce inflammation
3. leukotrienes antagonist
4. Histamine receptor antagonist (diphenhydrmaine)

Question 19

What happens in type II hypersensitivity

Answer 19

Antibodies made in an infection cross reacts with self antigens and causes associated hypersensitivity reactions. The cross reactions can be either with cells or ECM. The most famous example is in streptococcus infection antibodies made react with heart and causes rheumatic fever

Question 20

What is the first type of type II hypersensitivity reaction that she introduced in lecture

Answer 20

Disease with tissue injury that can happen in transfusion reactions and Rh incompatibility for a mother with the second baby. This happens by the following pathway

1. Complement activation
2. Fc receptor activation on neutrophils and macrohages
3. Opsonization of cells (such as RBCs or other self cells)

Question 21

Why doesnt this type 1 Type II hypersensitivity happens normally

Answer 21

Because our own cells have inhibitors that doesnt allow the activation of neutrophils or macrophages and also the antibodies are non reactive to self

Question 22

What is type II

Answer 22

In this other type of type II hypersensitivity reaciton, there is disease without tissue injury. Two examples are

1. Myasthenia Gravis: antibodies made against the acetyl choline receptors
2. Graves disease: antibodies againt the thyroid-stimulating hormone receptor that acutally STIMUALTE the receptor. (doesnt damage it!)

Question 23

What is type III hypersensitivity

Answer 23

It is immune complex mediated.

1. Immune complexes (antigen-antibody complex) are deposited in the vessels which attract and activate leukocytes.
2. Usually caused by IgG since it is the most abundant
3. Summarized by arthus reaction: if we immunize an animal for an antigen and then plant those antigens in their afterwards, mast cells will detect the antigen and antibody complex and degranulate causing inflammation and tissue damage. Look at the attached picture for details

Question 24

What is the clinical significance of type III hypersensitivity

Answer 24

Serum Sickness

1. Injection of large amount of foreign antigens
2. This would usually happen to patients after they were given horse serum for anti venin
3. Most common cause is penicillin
4. Occurs 7 to 10 days after serum injection because thats how long it takes the T cells and B cells to become active
5. Clinical manifestations are chills, fever, rash, arthritis and glomerulonephritius

Question 25

What are some of the other clinical manifestations of type III hypersensitivity

Answer 25

1. Post-streptococcal Glomerulonephritis - cross reactivity of the heart antigens with anti-streptococcal antibodies and nephritis 2. Systemic Lupus Erythmatosus - antibodies against DNA, nucleoproteins, also leads to nephritis

Question 26

What common between type II and type III

Answer 26

Both are antibody mediated, in one case we are forming these immune complexes but both are antibody mediated.

Question 27

What are the treatments for type II and type III

Answer 27

1. Corticosteorids 2. Intravenous IgG (IVIG) 3. Anti-CD20 antibodies (Rituximab), causes depletion of B cells, however not plasma cells 4. CD40 L (CD154) antagonist (Ruplizumab) 5. Antibody blockade of cytokines important for B cell and plasma cell survival

Question 28

What is type IV

Answer 28

1. T cell mediated 2. Directed against self-antigens 3. Directec against environmental antigens - poison ivy 4. Directed against microbes - TB test

Question 29

Is there tissue damagein type IV hypersensitivity

Answer 29

Yes. Tissue injury is caused by CD4 cells secrete cytokines: 1. TH1 makes IFN gamma, macrophages 2. Th17 makes IL-17, neutrophils Also CD8 cells can kill our own cells by their cytotoxic function

Question 30

What is another name of type IV hypersensitivity

Answer 30

It is also called delayed type hypersensitivity (DTH) since it takes 24 to 48 hours since antigen exposure for the immune system to respond. Also associated with this hypersensitivity reaction (since the adaptive immune system is involved in this response) is: 1. Edema 2. Fibrin deposition

Question 31

What diseases are associated with type IV

Answer 31

1. TB test 2. Poison Ivy 3. Contact dermatitus 4. All autoimmune diseases that somehow involve CD4 and CD8 cells

Question 32

Treatments for type IV

Answer 32

1. GC 2. Anti TNF 3. Costimulatory blockade (blocking CD28)

Question 33

What are Haptens

Answer 33

Chemicals that are too small to be immunogenic by themselves so they bind with other substances in the host tissue which causes development of an immune response.