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Cellular and Molecular pathology > 22. Hypersensitivity Reactions: Type 1 and 2 > Flashcards

22. Hypersensitivity Reactions: Type 1 and 2 Flashcards

1. Understand the fundamental differences in immunological mechanisms underlying type 1 and 2 hypersensitivity reactions 2. Explain how certain antigens elicit IgE leading to type 1 reactions, detailing the chemical mediators and cells involved 3. Describe how IgG and IgM antibodies interact with other components of the immune system to cause type 2 reactions 4. Provide examples of clinical manifestations of hypersensitivity

1
Q

What does adaptive immunity provide?

A

Antigen specific protection against infection

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2
Q

What causes the immunopathology of hypersensitivity reactions?

A

adaptive immune response to harmless antigens

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3
Q

What is an autoimmune disease?

A

An excessive immune response to a self-antigen

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4
Q

What is a hypersensitivity reaction?

A

An excessive immune response to a foreign antigen.

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5
Q

How are hypersensitivity reaction classified?

A

Immune response to harmless environmental antigens that are divided into 4 types based on effector mechanisms.
The original classification has been modified and expanded as immunology has developed.

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6
Q

What are the 4 types of hypersensitivity reaction?

A
  1. Type 1 - immediate hypersensitivity
  2. Type 2 - Cytotoxic
  3. Type 3 - Immune complex
  4. Type 4 - delayed-type hypersensitivity
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7
Q

What hypersensitivity reactions are antibody mediated?

A

Type 1 - immediate hypersensitivity
Type 2 - Cytotoxic
Type 3 - Immune complex

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8
Q

What hypersensitivity reactions are T-cell mediated?

A

Type 4 - Delayed-type hypersensitivity

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9
Q

What causes type 1 hypersensitivity reactions?

A

Allergens

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10
Q

What are allergens?

A
  1. An antigen which elicits an immediate allergic reaction.
  2. Allergens can be derived from grass pollen, dust mites, food, and bee venom.
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11
Q

When do allergic reactions occur?

A
  1. When sensitisation to an allergen occurs and allergen-specific IgE develops.
  2. Type 1 hypersensitivity reactions occur upon re-exposure to these allergens.
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12
Q

What are the properties of an allergen?

A
  1. Highly soluble proteins
  2. have diverse biological functions though most are enzymes
  3. They must be small enough to be carried by airborne particles
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13
Q

What are examples of allergens?

A
  1. Der p1 from House dust mite faeces
  2. Lol p1 from grass pollen
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14
Q

What happens with most allergens?

A

Most people inhale 5-50ng of allergen a day without adverse effects.

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15
Q

What mediates type 1 hypersensitivity?

A

IgE

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16
Q

What receptors does IgE bind?

A
  1. FcεR1 = A high affinity receptor on mast cells and basophils.
  2. FcεR2 = A low affinity receptor on eosinophils and B cells
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17
Q

What is unusual about IgE FcεR1 binding?

A

IgE binds to FcεR2 in the absence of a bound antigen

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18
Q

Why is IgE an unusual antibody isotype?

A
  1. Serum concentrations are very low.
  2. It is produced in small quantities against a select group of antigens.
  3. It has a very short serum half-life.
  4. IgE is mostly found bound to the high affinity FcεR1 on mast cells and basophils.
  5. FcεR1 receptors are usually saturated with IgE despite low serum concentrations and this can prolong the half life.
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19
Q

What molecular mechanism causes type 1 hypersensitivity reactions?

A
  1. Mast cells with bound IgE reside in the tissue and orchestrate the response.
  2. An antigen comes along and binds the IgE crosslinking them.
  3. This triggers degranulation of mast cells.
  4. Preformed granules are rapidly released. These include histamine.
  5. Newly-synthesised inflammatory mediators are released more slowly.
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20
Q

What does histamine do?

A

It is a toxic mediator that causes vasodilation.

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21
Q

What does mast cell activation cause?

A

an inflammatory cascade that is amplified by the recruitment of other leukocytes.

22
Q

What molecules are released by activated mast cells?

A
  1. Enzymes
  2. toxic mediators like histamine that cause vasodilation
  3. type 2 cytokines to promote a Th2 response.
  4. Other cytokines to promote inflammation.
  5. chemokines to recruit other immune cells.
  6. Lipid mediators that have a variety of functions.
23
Q

What is the effect of allergen-specific IgE response on a patient?

A
  1. IgE antibodies to a sensitised antigen.
  2. local reaction at the point of exposure.
  3. Within 20 minutes an immediate hypersensitivity reaction (type 1). Mast cells release histamine cause swelling.
  4. Then becomes a generalised reaction called anaphylaxis.
  5. This causes fall in blood pressure, Hives, and Bronchospasm.
  6. Can lead to anaphylactic shock.
24
Q

What is anaphylactic shock?

A
  1. Systemic vasodilation that causes a massive fall in blood pressure that could cause circulatory collapse.
  2. Can also cause Tracheal swelling a suffocation.
  3. These reactions can be unpredictable.
  4. A lot of people have these without knowing they are allergic.
25
Q

What can counter anaphylactic shock?

A
  1. EpiPens
  2. Contain epinephrine that can counter the effects of histamine.
  3. reduce vasodilation, angioedema and improve perfusion.
26
Q

How can we test for allergen-specific IgE?

A
  1. Use a skin prick and observe a response by putting a drop of allergen on the skin.
  2. Exposure to ~0.2µl of allergen extract
  3. Quick to see the effect.
  4. Indistinguishable from the response to infected histamine which acts a positive control.
27
Q

How are the allergen specific IgE produced?

A
  1. The allergen is taken up by dendritic cells for antigen presentation.
  2. The dendritic cells activate naive T cells and causes Th2 priming in the lymph node.
  3. The Th2 cells induce B-cells to produce IgE.
  4. The B plasma cells travels back to to tissue to produce IgE antibodies.
  5. IgE binds FcεR1 on mast cells.
  6. These mast cells are then primed for degranulation when reencountering the allergen.
28
Q

What can determine if a type 1 hypersensitivity reactions occurs?

A
  1. Genes encoding heavy chains are sequential on chromosome 14
  2. The gene segment encoding ε occurs directly after y4 segment.
  3. class switching to either IgG4 or IgE is dependent on IL-4.
  4. IL-10 skew the balance to IgG4 rather then IgE.
  5. Less IL-10 production then more likely a type 1 hypersensitivity reaction occurs.
28
Q

What does Der p1 from dust mites do?

A
  1. An enzyme
  2. Cleaves the occludin in tight junctions
29
Q

What are the genetic influences over allergenic disease?

A
  1. Conditions like hayfever, asthma and atopic dermatitis are common in families.
  2. 30% chance of allergic disease if 1 parent is allergic, 50% chance of allergic disease if both parents have it.
  3. Strong genetic component but multiple genes influence the risk of developing allergic disease. Very complex.
  4. These genes have products invovled in antigen presentation, IgE production, T cell differentiation and isotype switching.
30
Q

What else is important in developing allergic disease?

A

environmental factors can determine the development and severity of disease

31
Q

How can we measure the response to an inhaled allergen?

A
  1. Done in a controlled environment to ensure patient safety.
  2. Immediate hypersensitivity caused by mast cell degranulation acts within 30 mins.
  3. Other leukocytes are recruited to airways.
  4. The late-phase response is caused by Th2 cells, Eosinophils, Basophils and monocytes.
32
Q

What is the inflammatory response in asthmatic bronchi?

A
  1. Most molecules released from mast cells.
  2. Spasmogens induce edema, mucus and smooth muscle constriction.
  3. chemotactic factors recruit lymphocytes, eosinophils, basophils, macrophages and neutrophils.
  4. Airway remodelling causes bronchial hyperreactivity and so it is more likely to react to stimuli.
33
Q

How can asthma be treated?

A
  1. Inhaled corticosteroids that block the late phase response in the lung by inhibiting eosinophils, basophils and lymphocytes.
  2. ß2-adrenoceptor agonists which relax smooth muscle in the bronchi.
  3. Anti-IgE monoclonal antibodies that prevent them binding to FcεR1 on mast cells.
  4. Blocking IL-4 and type 2 cytokine activity.
  5. Immunotherapy for de-sensitisation.
34
Q

What is allergic de-sensitisation immunotherapy?

A
  1. This is an established treatment for hay fever and anaphylactic sensitivity to stings.
  2. micro dose patients with an increasing dose of allergen over time to reprogram the immune system.
  3. This results in a switch from IgE production to IgG4 production and a reduced T cell response
35
Q

What are type 2 hypersensitivity reactions?

A
  1. Mediated by IgG and IgM.
  2. Antibodies binds to antigens on cell surfaces and components of ECM.
  3. Damage caused to cells and tissue bearing the targeted antigen.
  4. The cell surface antigen complex can activate the complement and interact with Fc receptors on various cells.
36
Q

What are the mechanisms of tissue damage in type 2 hypersensitivity reactions?

A
  1. Phagocytosis
  2. Antibody dependent cellular cytotoxicity
  3. Classical complement cascade activated
37
Q

Phagocytosis in type 2 hypersensitivity

A

Fc receptor-bearing cells bind to antibodies bound to cell surfaces triggering phagocytosis.
OR
A complement receptor binds C3b on the cell surface triggering phagocytosis.

38
Q

Antibody dependent cellular cytotoxicity in type 2 hypersensitivity

A

ADCC via FcR bearing cells like NK cells

39
Q

Phagocytosis and ADCC in type 2 hypersensitivity reactions

A
  1. Fc receptors and complement receptors on phagocytes act synergistically to induce phagocytosis of the opsonised cell.
  2. If the cells are too big the phagocytes get frustrated so Fc receptor binding causes the phagocyte to exocytose the lysosomal contents and cause cell necrosis.
39
Q

Complement cascade in type 2 hypersensitivity

A

formation of the membrane attack complex to kill the cell

39
Q

How can IgM or IgG activate the complement?

A
  1. IgM or IgG coats the cell surface
  2. C1q binds
  3. classical complement cascade initiated and C3b, C3bi and C3d are deposited on the cell surface
  4. compliment cascade causes the membrane attack complex and lysis of the target cell
  5. complement activation recruits macrophages and granulocytes
40
Q

What are the most common type 2 hypersensitivity reactions?

A

against ABO blood groups during transfusion

41
Q

What happens during type 2 hypersensitivity reactions to donor blood?

A
  1. extensive destruction of the donor blood cells by IgM.
  2. IgM causes agglutination, complement activation and intravascular haemolysis.
  3. symptoms include fever, low blood pressure, vomiting, pain.
  4. 10% mortality rate
  5. IgM antibodies don’t cross the placenta so cannot harm a foetus
42
Q

What is haemolytic disease of the foetus and newborn?

A
  1. You have a Rh- mum with and Rh+ foetus
  2. Usually not a problem but if the 2 blood mixes then the mum will produce antibodies to the foetal blood.
  3. Mixing blood can occur due to amniocentesis or trauma
  4. IgG antibodies are produced and these can cross the placenta.
  5. usually not a problem for the first pregnancy but the second
43
Q

What are the most clinically significant blood groups?

A

ABO and Rh

44
Q

What are the symptoms of haemolytic disease of the foetus and newborn?

A
  1. Enlarged spleen
  2. macrophages phagocytose IgG coated foetal RBC
45
Q

What is preventing sensitisation by rhesus prophylaxis?

A
  1. Give anti RhD antibodies which will bind any foetal RBC and destroy them before the mother makes her own antibodies.
  2. This is a transient low dose of antibodies to eliminate the foetal RBC before the mother develops her own sensitisation.
46
Q

What is autoimmune haemolytic anaemia?

A

Antibodies against patient’s own RBC antigens that can arise spontaneously or induced by drugs.

47
Q

What are the types of autoimmune haemolytic anaemia?

A
  1. Warm-reactive antibodies - bind antigens at 37oC and accelerates RBC clearance
  2. Cold-reactive antibodies - bind antigen below 37oC, cause RBC lysis by complement activation
  3. Antibodies to drugs - provoked by allergic reactions. Produce new antigenic structures on cells that the immune system can then recognise and cause a response.
48
Q

What are some autoimmune diseases caused by type 2 hypersensitivity reactions?

A
  1. Goodpasture’s syndrome = antibodies to collagen type 4 in the basement membrane causing necrosis of the glomerulus
  2. Pemphigus = antibodies to desmoglein 1 or 3 in the desmosome of tight junctions. This causes blistering of the skin
  3. Myasthema graves = antibodies to the acetylcholine receptor causing severe muscle weakness
49
Q

What is myasthenia gravis?

A
  1. IgG antibodies bind acetylcholine receptors and block acetylcholine binding.
  2. this prevents muscle contraction and causes muscle weakness
  3. IgG can cross the placenta so infants born to mothers with myasthenia gravis may have transient muscle weakness.

Cellular and Molecular pathology (25 decks)

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