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Semester 4 - immune system > 1. Hypersensitivity Reactions > Flashcards

1. Hypersensitivity Reactions Flashcards

1
Q

What is the main cause of immunosuppression?

A

Malnutrition >65yrs

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2
Q

Define hypersensitivity.

A

the antigenspecific immune responses that are either inappropriate or excessive and result in harm to host

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3
Q

What exogenous antigens can cause hypersensitivity reactions? (3)

A
  • Non infectious substances (innocuous) - allergies like pollen
  • Infectious microbes
  • Drugs (Penicillin)
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4
Q

What can cause hypersensitivity reactions to intrinsic antigens?

A
  • Infectious microbes (mimicry)

- Self antigens (auto-immunity)

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5
Q

What is mimicry?

A

Hosts attacks itself due to structural similarities between microbe and host

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6
Q

WHat are the different types of hypersensitivity reactions?

A
  • Type I or immediate (Allergy)
  • Type II or antiBody mediated/ cytotoxic - tissue specific
  • Type III or immune Complexes mediated
  • Type IV or cell mediated(Delayed)
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7
Q

which of the types if hypersensitivities are antibody mediated and which antibody ?

A

type I -IgE
type II - IgG
type III - IgG

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8
Q

what is the difference between the antigen of type I and IV?

A

type I - Environmental non infectious antigens

type II - Environmental infectious agents and self antigens

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9
Q

hat is the sensitisation phase of hypersensitivity?

A

First encounter with the antigen. Activation of APCs and memory effector cells. A previously exposed individual to the antigen is said to be “sensitized”

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10
Q

What is the effector phase?

A

Pathologic reaction upon re-exposure to the same antigen and activation of the memory cells of the adaptive immunity

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11
Q

in which phase are the clinical manifestations of hypersensitivity present?

A

effector phase

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12
Q

How long does type II hypersensitivity reactions take to develop?

A

Usually develops within 5-12 hr

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13
Q

Which antibodies do type II hypersensitivity reactions involve?

A

IgG or IgM antibodies

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14
Q

What antigens are targeted in type II hypersensitivity reactions? give examples.

A

Targets cell bound antigens:
• Exogenous: Blood group antigens, Rhesus D antigens
• Endogenous: self antigens

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15
Q

What are the different outcomes of type II reactions?

A
  • Tissue/cell damage

* Physiological change

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16
Q

What 2 mechanism in type II reactions cause tissue/cell damage after the antibody binds to antigen?

A
  • complement activation

- antibody-dependent cell cytotoxicity (Natural Killer cells)

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17
Q

What is involved in the complement system in type II reactions?

A
  • Cell lysis (MAC, membrane attack complex) - influx of fluid
  • Neutrophil recruitment/ activation (C3a/C5a) - Fc receptors of neutrophils bind to antibodies on cell
  • Opsonisation (C3b) -m
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18
Q

Give examples of type II reactions involving complement activation. (2)

A
  • Haemolytic disease of the newborn (HDN) - Antigen = Rhesus D
  • Transfusion reactions - Antigen= ABO system
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19
Q

explain antibody-dependent cell cytotoxicity (NK cells)

A

natural killer cells can recognise (using Fc receptors) and kill antibody coated target cells that express pathogen antigens on their surface.
perforins –> cell lysis
granzymes –> apoptosis

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20
Q

Give examples of type II reactions involving Antibody-dependent cell cytotoxicity. (3)

A
  • Autoimmune haemolytic anaemia (warm and cold)
  • Immune thrombocytopenia Purpura
  • Goodpasture’s syndrome (anti-GBM)
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21
Q

what is Goodpasture’s syndrome

A
  • autoimmune disease in which antibodies attack the basement membrane in lungs and kidneys
  • attack the alpha-3 subunit of type IV collagen
  • binding of antibody to alpha 3 chain activates complement systems leading to chemoattraction of neutrophils which release ROS that damages the basement membrane
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22
Q

why are the lungs and kidney most affected by Goodpasture’s syndrome and how does it present?

A

toxins cause damage to collagen chain, exposing the antigens if alpha 3 chain. lungs and kidneys receive the most toxins through inhalation and filtrations

lungs (alveoli)- cough, haemoptysis, restrictive lung disease
kidneys (glomeruli)- haematuria, proteinuria, nephritic syndrome

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23
Q

What is the importance of complement pathway in type II reactions?

A

Its involved in the innate immune response, adaptive immune response as well as the disposal of unwanted substances within the body.

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24
Q

What is haemolytic transfusion reaction, what can it cause?

A

RBCs given in transfusion are destroyed by hosts immune system (IgM)
- Shock, kidney failure, circulatory collapse, and death

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25
Q

What is the immune mechanism underlying heamolytic transfusion reaction?

A
  • Incompatibility in the ABO or rhesus D antigens
  • Donor RBC destroyed by recipient’s immune system
  • RBC lysis induced by type II hypersensitivity involving by the naturally occurring antibodies (IgM)
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26
Q

what are the major blood groups and their antigens?

A
  • blood group A – has A antigens on the red blood cells • blood group B – has B antigens
  • blood group O – has no AB antigens
  • blood group AB – has both A and B antigens
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27
Q

what antibodies do each of the major blood groups have?

A
  • blood group A subjects – have anti-B antibodies in the plasma
  • blood group B subjects – have anti-A antibodies in the plasma
  • blood group O subjects – have both anti-A and anti-B antibodies in the plasma blood group
  • AB subjects – have NO antibodies in the plasma
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28
Q

what is the rule for blood transfusions?

A

the donated RBCs must lack the same ABO that the recipient’s red blood cells lack.

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29
Q

which blood groups are universal blood donors and universal plasma donors and why?

A

group O individuals lack any A or B antigens on their red cells, they are considered universal blood donors.

Group AB individuals are universal plasma donors, as they lack AB antibodies

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30
Q

What is the mechanism behind haemolytic disease of the newborn?

A
  1. Rh+ father
  2. Rh- mother carrying first Rh+ fetus. Rh antigens from the developing fetus can enter the mother’s blood during delivery.
  3. In response to the fetal Rh antigens, the mother will produce anti-Rh antobodies
  4. If the woman becomes pregnant with another Rh+ fetus, her anti-Rh antibodies will cross the placenta and damage fetal RBCs
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31
Q

which antigen is found in Rh+ individuals

A

Rh-positive blood denotes the presence of the D antigen on the red cells of an individual’s blood.

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32
Q

What is the treatment to prevent HDN?

A

Rh-negative pregnant women are given a small amount of Rh immunoglobulin (anti-D), RhoGAM, which prevents their own formation of anti- D antibodies. - It does this by binding to the antigens in the mothers blood and preventing them from coming into contact with the mothers immune system.
The aim of this is to prevent initial sensitisation of the mother.

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33
Q

what are the clinical features of HDN?

A

Destruction of red blood cells causes elevation of bilirubin level in the bloodstream. After delivery of baby with Haemolytic Disease of the Newborn (HDN), bilirubin present in the neonate’s blood is no longer cleared via the placenta, leading to the accumulation of bilirubin in the baby’s bloodstream (called hyperbilirubinemia) and other tissues/fluids resulting in JAUNDICE.

34
Q

What is the main complication of increased bilirubin levels for the baby in HDN?

A

If levels continue to rise, bilirubin may enter the brain to cause kernicterus, a potentially fatal condition that leaves permanent neurological damage in the babies that survive.

35
Q

Explain the type of hypersensitivity reaction responsible for the HDN

A

This is an example of type II hypersensitivity reaction leading to loss of function (cytotoxicity). HDN is caused by the presence of maternal IgG directed against the rhesus D antigen, which has crossed the placenta and opsonised foetal red cell blood cells. These red cells with antibody attached are cleared from the circulation by the liver and spleen macrophages.

36
Q

Why does a mismatch of the ABO system rarely causes HDN?

A

The naturally occurring anti-A or anti-B antibodies are IgM and do not cross the placenta

37
Q

What are the mechanism to induce physiological change in type II reaction?

A
  • receptor stimulation

- receptor blockade

38
Q
  • receptor stimulation

- receptor blockade

A

Graves’ disease
− Increased thyroid activity
− Antigen = TSH receptor

39
Q

Give an example of type II reaction with receptor blockade.

A

Myasthenia gravis
− Impaired neuromuscular signalling
− Antigen = Acetylcholine receptor

40
Q

describe the steps in neuromuscular transmission

A

(i) An action potential is propagated down the motoneuron until the presynaptic terminal is depolarized. (ii) Depolarization of the presynaptic terminal causes voltage-gated Ca2+ channels to open, and Ca2+ flows into the nerve terminal.
(iii) Uptake of Ca2+ into the nerve terminal causes exocytosis of stored acetylcholine (ACh) into the synaptic cleft.
(iv) ACh diffuses across the synaptic cleft to the muscle end plate, where it binds to nicotinic ACh receptors (AChRs).
(v) The nicotinic AChR is also an ion channel for Na+ and K+. When ACh binds to the receptor, the channel opens. (vi) Opening of the channel causes both Na+ and K+ to flow down their respective electrochemical gradients. As a result, depolarization occurs.
(vii) This depolarization, called the end plate potential, spreads to the neighboring regions of the muscle fiber. (viii) Finally, the muscle fibers are depolarized to threshold and fire action potentials.

41
Q

what is the pathophysiology of Myasthenia gravis?

A
  • abnormal antibodies to AChR (AChR-ab) are produced, circulate in the blood, and bind to nicotinic receptors on the muscle end plates.
  • now the receptors are not available to be activated by the ACh that is released physiologically from motoneurons.
  • Thus, while normal action potentials occur in the motoneurons and ACh is released normally, the ACh cannot cause depolarization of muscle end plates.
  • Without depolarization of muscle end plates, there can be no action potentials or contraction in the muscle.
42
Q

once bound to receptors, how is Ash normally degraded?

A

After ACh binds to and activates AChR on the muscle end plate, it is degraded by acetylcholinesterase. This degradative step, whose byproducts are choline and acetate, terminates the action of ACh on the muscle fiber. Choline is taken up into the motoneuron terminal and recycled into the synthesis of more ACh.

43
Q

how is myasthenia gravis treated?

A

Pyridostigmine

  • acetylcholinesterase inhibitor
  • reduces degradation of ACh at the muscle end plate, increasing its synaptic concentration and prolonging its action.
  • The longer the muscle end plate is exposed to high concentrations of ACh, the greater the likelihood that action potentials and contraction in the muscle will occur.
44
Q

What are therapeutic approaches to type II reactions that cause cell/tissue damage?

A
  • Anti-inflammatory drugs: Complement activation
  • Plasmapheresis: Circulating antibodies and inflammatory mediators
  • Splenectomy: Opsonisation/Phagocytosis
  • Intravenous immunoglobulin (IVIG): Blockage of Fc receptor
45
Q

What are therapeutic approaches to type II reactions that cause physiological change?

A
  • Correct metabolism: Antithyroid drugs in Graves’s disease

* Replacement therapy: Pyridostigmine in Myasthenia gravis

46
Q

WHat conditions is plasmapheresis therapy used in?

A
  • Myasthenia gravis
  • Goodpasture’s syndrome
  • Graves’ disease
47
Q

What is plasmapheresis?

A

Process in which the liquid part of the blood, or plasma, is separated from the blood cells. Typically, the plasma is replaced with another solution such as saline or albumin, or the plasma is treated and then returned to your body

48
Q

How long does type III hypersensitivity take to develop?

A

Usually develops within 3-8 hr

49
Q

WHat does type III reactions involve?

A

Involves immune complexes between IgG or IgM and antigens

50
Q

what is the complement system?

A

a family of small proteins that work in an enzymatic cascade to fight infection

51
Q

describe how the complement system is activated

A

an antibody binds to the antigen which means a complement protein is now able to bind to the Fc portion antibody and activate other complement proteins

52
Q

how do neutrophils kill cells once drawn to them chemoattractants C3a etc?

A

release enzymes that generate reactive oxygen species that damage the cell

53
Q

how does the membrane attack complex formed by the complement system attack cells?

A

MAC inserts itself into cell membrane that creates channel for fluid to move into cell and cause cell lysis –> cell death

54
Q

how can HDN be diagnosed

A

indirect Coombs test

55
Q

describe the direct Coombs test

A
  • red blood cells from blood separated from plasma.
  • Coombs reagent added which is antibody against human antibidy
  • if the red blood cells contain antibodies on their surface, then they will agglutinate
56
Q

describe the indirect Coombs test

A

patients serum added with lab RBC with known antigen on surface
then mixed with Coombs reagent
if RBC agglutinates, indicates antibodies or complement present in serum

57
Q

what is indirect Coombs test usually used for

A

to see if antibodies present before exposure to antigen e.g blood group incompatibility, HDN

58
Q

what’s direct Coombs test used for

A

autoimmune haemolytic anaemia

59
Q

What antigens does type III reactions involve?

A

Targets soluble antigens

  • Foreign (Infection)
  • Endogenous (self antigens)
60
Q

How is damaged caused in type III reactions?

A

deposition of immune complexes (antibody +antigen) in host tissues/ blood vessel walls leading to inflammation and tissue damage

61
Q

What are 2 key factors affecting immune complex pathogenesis?

A

Complex size:

  • Small and large size ICs cleared
  • Intermediate size ICs

Host response

  • Low affinity antibody
  • Complement deficiency (poor clearance on ICs??)
62
Q

Where are ICs typically deposited?

A

• Joint (plasma filtered to form synovial fluid) • Kidney (blood filtered)• Small vessels • Skin
(multi system disease)

63
Q

What is the mechanism in type III reactions?

A
  1. intermediate sized immune complexes that are not removed by macrophages, circulate in blood and are deposited in blood vessels wall of tissue
  2. complement activated - increased vascular permeability - oedema
  3. neutrophil chemotaxis
  4. neutrophil adherence and degranulation - Fc receptor on neutrophil binds to Fc portion on antibody
  5. enzymes, ROS causing damage to endothelial cell and basement membrane
  6. leakage into surrounding tissue leading to further inflammation and damage to tissues
64
Q

Give examples of conditions caused by type III reactions. (3)

A
  • Rheumatoid arthritis (self-antigen)
  • Glomerulonephritis (infectious)
  • Systemic lupus erythematosus
65
Q

What infections can lead to glomerularnephritis?

A
  • Bacterial endocarditis

* Hepatitis B infection

66
Q

WHat is the antigen in rheumatoid arthritis and what does it bind to?

A

self antigen

binds to Fc portion of IgG (75%)

67
Q

contrast type II and Type III

A

type II - cell surface antigen, complement used in small amounts, clinical symptoms correspond to where antibodies attach
Type III - soluble antigen, complement used in large amounts, clinical symptoms correspond to where immune complexes are deposited

68
Q

in the complement system, how are the proteins activated

A

by enzymatic cleavage into two parts

69
Q

What is the antigen in SLE?

A

Ds-DNA

70
Q

What are some symptoms of SLE?

A

Fever, Joint Pain, and Butterfly Rash

71
Q

what organs are affected in SLE?

A
  • 40-60% patients with cardiac, respiratory, renal, joint and neurological features
  • Repeated miscarriage
72
Q

How long do type IV hypersensitivity reactions take to develop?

A

Usually develops within 24-72hr

73
Q

What do type IV reactions involve?

A

lymphocytes (TH1) and macrophages

74
Q

What are the different subtypes of type IV reactions?

A
  • Contact hypersensitivity
  • Tuberculin hypersensitivity
  • Granulomatous hypersensitivity
75
Q

What is the mechanism of type IV reactions?

A
  • sensitisation: macrophages present to T helper cells which differenciate into TH1 cells

Effector phase: TH1 cells activate resting macrophages and mount a response

76
Q

Dexcribe the features of Contact hypersensitivity, give examples of what can cause it.

A
  • Occurs 48-72 hr postexposure
  • Epidermal reaction
  • Require endogenous proteins
  • Examples o Nickel o Poison ivy o Organic chemicals
77
Q

How long after exposure do granulomatous reactions occur?

A

21-48 days post-exposure

78
Q

Give examples of conditions that are associated with granulomas.

A

o Tuberculosis o Leprosy (tuberculoid) o Schistosomiasis o Sarcoidosis

79
Q

Give examples of diseases caused type IV reactions to endogenous antigens.

A
  • Pancreatic Islet cells: Insulin-dependent diabetes mellitus
  • Thyroid gland: Hashimoto’s thyroiditis
  • Fc portion of IgG: Rheumatoid arthritis
80
Q

How are type III and IV reactions treated?

A

Anti-inflammatory drugs
• Non-steroidals
• Corticosteroids (oral prednisolone)
• Second drugs as steroid-sparing agents (<10 mg oral steroid) e.g. Azathioprine, Mycophenolate mofetil, Cyclophosphamide

Monoclonal antibodies
• B Cells and T cells
• Cytokine network
• APCs

Semester 4 - immune system (6 decks)

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