Lecture 1 - Hypersensitivity Flashcards
What is haemolytic anaemia??
When the body destroys more RBC than normal often due to a structural defect in the RBC like hereditary Spherocytosis, DIC
What is good pastures syndrome?
Type of nephritic syndrome
Antibodies to type IV collagen in the glomerular basement membrane leading to inflammation within the kidney
What is myasthenia gravis?
Neuromuscular junction disorder where anti bodies to the ACh receptors on the skeletal muscle are blocked or destroyed
What is Graves’ disease?
Where autoantibodies that are like TSH bind to TSH receptors
Immune system produces proteins that mimic thyroid stimulating hormone leading to hyperthyroidism
What are some non organ specific autoimmune conditions/
Systemic lupus eryhtrematous
Rheumatoid arthritis
What is the definition of hypersensitivity?
The antigen specific immune responses that are either inappropriate or excessive and result in harm to the host
What is an antigen?
Any substance that triggers an immune repsonse as form of effector T/B cells and antibodies
What are some exogenous antigens that can trigger hypersensitivity?
Non infectious substances
Infectious microbes
Drugs
What are some intrinsic antigens that may trigger hypersensitivity?
Infectious microbes (mimicry)
Self antigens
What are type of hypersensitivity reactions?
Type I (A)
Type II (B)
Type III (C)
Type IV (D)
Broadly what are Type I hypersensitivity reactions?
Immediate / Allergy reaction (Environmental non infectious antigens)
Broadly what are Type II hypersensitivity reactions?
AntiBody - dependant cytotoxicity
Antibodies to membrane bound antigens
Broadly what are type III hypersensitivity reactions?
Immune Complex mediated to soluble antigens
Broadly what are type IV hypersensitivity reactions?
Delayed or cell mediated to environmental infectious agents and self antigens
What are the 2 phases to hypersensitivity reactions?
Sensitisation phase
Effector phase
What is the sensitisation phase of hypersensitivity reactions?
The first encounter with the antigen leading to activation of APCs and memory effector cells
What is the effector phase of hypersensitivity reactions?
The pathological reaction upon re-exposure to the same antigen and activation of the memory cells of tthe adaptive immunity
What antibodies drive Type II hypersensitivity reactions?
IgG or IgM antibodies
How long does it take for a Type II hypersensititvy reaction to develop?
5-12hrs after re encountering the antigen
What are some examples of cell bound antigens that type II hypersensitivity reactions can be set up against?
Exogenous:
Endogenous:
Exogenous = blood group antigens, Rhesus D antigens
Endogenous = self antigens (auto immune)
What are the 2 immune mechanisms by which Type II hypersensitivity can cause tissue damage?
Complement activation
Antibody-dependant cell toxicity
What can be activated in complement activation causing tissue damage in Type II hypersensitivity?
Cell lysis
Neutrophil recruitment by C3a/C5a
Opsonisation (C3b)
What are some clinical examples of Type II hypersensitivity which causes tissue damage via complement activation?
Haemolytic disease of newborn
Transfusion reactions
What are some clinical examples of Type II hypersensitivity reactions that involve antibody dependent cell cytotoxicity?
Autoimmune haemolytic anaemia
Immune thrombocytopenic purpura
Good pastures syndrome
What is the antigen in Haemolytic disease of newborn?
Rhesus D
What is the antigen in transfusion reactions?
ABO system
What is the antigen in Autoimmune Haemolytic anaemia?
RBCs
What is the antigen in immune thrombocytopenic purpura?
Platelets
What is the antigen in good pastures syndrome?
Collagen IV in basement membrane of kidney
What antibody drives Type II hypersensitivity reactions in a haemolytic transfusion reaction?
IgM
What is a haemolytic transfusion reaction?
When the wrong type of blood is transfused into a patient either due to:
-error in identifying
-testing error
-improper labelling
Leading to an immune response being set up
What are the antigens and what are the antibodies involved in haemolytic transfusion reactions?
Describe the mechanism
When there’s incompatibility in the ABO antigens from the donor blood on the RBCs so donor lysis is induced by the IgM from the recipient in a Type II hypersensitivity reaction
What is the clincal outcome for haemolytic transfusion reactions? (Type II hypersensitivity)
Shock
Respiratory distress
Kidney failure
Death
What are the 4 different blood groups?
A
B
AB
O
What are the antibodies and antigens in blood Group A?
Antibodies in plasma: Anti-B
Antigens on RBC: A antigen
What are the antibodies and antigens in blood Group B?
Antibodies in plasma= anti A
Antigens on RBC= B antigen
What are the antibodies and antigens in blood Group AB?
Antibodies in plasma= NONE
Antigens on RBC= A and B antigen
What are the antibodies and antigens in blood Group O?
Antibodies in plasma = Anti A and Anti B
Antigens on RBC = none
What makes blood group O the universal donor group?
Has no antigens on the red blood cell so no anti antibodies will attach to them
What is the main Type II hypersensitivity disease that’s driven by IgG?
Haemolytic disease of the newborn
What is pathological process of haemolytic disease of the new born?
(Type II hypersensitivity)
Mother is Rhesus D -ve but fetus/baby is Rhesus D +ve
During delivery Fetal Rhesus D antigens enter into maternal circulation, mother then produces rhesus D antibodies (This is the Sensitisation stage)
If mother gets pregnant again with another rhesus D +ve baby, the rhesus D antibodies will cross the placenta and cause damage to fetal red blood cells
What are the complications of Haemolytic disease of the new born?
Hydrops fetalis
Liver/splenomegaly
Severe hyperbilirubinemia
Kernicterus
What is the antigen for Haemolyitc disease of the newborn?
Rhesus factor D
How does haemolytic disease of the new born cause severe hyperbilirubinaemia?
Increased amount of haemolysis leads to prehepatic jaundice
How does haemolytic disease of the new born cause hydrops fetalis, liver/splenomegaly?
The high levels of bilirubin cause hepatic damage
This leads to impaired ability to produce albumin leading to hydrops fetalis
Leading to liver and splenomegaly
What is kernicterus?
When the high levels of bilirubin in the blood due to haemolytic disease of newborn damages the brain
What is the treatment for the Type II hypersensitivity reaction for Haemolytic disease of the newborn?
RhoGAM
When is RhoGAM administered?
3days after delivery or miscarriage of a rhesus Postive infant
How does RhoGAM treat haemolytic disease of newborn?
RhoGAM binds to the rhesus D antigens preventing maternal circulation from detecting it preventing the production of Rhesus D antibodies to prevent the formation of the Type II hypersensitivity reaction
What are some examples of Type II hypersensitivity reactions associated with physiological changes?
Where an immune response is raised against a receptor
Graves’ disease
Myasthenia gravis
Pernicious anaemia
What is the immune mechanism of Graves’ disease?
IgG antibodies (TSH like protein) that bind to TSH receptors (antigen) leading to Hyperthyroidism
What is the immune mechanism of myasthenia gravis?
IgG antibodies produced to block/destroy ACh receptors (antigen) on the muscle at neuromuscular junctions
What is the immune mechanism behind pernicious anaemia?
IgG prevents the production of intrinsic facotr in gastric parietal cells leading to lack of uptake of B12
How do we treat type II hypersensitivity reactions?
Treat the tissue/cell damage
Physiological change
How do you treat the tissue /cell damage in Type II hypersensitivity?
Corticosteroids (anti-inflammatories)
Plasmapheresis (removes circulating antibodies and infammaotry mediators)
Splenectomy (reduce opsonisation adn phagocytosis)
Intravenous immunoglobulin (block Fc receptor)
How do you treat the physiological changes seen in Graves’ disease type II hypersensitivity reactions?
Antit thyroid drugs
Thyroidectomy
What drug is used to treat myasthenia gravis?
How does it work?
Pyridostigmine
Reduces/inhibits acetylcholinesterase so increases levels of ACh at neuromuscular junctions
How do you treat pernicious anaemia?
Vitamins B12
What type II hypersensitivity reactions does plasmapheresis treat?
Myasthenia. Gravis
Goodpastures syndrome
Graves’ disease
How does plasmapheresis therapy work to treat type II hypersensitivity reactions?
Removes inflammatory mediators and auto-antibodies
Only short term relief, allows healing of damaged tissue (since body still making autoantibodies)
What type of reaction are Type III hypersensitivity reactions?
Immune complexes between IgG or IgM and antigens
What type of antigens are involved in Type III hypersensitivity reactions?
Soluble antigens tthat form immune complexes
What are immune complexes?
A multi-molecular complex of antibodies and bound antigen
Tissue damage caused by deposition of immmune complexes in blood vessels
What are some factors affecting immune complex pathogenesis?
Intermediate size immune complexes
Chronic infections
Low affinty antibodies
What is the pathological mechanism for Type III hypersensitivity reactions?
Intermediate sized immune complexes in the tissue
Comeplement activated (C5a) leading to neurotrophic chemotaxis
Neutrophil adherence and degranulation of mast cells attacking self membranes causing dysregualted inflammation
What are some examples of Type III hypersensitivity reactions?
Rheumatoid arthritis
Infectious glomerulonephritis (post streptococcal glomerulonephritis)
Systemic lupus erythematosus
What is the antigen of rheumatoid arthritis?
The Fc portion of IgG (self-antigen)
What is the timing of how rheumatoid Arthritis presents?
Episodes of inflammation and then remission
When does rheumatoid arthritis have a poor prognosis?
<30 yr old
High titre of rheumatoid arthirits antibodies
Female
Joint erosions
DR4 allele
What is the antigen to Systemic lupus Erythematosus?
Double stranded DNA
What is the most complex Type III (C) hypersensitivity reaction?
Systemic lupus erythematosus
What is the pathological mechanism of Type IV hypersensitivity reactions?
Not antibody mediated
Involves lymphocytes and macrophages becoming sensitised to an antigen which then activates T cells to evoke a response
What triggers Type IV hypersensitivity reactions?
Environmental factors
Infectious microbes
Drugs
What are the 3 different subtypes of Type IV hypersensitivity reactions (delayed)?
Contact hypersensitivity
Tuberculin hypersensitivity
Granulomatous hypersensitivity
What is a granuloma?
Local immune repsonse composed of macrophages and lymphocytes in response to foreign antigens that can’t be removed or destroyed from the host
How long does it take for Type IV hypersensitivity reactions to take place?
24-72hr
How does pathogenesis of type Iv hypersensitivty occur?
Sensitisation activates TH1 cells
Th1 cells make interferon gamma and TNF beta activating macrophages
What is contact hypersensitivty?
Epidermal reaction (type IV hypersensitivity)
Occurs 48-72hrs post exposure
How do you diagnose contact hypersensitivty?
Patch testing
What is granulomatous hypersensitivity?
Type IV hypersensitivty
Occurs 21-48 days after exposure leading to tissue damage
What are some causees of granulomatous hypersensitivty?
Tuberculosis
Leprosy
Schistosomiasis
Sarcoidosis
What are some Type IV hypersensitivity reactions caused by endogenous antigens?
Insulin-dependant diabetes Mellitus
Hashimotos Thyroiditis
What is the pathology of insulin dependant diabetes Mellitus?
Antigen is pancreatic islet cells
What is the difference in n type of hypersensitivty reaction for Graves’ disease and Hashimoto’s disease?
Graves’ disease = Type II hypersensitivty
Hashimoto’s disease = Type IV hypersensitivty
What is the pathology of Hashimotos thyroiditis?
Antibodies destroy thyroid tissue
What are some corticosteroids that can treat type III and IV hypersensitivty?
Oral Prednisolone
