4.13 - Hypersensitivity

Question 1

T cell responses

Answer 1

• process of activation of naive T cells requires them to encounter a specific antigen, results in rapid proliferation (clonal expansion) –> effector cells and memory cells
• CD4 T cells can acquire distinct functional capacities (or helper functions) that promote distinct parts of the immune system
• e.g. cells that become Th1 cells produce molecules that promote control of intracellular pathogens

Question 2

What is type I hypersensitivity?

Answer 2

• AKA immediate / anaphylactic hypersensitivity
• an allergic reaction provoked by re-exposure to a specific type of multivalent antigen referred to as an allergen
• multivalent antigen has multiple sites at which an antibody can attach/antigen can be produced
• type I hypersensitivity causes asthma, allergic rhinitis and atopic dermatitis

Question 3

What different substances can be allergens?

Answer 3

• food
• plants
• animal dander
• drugs
• insect products
• all allergens have proteins/protein conjugates as part of them

Question 4

What type of antibodies are type I hypersensitivity reactions mediated by?

Answer 4

• IgE antibodies
• non-allergic individuals predominantly only make IgE in response to parasitic reactions or very potent venoms

Question 5

How can you test for allergies?

Answer 5

• skin prick tests - expose skin to small amounts of allergen and look for inflamed, raised tissue (AKA wheal and flare)

Question 6

What factors influence the initial sensitisation of the immune response to allergens?

Answer 6

• genetics, age, environment

Question 7

How do allergies happen immunologically?

Answer 7

• generation of Th2 cells and B helper follicular T cells that produce type 2 cytokines IL-4 and IL-13
• when these act on B cells, the cells switch to producing antigen specific IgE
• once IgE made, it is rapidly bound to the surface of innate immune cells like mast cells + basophils - express high affinity IgE receptor (Fc epsilon receptor I)
• if allergen encounters cell-bound IgE it results in rapid crosslinking and degranulation of mast cell/basophil

Question 8

What is the end product of allergic reactions?

Answer 8

Release of:

• histamine
• cytokines that can recruit other cells and promote further Th2 differentiation
• prostaglandins
• highly active smooth muscle contracting molecules like leukotrienes

Question 9

What are the three phases of a type I response?

Answer 9

• early phase - result of bioactive small molecules produced directly by mast cells, occurs within minutes of allergen exposure
• later response - often seen within few hours and is a result of recruitment of early inflammatory cells like neutrophils
• late response - often peaks 3-4 days after exposure where high frequencies of eosinophils are recruited and Th2 cells are present

Question 10

What is type II hypersensitivity?

Answer 10

• AKA antibody mediated cytotoxic hypersensitivity
• destruction of cells by IgG/IgM antibodies bound to antigens present on the surface of the cells

Question 11

What are some examples of type II hypersensitivity?

Answer 11

• mismatched blood transfusion - antibodies recognise different, non-self, carbohydrate groups of transfused RBCs –> destruction of those RBCs, inflammation and tissue damage
• haemolytic disease of newborns - maternal antibodies can cross placenta and destroy foetal RBCs if foetus and mother have mismatched RhD alleles
• immune thrombocytopenia - antibodies develop against platelet surface proteins
• Graves disease - patients develop thyroid stimulating antibodies that bind the thyrotropin receptor = secretion of thyroid hormones

Question 12

What are two causes of type II hypersensitivity?

Answer 12

• exposure to a foreign antigen (e.g. some drugs can bind to surface of blood cells, or non-self antigens blood transfusion or organ transplants)
• aberrant response to a self-antigen resulting in IgGs / IgMs that recognise cell surface structures

Question 13

What are three mechanisms through which IgG and IgM antibodies can cause disease?

Answer 13

• anti-receptor activity - blocking or activating its function
• antibody dependent cell-mediated toxicity (ADCC)
• classical activation of the complement cascade

Question 14

What happens in antibody dependent cell-mediated toxicity? (ADCC)

Answer 14

• antibody-antigen complexes on the surface of cells are bound by Fc receptors (which bind the constant regions of IgM/IgG) expressed by cells like granulocytes and NK cells
• leads to direct lysis of target cell and release of inflammatory mediators - chemokines and cytokines

Question 15

What is the classical complement cascade?

Answer 15

• process by which antibody on the surface of cells is recognised by complement components, leading to the formation of membrane attack complex (MAC) in cell surface, and cell death due to loss of osmotic integrity
• activation of complement cascade results in inflammation, opsonisation, recruitment and activation of immune cells

Question 16

How does type II hypersensitivity cause tissue damage?

Answer 16

• local or systemic inflammation
• cell depletion leading to loss of function
• imbalance in organ function

Question 17

What are immune complexes?

Answer 17

• non-cell bound antigen-antibody complexes which are normally cleared through activity of the immune system

Question 18

What is type III hypersensitivity?

Answer 18

• AKA immune complex driven disease
• when immune complexes cannot be cleared efficiently e.g. if they are the result of antibodies acting against self-antigens like nuclear DNA, the complexes are deposited in blood vessel walls and tissues, promoting inflammation and tissue damage

Question 19

What issues can type III hypersensitivity lead to?

Answer 19

• fevers, rashes, joint pain, protein in urine
• vasculitis if deposited in blood vessels
• glomerulonephritis if in kidneys
• arthritis if in joints
• many autoimmune diseases including rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus (SLE) involve type III reactions

Question 20

What happens in systemic lupus erythematosus?

Answer 20

• patients develop IgGs against DNA/proteins present in the nucleus of cells (nucleoproteins), which form persistent immune-complex deposits and a variety of pathologies

Question 21

What types of antigens cause type III hypersensitivity?

Answer 21

• most diseases associated with type III hypersensitivity are autoimmune in origin
• some can result from encounters with foreign antigens e.g. persistent infections like hepatitis virus infections can result in immune complex deposition, as can exposure to freely circulating foreign antigens like drugs
• the same immunological processes present in inflammation and active in type II hypersensitivity are also involved in type III hypersensitivity

Question 22

How does serum sickness work?

Answer 22

• say someone is bitten by a snake, they may be given anti-serum (antibodies specific to the snake venom proteins) to neutralise the snake venom
• these are foreign proteins and while they neutralise the venom, our bodies will react against them to produce antibodies that recognise the anti-venom antibodies
• process takes several weeks and does not represent a problem as the anti-sera and venom will be long cleared
• but if they get bitten again, these antibodies will rapidly recognise the anti-serum and drive rapid inflammation

Question 23

What is type IV hypersensitivity?

Answer 23

• AKA delayed-type / T cell mediated hypersensitivity
• initiated by T cells (not antibodies)
• sensitisation phase occurs where antigen is presented to naive T cells by APCs (DCs) = generation of antigen specific memory T cells (several weeks)
• subsequent exposure = memory cells respond promoting inflammation at site of exposure
• any memory T cell is capable of driving an immune response (not just Th1 cells)

Question 24

When is the memory T cell response shown and why?

Answer 24

• 2-3 days after inflammation
• because memory T cell response requires recruitment and expansion = slower than antibody mediated memory = delay between exposure and response

Question 25

What is the most common example of type IV hypersensitivity and what happens?

Answer 25

- contact dermatitis caused by exposure to poison ivy, where a small molecule called urushiol acts as a hapten (and binds to proteins in skin), driving T helper 1 response - rarely results in antibody production as the molecule is so small - on re-exposure, the memory cells produce cytokines such as IFN-gamma which promote the pro-inflammatory activation of macrophages = swelling, oedema, blister-like regions

Question 26

What other antigens can cause type IV hypersensitivity?

Answer 26

- nickel salts or hair dyes can also drive Th1 based inflammation - intracellular pathogens like measles virus and tuberculosis bacteria - (positive readout of tuberculin skin test is a type IV reaction)

Question 27

What is an example of where Th2 cells cause type IV hypersensitivity?

Answer 27

- in asthma, allergens cause overreaction of Th2 cells --> soluble mediators that promote bronchoconstriction

Question 28

What is an example of where CD8 T cells cause type IV hypersensitivity?

Answer 28

- can lead to inflammation and rejection of tissue graft by directly killing transplanted cells

Question 29

What are the two steps to getting hypersensitivity?

Answer 29

1. sensitisation - where T cells are initially sensitised to the molecule and get an immune response ready 2. second exposure - where the molecule is introduced again at a later date to the body and the body reacts immunologically - many diseases - more than one type of hypersensitivity may be contributing to pathology at the same time