Hypersensitivty reactions

Question 1

What’s the main cause of immunodeficiency in the UK?

Answer 1

Malnutrition

esp >65yrs

Question 2

Define hypersensitivity

Answer 2

The antigen- specific immune responses that are either inappropriate or excessive and result in harm to host
- tissue destruction or change in function

Question 3

What are the two types of hypersensitivity triggers (antigens)?

Answer 3

Exogenous antigens - non infectious substances (innocuous)
Infectious microbes
Drugs (penicillin)

Intrinsic antigens - infectious microbes with similar structure to internal antigen e.g. Rheumatic fever (mimicry), self antigens (auto-immunity)

Question 4

Types of hypersensitivity reactions

Answer 4

Type 1/ immediate (allergy) (IgE mediated)
- environmental non infectious antigens

Type 2/ antibody mediated (against membrane bound antigen, organ specific - IgG, sometimes IgM

Type 3/ immune complexes mediated - soluble antigen so immune complex circulates (mostly systemic) - IgG mediated, sometimes IgM

Type 4/ cell mediated (delayed) (environmental infectious agents and self antigens)

Question 5

Two phases of hypersensitivity reactions

Answer 5

Sensitisation phase - first encounter with antigen, activation of APCs & memory effector cells (once exposed = sensitized)

Effector phase - pathologic reaction upon re-exposure to same antigen & activation of memory cells of the adaptive immunity

Question 6

Describe type 2 hypersensitivity reactions

Answer 6

Usually develops within 5-12hrs

Involves IgG or IgM antibodies

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

Induces different outcomes: tissue/ cell damage, physiological change

Question 7

Type 2 hypersensitivity mechanisms

Answer 7

Tissue/ cell damage ~
Complement activation (to a new foreign tissue) : cell lysis (MAC), neutrophil recruitment/ activation (C3a/ C5a)/ opsonisation (C3b)
OR
Antibody- dependent cell cytotoxicity (to you own self tissue) : NK cells

Physiological change ~
Receptor stimulation or receptor blockade

Question 8

Give examples of type 2 hypersensitivity diseases involving tissue/ cell damage

Answer 8

Complement activation:
- haemolytic disease of the newborn, antigen = Rhesus D e.g. Rh+ father & Rh- mum have Rh+ bby, 1st pregnancy Rh+ antigens enter mum during delivery -> mother produces anti-Rh antibodies. 2nd Rh+ pregnancy - antibodies cross placenta & damage fetal RBCs 3rd trimester

Haemolytic Transfusion reactions, antigen = ABO system/ RhesusD - life threatening, shock, kidney failure, circulatory collapse

Antibody- dependent cell cytotoxicity:
Autoimmune haemolytic anaemia (warm & cold), immune thrombocytopenia purpura, Goodpasture’s syndrome (glomerulonephritis)

Question 9

Which blood type is best to give if unsure? Which blood type can receive any type?

Answer 9

If unsure give: O-

Can receive anything: AB+
(Although transfused blood may have antibodies, won’t be a cascade increasing supply so will have no effect)

Question 10

Which antibodies does each blood type contain?

Answer 10

Rhesus negative has antibodies against positive

Type A - antibodies against B
Type B - antibodies against A
Type AB - no antibodies
Type O - antibodies against A and B

Question 11

How can you prevent haemolytic disease of the newborn?

Answer 11

Give Rho(D) immune globulin (human)/ RhoGAM to mum before delivery

Binds fetal RBCs & clears Rh+

Question 12

Give 2 examples of type 2 hypersensitivity reactions involving physiological change

Answer 12

Receptor stimulation: Grave’s disease - increased thyroid activity, antigen = TSH receptor (antibodies bind receptor & stimulate)

Receptor blockade: myasthenia gravis, impaired neuromuscular signalling, antigen = acetylcholine receptor (numbness, paralysis, weakness)

Question 13

Therapeutic approaches for type 2 hypersensitivity reactions caused by tissue/ cell damage

Answer 13

• anti-inflammatory drugs (complement activation targeted)
• plasmapheresis (separate plasma, clear it from antibodies/ inflammatory mediators then return)
• splenectomy (reduces opsonisation/ phagocytosis, risk encapsulated organisms)
• intravenous immunoglobulin (IVIG) IgG degradation

Question 14

Therapeutic approaches for type 2 hypersensitivity reactions caused by physiological change

Answer 14

Correct metabolism - anti thyroid drugs in Grave’s disease

Replacement therapy - pyridostigmine in Myasthenia Gravis (increases Ach)

Question 15

What can plasmapheresis therapy be used to treat?

Answer 15

Myasthenia gravies
Goodpasture’s syndrome
Grave’s disease

Short term relief & allows healing of damaged tissue

Question 16

Describe type 3 hypersensitivity reactions

Answer 16

Usually develops within 3-8hrs

Involves soluble immune complexes between IgG or IgM and antigens

Targets soluble antigens - foregoing (infection) or endogenous (self antigens)

Tissue damage caused by deposition of immune complexes in host tissues

Question 17

Key factors affecting immunocomplexes pathogenesis for type 3 hypersensitivity

Answer 17

Complex size (small & large size ICS cleared easier than intermediate size)

Host response (low affinity antibody or complement deficient)

Local tissue factors (haemodynamic factors, physiochemical factors)

All of these affect the persistence of immunocomplexes deposition in: joints, kidney, small vessels, skin etc.

Question 18

Give three examples of diseases caused by type 3 hypersensitivity reactions

Answer 18

• Rheumatoid arthritis (self-antigen) - antigen = Fc portion of IgG (75%), articular & extra-articular features, episodes of inflammation/ remission
• glomerulonephritis (infectious) - bacterial endocarditis, hepatitis B infection (immune complexes deposit)
• systemic lupus erythematosus, antigen = Ds- DNA, most prevalent immune complexes disease, female X9 (mouth, muscles, joints,psychological, face, pleura, pericardium, respiratory, renal, miscarriages)

Question 19

Describe type 4 hypersensitivity

Answer 19

Usually within 24-72hrs

Involves lymphocytes and macrophages (antibodies come later)

Different subtypes (clinical outcomes)

• contact hypersensitivity
• tuberculin hypersensitivity
• granulomatous hypersensitivity

Question 20

2 steps in type 4 hypersensitivity tissue destruction

Answer 20

1. Sensitisation phase: APCs: macrophages -> delayed typed hypersensitivity cells -> TH1 response (CD8)
2. Effector phase: TH1 products (IFN gamma, TNF beta, IL-2/3/8) -> macrophage activation (TNF receptor, O2 radicals, NO) -> granuloma

Question 21

3 diseases caused by type 4 hypersensitivity to exogenous antigens

Answer 21

• contact hypersensitivity (48-72hrs post exposure), epidermal reaction, needs endogenous proteins e.g. nickel, poison ivy, organic chemicals
• granulomatous hypersensitivity (21-48hrs post exposure), tissue damage e.g. TB, leprosy, schistosomiasis, sarcoidosis (when host can’t remove microbe)
• tuberculin hypersensitivity (48-72hrs) dermal reaction

Question 22

3 diseases caused by type 4 hypersensitivity to endogenous antigens

Answer 22

Pancreatic islet cells: insulin dependent diabetes mellitus

Thyroid gland: Hashimoto’s thyroiditis

Fc portion of IgG: Rheumatoid arthritis

Question 23

Type 3 & 4 hypersensitivity therapy

Answer 23

Anti-inflammatory drugs: non-steroidals, corticosteroids (oral prednisolone), second drugs as steroid sparing agents (<10mg oral steroids) e.g. azathioprine

Monoclonal antibodies: B cells and T cells, cytokines network, APCs