Immunopathology

Question 1

What are the different types of hypersensitivity?

Answer 1

Type 1 - anaphylactic 
Type 2 - cytotoxic 
Type 3 - immune complexes
Type 4 - delayed-type hypersensitivity (DTH)
Type 5 - stimulatory hypersensitivity

Question 2

What is immunopathology?

Answer 2

The concept that immune responses can cause harm to the host and are central to many clinically important diseases

Question 3

Summarise immune reactants part of each type of hypersensitivity

Answer 3

Type 1 → IgE
Type 2 → IgG
Type 3 → IgG
Type 4 → Th1, Th2 or CTL

Question 4

What type of hypersensitivity involves only T cells?

Answer 4

4

Question 5

What is the effector mechanism in type 1?

Answer 5

Mast cell degranulation and release of granular mediators, such as histamine, as well as second phase lipids (PG and TX)

Question 6

What diseases is type I hypersensitivity associated with?

Answer 6

• hayfever
• eczema
• asthma
• gastroenteritis
• anaphylaxis

Question 7

Describe primary exposure to an allergen in T1?

Answer 7

• first exposure = activation of T cell response
• T cell response, through IL-4, drives IgE production in B cells
• IgE binds mast cells and is pollen specific
• causes release of mast cell contents

Question 8

What do the two phases of mast cells response depend on?

Answer 8

Whether the mediators are in pre-formed granules or are synthesized de novo

Question 9

Describe mast cell response w pre-formed granules

Answer 9

Histamine, Heparin –> toxic to parasites, increase vascular permeability and cause Smooth Muscle Contraction

Enzymes which remodel the connective tissue matrix

Question 10

Describe mast cell response when mediators are formed de novo

Answer 10

Cytokines (IL-4; stimulates Th2 cell response which skews an anti-parasitic response) (IL-3, IL-5 and GM-CSF; promotes eosinophil production and activation) (TNFa; promotes inflammation and activates endothelium)

Eosinophils secrete granule proteins (toxins and enzymes) as well as cytokines and leukotrienes to potentiate the response

CCL3 chemokine for monocyte, macrophage and neutrophil attraction

PGD2, PGE2 and LTB4, LTC4 - Lipids which increase vascular permeability, cause SM contraction and stimulates mucus secretion

PAF - lipid which attracts leukocytes, amplifies production of lipid mediators, and activates neutrophils, eosinophils and platelets

Question 11

What do IgE antibodies bind to on mast cells?

Answer 11

FcεRI

Question 12

Mnemonic for types of hypersensitivity

Answer 12

The hypersensitivity reactions can be memorized with the mnemonic ACID: A – Allergic/Anaphylactic/Atopic (Type I); C – Cytotoxic (Type II); I – Immune complex deposition (Type III); D – Delayed (Type IV)

Question 13

Clinical findings of T1

Answer 13

Immediate reaction: allergic reaction within minutes of contact with the antigen - (signifies the preformed antibody presence) - vasodilation and increased vascular permeability, with smooth muscle contraction (eg. Bronchi - respiratory distress)
Late-phase reaction: occurs hours after immediate reaction for a duration of 24–72 hours - where the endothelium expresses adhesion molecules and chemokines cause recruitment of cells - not blocked by anti-histamines.

Question 14

Treatment of T1

Answer 14

Prevention of Histamine effects - anti-H1

Targeting SM (e.g in anaphylaxis we give EPIPEN - adrenaline, to cause vasoconstriction and increase BP)

Suppress inflammation - corticosteroids reduce lipid mediator formation

Cromoglycate - mast cell stabiliser

Leukotriene receptor antagonists

Induce tolerance - Treg; desensitize individuals by injecting incremental doses of the allergen. It has been noted that nasal or oral application of allergen can induce tolerance through the mucosal immune network (either through inducing anergy in the antigen specific effector cells, or through upregulation of Treg cells specific to that antigen).

Question 15

Describe pathophysiology of T2 reactions

Answer 15

IgG (and IgM) bind to antigens on body cells and complement - leading to:
1 - opsonisation & phagocytosis
2 - complement activation
3 - antibody-dependent cell cytotoxicity (ADCC)

Question 16

What conditions can result from T2 hypersensitivity?

Answer 16

1 - transfusion reactions - ABO and Rhesus blood groups
2 - Haemolytic disease of the new-born
3 - hyper-acute allograft rejection (initiated by pre-existing humoral immunity)

Question 17

Describe haemolytic disease of newborn

Answer 17

here Rh -ve mother is sensitized by Rh+ baby at the time of birth when there is slight mixing of blood. If the mother becomes pregnant with a Rh+ fetus, IgG antibodies cross the placenta and damage fetal RBC. We can treat this anti-Rh antibodies to prevent sensitization against Rh+ pregnancies.

Question 18

Describe pathophysiology of T3

Answer 18

Antigen (e.g., the molecules of a drug in circulation) binds to IgG to form an immune complex = antigen-antibody complex

Harmless in circulation

Immune complexes are deposited in tissue, especially blood vessels → initiation of complement cascade → release of lysosomal enzymes from neutrophils → cell death → inflammation → vasculitis

Question 19

Example of local T3 reaction

Answer 19

Farmers Lung, where antigen is inhaled and the deposits are in the lung - antigens include spores and other biological antigens such as hay dust. This leads to a hypersensitivity pneumitis

Question 20

Example of diffuse (circulating) T3 reaction

Answer 20

Systemic lupus erythematosus - antibodies form against nuclear proteins such as laminin, histones and DNA, and lead to a number of consequences specific to sites of deposition; renal –> glomerulonephritis, vascular –> vasculitis, joints –> arthritis. Characteristic butterfly rash

Question 21

What is T4 hypersensitivity?

Answer 21

DELAYED TYPE HYPERSENSITIVITY ‘DTH’ (TYPE 4)

Question 22

Summarise T4 hypersensiivity

Answer 22

• Contact of antigen with presensitized T lymphocytes
• Presensitized CD4+ T cells recognize antigens on antigen-presenting cells → release of inflammatory cytokines
• Presensitized CD8+ T cells recognize antigens on somatic cells → cell-mediated cytotoxicity
  OR
  Sensitization: antigen penetrates the skin → uptake by Langerhans cell → migration to lymph nodes and formation of sensitized T lymphocytes
  Eruption: repeated contact with antigen → secretion of lymphokines and cytokines (e.g., IFNγ, TNF α) by presensitized T lymphocytes → macrophage activation and inflammatory reaction in the tissue

Question 23

What is allergic contact dermatitis?

Answer 23

T4 reaction - skin rash + blisters from environmental chemicals from poison ivy/oak, nickel or topical medication

Question 24

An infection by what microorganism can lead to T4 reaction?

Answer 24

TB Ag

Question 25

What is the Mantoux test?

Answer 25

a small amount of tuberculin is injected into the skin of a person previously exposed to Mycobacterium tuberculosis, mononuclear cells accumulate in the subcutaneous tissue along with abundance of CD4 Th1 cells leading to induration and redness developing at its peak in 24–72 hours.

Question 26

Describe type 5 hypersensitivity

Answer 26

Mediated by autoantibody acting as agonists on cell surface receptors
e.g. Graves’s Disease (hyperthyroidism).