Lecture 20: immunology II

Question 1

What is an example of a disease that causes immune dysfunction?

Answer 1

allergy

Question 2

Which cells act in the allergy response?

Answer 2

histamine
leukotriene
prostaglandins
mast cells
and more

Question 3

What is the implication of prostaglandins being part of the allergic response?

Answer 3

there are some uses of NSAIDs in allergy treatment

Question 4

How do mast cells contribute to the allergic resposne?

Answer 4

release tryptases which degrade surrounding tissue

Question 5

What is the allergic response?

Answer 5

• first exposure causes APC (tissue macrophages and dendritic cells) to take some of the allergen and present to T cells and B cells in the lymph node
• T cells which recognise the fragment become a TH2 T cell which produces key cytokines like IL4 and IL14 which work with other T cells to convert B cells into plasma cells
• plasma cells will create a population of IgE antibodies specific to the allergen (each class of B cells produces a class of antibody)
• When body is re-exposed, the IgE produced by plasma cells bind to the substance and trigger the next level of allergy reaction
• basophils (circulatory) and mast cells (residing in tissue) produce histamine which is involved in vasodilation, and activation of nerves resulting in erythema, welts, itchiness.

Question 6

How can hypersensitivity be treated?

Answer 6

• reduce antibodies
• block receptors
• reduce T and B cell populations

Question 7

What are the drug treatments for hypersensitivity?

Answer 7

1. antihistamine

2. steroidal (creams/inhalers), avoidance of allergen, NSAIDs can provide some benefit

Question 8

How is severe allergy (anaphylaxis) treated?

Answer 8

with immediate injection of adrenaline, particularly if bronchial spasm occurs, via IM injection into the thigh

Question 9

What is omalizumab?

Answer 9

an anti-IgE monoclonal antibody used for severe asthma. Currently FDA, US and Europe approved

Question 10

What is the basic pathophysiology of MS?

Answer 10

clonal autoreative T cells are present which attacks the self and destroys myelinated cells in the CNS.

Question 11

What would brain tissue from an MS patient typically show?

Answer 11

the presence of dendritic, APC, macrophages, T cells and B cells

• normally, the brain should be free from these cells
• presence of these indicates this is what eats away at the healthy brain tissue
• the dendritic, antigen presenting cells and macrophages do most of the damage, but some B cells produce different classes of antibodies (IgG and IgM)

Question 12

What is leukocyte diapedesis?

Answer 12

-when immune cells circulating the blood move into the tissue

Question 13

What is the blood brain barrier composed of?

Answer 13

endothelial cells
astrocytes
pericytes and the basal membrane

Question 14

What causes leukocyte diapedesis into the bbb?

Answer 14

• normally leukocytes would simply flow on past
• in diseases like MS, the endothelium is activated resulting in expression of molecules like VCAM-1 and ICAM-1 (family of cellular adhesion molecules)
• VCAM interacts with VLF4 on immune cells which facilitates tethering and rolling
• immune cells reach the barrier and enter.

Question 15

What are potential targets to stop leukocyte diapedesis into the bbb?

Answer 15

• targeting the molecules involved in tethering

- targeting molecules that control the actual process

Question 16

What is Fingolimod?

Answer 16

recently approved by PHARMAC

-traps T cells to prevent their damage to brain tissue to delay the onset of MS attacks

Question 17

What is Natalizumab?

Answer 17

MAB which acts against cell adhesion molecule alpha-4 integrin.
-It recognises the alpha-4 which recognises the VCAM-1 to stop leukocyte diapedesis into the bbb

Question 18

How do Rutaximab and Alizuimab work?

Answer 18

Rutaximab targets CD20 while Alituzimab targets CD52.

These drugs bind to the proteins and will coat the outside of the cell with antibodies which reduce the function of these cells

They will also highlight those cells to the immune system so they are recognised by NK cells and other macrophages which can destroy them via antibody directed cell mediated cytotoxicity.

They also block migration of leukocyte moving and thethering and blocks function of certain antibodies

Question 19

How does MAB used as trojan horse work?

Answer 19

• antibodies are conjugated with either a toxin or another biomolecule which then induces toxicity
• antibodies then cytotoxose
• trojan horse MAB used more in cancer development

Question 20

What are the limitations with MAB therapy?

Answer 20

• can generate immune response to such a critical population of immune cells
• may leave patient with sporadic infections
• MABs very expensive so eligibility is also very strict
• Therapy is expensive due to monitoring, follow up, tests, screening for JC virus etc.