Antibodies in health and disease

Question 1

Which immunoglobulin is produced on primary infection?

Answer 1

first IgM, then IgG (or IgE/IgA).

Question 2

Which immunoglobulin is produced on second infection?

Answer 2

IgG.

Question 3

Why is IgG flexible and what does it depend on?

Answer 3

The IgG molecule is very flexible which is crucial for binding simultaneously to pathogens and to effector molecules and receptors of the immune system. The flexibility is dependent on the hinge structure which is different for every subclass of IgG.

Question 4

What is the function of IgG4?

Answer 4

IgG4 becomes functionally monovalent in the circulation, which means it can only bind with 1 arm to an antigen so there’s not a strong binding. It’s more an anti-inflammatory antibody that can interfere with bindings to other antibodies.

Question 5

How does IgA go from a dimeric antibody to an secretary antibody?

Answer 5

IgA is secreted by plasma cells as a dimeric antibody in the lamina propria. It is bound by the PIgR receptor on the epithelial cells and then transported to the lumen on the other side of the cell. There the receptor is cleaved and the IgA is bound to the mucus through the secretory piece (a part of the receptor that stays on).

Question 6

What is the function of IgA at the mucosa?

Answer 6

Immune exclusion (binding pathogens) and anti-inflammatory properties.

Question 7

What are the functions of antibodies?

Answer 7

The functions of antibodies are prevention of infections by neutralization, complement activation and opsonization.

Question 8

Which Fc receptor is inhibitory (in contrast to most others)?

Answer 8

The FcyRIIB receptor.

Question 9

To which antigens can you develop auto-antibodies?

Answer 9

You can develop auto-antibodies against nuclear antigens, cytoplasmic/mitochondrial antigens, modified proteins or extracellular proteins.

Question 10

What is the immune defect in systemic lupus erythematosus (SLE)?

Answer 10

In systemic lupus erythematosus (SLE) there is impaired clearance of apoptotic cells or NETs, so these cells will go into necrosis which will lead to autoantigens and the break of B-cell tolerance in germinal centers.

Question 11

What is the immune defect in rheumatoid arthritis (RA)?

Answer 11

In rheumatoid arthritis (RA) there is a chronic inflammation of the joints. RA patients have higher concentrations of RF-IgM and anti-CCP-IgG.
IgA and IgM are increased in RA, with the IgA auto-antibody complexes being taken up by neutrophils.
IgA auto-antibody complexes in RA also induce NETS, dependent on FcaRI.

Question 12

What effects does IgA induce on FcaRI activation?

Answer 12

IgA mediates FcaRI dependent neutrophil migration and tissue damage. IgA auto-antibody complexes in RA also induce NETS.

Question 13

How are monoclonal antibodies produced?

Answer 13

Antibodies can be derived from mouse B-cells immunized with antigens, which are fused with myeloma cells and the antigen-specific hybrid cells that derive are cloned

Question 14

What do therapeutic antibodies do and what is an example?

Answer 14

Target the environment or tumor, like anti-VEGF. VEGF is involved in angiogenesis, so you block the formation of blood vessels in the tumor.

Question 15

What is an example of an checkpoint inhibitor and what does it do?

Answer 15

blocking PD-L1 which allows T-cell killing of the tumor.

Question 16

What are humanized antibodies?

Answer 16

Patients have to be treated with antibodies with human constant regions and mouse variable regions (only the necessary parts).

Question 17

What effects do mAbs have?

Answer 17

mAbs have direct effects, like blocking growth factors, they have effects on complement-dependent cytotoxicity and Fc receptor mediated effector functions.

Question 18

How are NK cells activated?

Answer 18

NK cells have inhibitory and activating receptors. The inhibitory receptor binds MHC class I and this will overrule all other signals so the NK cell won’t be activated by the healthy cell. When there’s no MHC class I present the NK cell will start to produce cytokines and cytotoxic mediators to kill the cell. The NK cell can also get activated by binding stress-induced ligands.

Question 19

What does Rituximab do?

Answer 19

Rituximab kills the B-cells and so also depletes (auto)antibodies. This is standardly used in therapy in combination with chemotherapy.

Question 20

What does Cetuximab-IgA do?

Answer 20

Cetuximab-IgA can induce neutrophils to tear apart the tumor cell.

Question 21

How can you improve mAb efficiency?

Answer 21

To improve mAb efficiency you can change the Ab isotype or glycolysation (improves affinity for Fc receptors).
You can label Abs with toxins or radionuclides for more efficient tumor killing.

Question 22

What are BiTes and DARTs and what are their effects?

Answer 22

BiTes and DARTs are recombinant proteins (the variable regions of mAbs) which can induce T-cells as effector cells. The downside is that it has a short half-life.