(Auto)antibodies in infection and inflammation

Question 1

What happens to autoreactive B-cells in the bone marrow?

Answer 1

B-cells expressing autoreactive BCR are made anergic and commit apoptosis.

Question 2

Where to B-cells from the bone marrow mature?

Answer 2

The spleen

Question 3

What happens to B-cells in the germinal center?

Answer 3

1. Clonal expansion
2. Affinity maturation
3. diff to Memory B or Plasma cells

Question 4

What is often found in patients with autoimmune diseases?

Answer 4

Defects in early B-cell tolerance.

Question 5

What is the most direct route of T-helper induced autoimmune B-cells?

Answer 5

It is when the T-cell can recognise the same antigen as the B-cell.

Question 6

What is the concept of molecular mimicry in autoimmune B-cell activation?

Answer 6

Some pathogen peptides displayed on T-cells can give rise to B-cells which react with the pathogen peptide but also cross-react with self peptide. Those autoreactive B-cells are then selected and cause autoimmunity.

Question 7

What is class switching?

Answer 7

Class switching is when a B-cell switches the production of one type of antibody (mostly IgM) to another kind of antibody (IgA, IgG or IgE) depending on the situation.

Question 8

How may B-cell activation happen outside the germinal center?

Answer 8

Ectopic (out of place) lymphoid organs can form (synovial tissue in RA and kidney in SLE). They closely resemble germinal centers and are associated with the production of autoreactive antibodies.

Question 9

Name three ways of T-cell-dependent autoimmune B-cell activation

Answer 9

1. Direct pathway, in which T and B cells react to the same antigen
2. The mimicry pathway, in which a presented antigen by T-cells can give rise to self-antigen cross-reacting B-cells
3. In ectopic germinal

Question 10

Name three ways of T-cell-dependent autoimmune B-cell activation

Answer 10

1. Direct pathway, in which T and B cells react to the same antigen
2. The mimicry pathway, in which a presented antigen by T-cells can give rise to self-antigen cross-reacting B-cells
3. In (pathogenic) ectopic germinal centers, where autoimmune B-cells are produced.

Question 11

What is most often the target of autoantibodies and when do they get the chance to bind to their target?

Answer 11

They most often target common intracellular molecules. They usually bind to those molecule when a cell dies and its insides are spilled out into the interstitial space.

Question 12

What do autoantibodies in RA target?

Answer 12

One common example is Rheumatoid Factor (RF) which targets the Fc portion of an IgG antibody (which are abundantly found in the serum)

Question 13

What goes wrong with apoptosis in RA and SLE patients?

Answer 13

In RA and SLE, macrophages fail to clear the apoptotic mess effectively, letting spilled proteins from the intracellular space float freely, thus activating the immune system

Question 14

What two examples of modifications are induced in the nucleus during apoptosis and how are they relevant in RA and SLE?

Answer 14

Citrullination and acetylation of the histones, which can be recognized by RA and SLE autoreactive antibodies (along with several more nucleic proteins)

Question 15

What is cross-reactivity?

Answer 15

Cross-reactivity measures the extent to which different antigens appear similar to the immune system

Question 16

What are the two main hypotheses on the generation of autoantibodies?

Answer 16

1. Autoantibodies arise when failure to clear out debris after apoptosis leads to a self-immune reaction.
2. Cross-reactivity leads to B-cells “mistaking” self-antigen with harmful antigen, thus producing antibodies against this self-antigen.

Question 17

Why are TLR7 and TLR9 deficient mice more resistant to lupus-like symptoms?

Answer 17

TLR recognition of self-antigen is an important step in reducing B-cell tolerance.

Question 18

What is tolerance defined as?

Answer 18

Tolerance is when an immune cell has the capacity to not react to self-antigen presented to it.

Question 19

What is the hypothesis behind TLR/BCR signaling and escaping tolerance?

Answer 19

It is hypothesized that simultaneous activation of TLR and BCR in immature B-cells can lead to positive selection in the germinal center.

Question 20

Where are TLR7 and TLR9 found and what do they react to?

Answer 20

They are found in endosomes, in B-cells and other antigen-presenting cells, and they react to nuclear antigens (DNA, RNA etc).

Question 21

What is important to know about TLR and BCR signaling together?

Answer 21

They have a synergistic response.

Question 22

What cytokine is involved in T-cell-independent autoreactive B-cell activation?

Answer 22

B-cell activating factor (BAFF), which is involved in TLR activation in B-cells.

Question 23

What does BAFF do in B-cells?

Answer 23

BAFF is shown to activate TLR in B-cells, leading to somatic hypermutation and class-switching.

Question 24

How can TLR activation lead to somatic hypermutation in autoreactive B-cells?

Answer 24

Activation of TLR in B-cells can lead to enhanced antigen presentation and increase in surface expression of co-stimulatory molecules

Question 25

What kind of recognition pattern is needed to escape tolerance?

Answer 25

BCR and PRR (TLR etc) recognition of antigens, due to their synergistic nature.

Question 26

What are the most common systemic auto antibodies?

Answer 26

ANAs (Antinuclear antibodies) and ACPAs (anticitrullinated protein antibodies)

Question 27

How does autoantibody IgM lead to less production of autoantibody IgG?

Answer 27

auto IgM can activate the inhibitory LAIR1, which inhibits the immune effector response.

Question 28

Why do antibodies bind to the synovium in RA?

Answer 28

Because the synovium contains a lot of citrullinated molecules.

Question 29

What is the multiple-hit theory?

Answer 29

Genetic and environmental factors induce an initial break in tolerance, leading to the production of autoimmune antibodies. A second hit is often needed (apoptosis and spilling of nuclear enzymes) to induce pathogenesis

Question 30

What is the vicious cycle of chronic inflammation?

Answer 30

Autoantibodies bind to spilled nuclear protein, which induces an immune reaction. This reaction can potentially cause more tissue damage, leading to more spill

Question 31

What is the variable and what is the constant region of an antibody?

Answer 31

The Fab region is the variable one and the Fc region is the constant one.

Question 32

What is the direct and indirect pathway of antigen recognition?

Answer 32

1. Direct: antigen from a pathogen directly binds to PRR (TLR, NLR etc) and activates an immune reaction
2. Indirect: antibody binds to pathogen. Fc receptors then bind to the Fc domain on the pathogen-bound antibodies, where opsonization is facilitated

Question 33

What is the most abundant antibody during the whole course of an infection?

Answer 33

IgG

IgM is abundant in the early phase, but gets outnumbered by IgG once adaptive immunity kicks in

Question 34

What is a crucial element in IgG function?

Answer 34

Its hinge and bending flexibility, which enables it to bind to pathogens and effector molecules simultaneously

Question 35

What are the three functions of an antibody?

Answer 35

1. Neutralization: the antibody binds to a pathogen or toxin, blocking its structure and rendering it useless
2. Complement activation: antibodies can lead to the recruitment of the membrane attack complex
3. Opsonization: antibodies bind to a pathogen, exposing their Fc domain. The Fc domain binds to Fc receptors on macrophages, which enhances phagocytosis