Immunopathology

Question 1

What is auto-immunity?

Answer 1

The failure of an organism in recognizing its own constituent parts as self, leading to an immune response against its own cells and tissues

Question 2

True or false: auto-immune processes always cause disease

Answer 2

False; it is a physiological process with several functions:
1. Clearance of immune complexes and cell debris
2. Regulation of the immune response
3. Immune surveillande of dysplastic/neoplastic cells

Question 3

When is auto-immunity pathological?

Answer 3

When disease arises due to autoreactivity

Question 4

What is M. Graves?

Answer 4

A hypertyrhoid auto-immune disease, caused by activating antibodies against the TSH-receptor

Question 5

What is M. Hashimoto?

Answer 5

A hypothyroid auto-immune disease, caused by antibodies and autoreactive T-cells against thyroid antigens

Question 6

What are Witebsky’s postulates?

Answer 6

A set of postulates that describes the characteristics of auto-immune disease:
-Presence of auto-antibodies and/or autoreactive T-cells that are:
1. Disease-associated
2. Specific for the affected organ
3. Present at the site of tissue damage
4. Reflective of disease activity (higher level = more activity)
5. Cause for disease when transferred to a second host
6. Cause for disease when induced by immunsation
-Reduction of auto-immune response leads to improvement

Question 7

True or false: auto-immune diseases always follow Witebsky’s postulates

Answer 7

True; auto-immune diseases always follow SOME of Witebsky’s postulates, but not always all of them

Question 8

What is the prevalence of auto-immune disease in (Western) society?

Answer 8

~3%

Question 9

What are the peaks of onset of auto-immune disease? (2)

Answer 9

1. Puberty
2. Retirement

Question 10

Auto-immune disease is more common in [men/women]. Why?

Answer 10

Women; sex hormones are thought to strengthen immune response

Question 11

What is the effect of pregnancy on auto-immune disease?

Answer 11

Pregancy shifts the Th1/Th2 balance & immune balance -> can aggravate or subdue auto-immune systems during pregnancy

Question 12

Which auto-immune disease characteristically is (far) more present in men?

Answer 12

Ankylosing spondylitis (M. Bechterew)

Question 13

What are the thymic/central tolerance mechanisms for T-cells? (2)

Answer 13

1. Positive/negative selection
2. Receptor editing

Question 14

What are the peripherhal tolerance mechanisms for T-cells? (4)

Answer 14

1. Segregation -> tissue layers that prevent T-cells from reaching certain sites (such as immune-privileged sites)
2. Anergy
3. Apoptosis
4. Suppression by Tregs

Question 15

What is anergy? How is it induced?

Answer 15

A state of non-reaction caused by stimulation of the TCR in absence of co-stimulatory/cytokine signals

Question 16

What is an example of an immune-privileged site?

Answer 16

Eye

Question 17

What are the three main mechanisms that can lead to breakdown of tolerance?

Answer 17

1. Inappropriate access of auto-antigens to APC and/or expression of MHC/co-stimulation
2. Loss of T-reg cells
3. Molecular mimicry

Question 18

How can inappropriate access of APC’s and T-cells to auto-antigens come to be? (2)

Answer 18

1. Infection
2. Tissue damage

Question 19

What can cause a loss of Treg cells?

Answer 19

1. Cytotoxic drugs
2. FoxP3 mutation

Question 20

Why does a FoxP3 mutation increase susceptibility to auto-immune disease?

Answer 20

This is an important transcription factor in the development of Treg cells

Question 21

What is molecular mimicry?

Answer 21

Cross-reactivity of antibodies or T-cells that were originally aimed at a pathogen

Question 22

What is an important example of molecular mimicry?

Answer 22

Guillain-Barré

Question 23

What is the most important genetic factor that modulates the (susceptibility to) auto-immune disease?

Answer 23

HLA-serotype -> some serotypes are associated with a higher or lower chance of certain auto-immune disease

Question 24

In addition to the HLA-type, which genetic factors have an influence on (susceptibility to) auto-immune disease?

Answer 24

Genes involved in the immune system, such as AIRE (negative selection), FoxP3 (Treg development), Fas (defective apoptosis of auto-reactive cells), C1q (defective clearance of immune complexes and apoptotic cells)

Question 25

How does a mutation in AIRE cause auto-immune disease?

Answer 25

Decreased expression of self-antigens in the thymus -> defective negative selection of auto-reactive T-cells

Question 26

How does a mutation in CTLA4 cause auto-immune disease?

Answer 26

Failure of T-cell anergy and reduced activation threshold of auto-reactive T-cells

Question 27

How does a mutation in FoxP3 cause auto-immune disease?

Answer 27

Decreased function of Treg-cells

Question 28

How does a mutation in FAS cause auto-immune disease?

Answer 28

Failure of apoptotic death of auto-reactive cells

Question 29

How does a mutation in C1q cause auto-immune disease?

Answer 29

Defective clearance of immune complexes and apoptotic cells

Question 30

Which four types of auto-reactions can be identified?

Answer 30

1. Type I: degranulation of mast cells with (auto-reactive) IgE
2. Type II: presence of antibodies against cell-surface or matrix antigens
3. Type III: deposition of immune-complexes in tissue
4. Type IV: T-cell mediated disease

Question 31

What are the two main strategies to treat auto-immune disease? (2)

Answer 31

1. Replacement of function of damages organs
2. Immunosuppression/immunomodulation

Question 32

What drugs are available to suppress T-cells? (6)

Answer 32

1. Corticosteroids
2. Azathioprine
3. Cyclophosphamide
4. Cyclosporine
5. Alemtuzumab (anti-CD52)
6. Influximab/adalimumab (anti-TNFα)

Question 33

What drug is often used to suppress B-cells?

Answer 33

Rituximab (anti-CD20)

Question 34

Which strategies can be used to suppress/modulate auto-antibodies? (2)

Answer 34

1. IVIG
2. Plasmapheresis