Immune Tolerance/Auto-immunity

Question 1

Define tolerance.

Answer 1

The elimination or control of latent auto-reactivity (the control of the destructive power of the immune system).

Question 2

Define auto-immunity.

Answer 2

A failure of tolerance.

Question 3

Define deletion or negative selection.

Answer 3

Destroy auto-reactive cells at their source.

Question 4

Define regulation.

Answer 4

Inactivate or suppress auto-reactive cells.

Question 5

Define co-stimulation.

Answer 5

2 signals required for lymphocyte activation.

Question 6

What are privileged sites?

Answer 6

Locations hidden from immune system under normal circumstances.

Question 7

What do active tissue-defense mechanisms do?

Answer 7

Destroy invading auto-reactive T-cells.

Question 8

What are the 2 types of tolerance?

Answer 8

Central Tolerance: Destruction of auto-reactive cells at the source (negative selection or deletion)

Peripheral Tolerance: Inactivation, elimination, or control of auto-reactive cells after development

Question 9

Where is the Central tolerance located? Peripheral tolerance?

Answer 9

Primary lymphoid organs (thymus and Bone marrow); Periphery

Question 10

T-cells develop from which cell types and where?

Answer 10

From hematopoietic stem cells in the bone marrow.

Question 11

Where do the stem cells become T-cell precursors/rearrange their TCR genes and what are they called here?

Answer 11

In the thymus, called thymocytes.

Question 12

What percent of thymocytes survive to become T cells? Where do they die?

Answer 12

Only 1% survive, the other 99% die in the thymus.

Question 13

Why do thymocytes die?

Answer 13

Either their T-cell receptors are not useful (they do not recognize anything) or are harmful (auto-reactive).

Question 14

What are the limitations of Central tolerance?

Answer 14

• Self antigens must be expressed in the thymus or bone marrow (so what about tissue-specific antigens and pregnancy/puberty antigens?)
• Somatic mutation of Ig genes could also generate auto-reactive antibodies.

Question 15

Where would a tissue graft never be rejected and why?

Answer 15

Brain, eye or testis since these are “privileged sites” where immune responses are either impaired or suppressed.

Question 16

What are special characteristics of these sites?

Answer 16

Anatomical (fluid drainage); Cytokine expression (i.e. immunosuppression by TGF-beta); expression of Fas Ligand (causes apoptosis of invading T-cells)

Question 17

In co-stimulation, what does signal 1 refer to? Signal 2?

Answer 17

Signal 1: Antigen receptor signal

Signal 2: Costimulation signal

Question 18

Which signal is linked to infection?

Answer 18

Signal 2

Question 19

What happens when you have signal 1 and not signal 2?

Answer 19

Causes lymphocyte non-responsiveness (anergy) and/or apoptosis of T-cell.

Question 20

Where does Signal 2 come from in B-cells? In T-cells?

Answer 20

B cells – Helper T-cells

T cells – specialized antigen presenting cells (i.e. macrophages, dendritic cells, B cells)

Question 21

In Signal 1, what is involved with the T cell and the Antigen presenting cell?

Answer 21

T cell: CD4, TCR and CD3

Antigen Presenting Cell: MHC class II + peptide

Question 22

In Signal 2, what is involved with the T cell and the Antigen presenting cell?

Answer 22

T cell: CD28, CD40L

Antigen Presenting Cell: B7, CD40

Question 23

How is B7 up-regulated into the T cell? Why is it important?

Answer 23

Pathogen recognition process causes B7 up-regulation; it signals macrophages to produce more MHC and helps with binding.

Question 24

What are the only cell types that can provide co-stimulation to T-cells?

Answer 24

Dendritic cells, B-cells and macrophages.

Question 25

What is the only time that co-stimulation is effectively provided? During this time, what is induced at high expression?

Answer 25

During infections; B7 molecules

Question 26

Without co-stimulation, can T cells be activated properly?

Answer 26

No

Question 27

How do T-cells “help” B cells in providing signal 2?

Answer 27

T-cell surface molecule CD40. Ligand binds to CD40 on B cells.

Question 28

How do regulatory/suppressor cells suppress immune responses?

Answer 28

They secrete cytokines.

Question 29

TH1 cells secrete _____ that can promote or suppress disease.

Answer 29

IFN-gamma can promote.

Question 30

TH2 cells secrete _____ that can promote or suppress disease.IL-

Answer 30

IL-4 can suppress.

Question 31

Are autoimmune diseases often family linked?

Answer 31

Yes.

Question 32

What does incomplete penetrance mean?

Answer 32

Genetics confer susceptibility to disease, but disease will not always occur in susceptible individuals.

Question 33

Genetics collaborate with what to induce disease in susceptible individuals?

Answer 33

With the environment (e.g. infections may trigger an autoimmune disease).

Question 34

Autoimmune disease has a higher incidence in men or women?

Answer 34

Women.

Question 35

How do you identify alleles of genes that confer susceptibility to autoimmune disease?

Answer 35

Compare genomes of unaffected vs. infected individuals and find the differences (polymorphisms) in genomes of diseased individuals.

Question 36

Variations at how many loci collaborate to confer susceptibility to autoimmune (type I) diabetes?

Answer 36

> 10

Question 37

Most autoimmune diseases show linkage to what type of molecules?

Answer 37

MHC haplotypes (i.e. shows importance of T cells).

Question 38

What are the most common triggers initiating autoimmune diseases?

Answer 38

They are mostly unknown.

Question 39

What triggers Rheumatic fever?

Answer 39

Antibodies of Streptococcal antigens that cross-react with heart muscle.

Question 40

What triggers Reiter’s syndrome?

Answer 40

Arthritis following infection with Chlamydia or Yersinia.

Question 41

What triggers Ankylosing spondylitits and how can you treat it?

Answer 41

Associated with Kiebsiella pneumoniae, treat with a diet low in carbohydrate which starves the organism, producing a clinical improvement (also, can be treated with salazopyrine).