10. Immunological Tolerance and Autoimmune Disease

Question 1

What is the role of specific immunological tolerance?

Answer 1

Prevents undesirable immune response such as those to self-antigens

Question 2

What are the two types of tolerance?

Answer 2

Central - involves T and B cells in bone marrow/thymus - occurs as lymphocytes are developing
Peripheral - everywhere else - backs up central

Question 3

What is autoimmunity and autoantibodies? How is autoimmune disease different to these?

Answer 3

Autoimmunity - immune response of an organism against self tissues
Autoantibodies - T cells which can recognise self antigens
Autoimmune disease - negative symptoms arise, increase in differentiation and amount of autoantibody

Question 4

What cells does specific immunological tolerance mainly involve?

Answer 4

Lymphocytes (NOT macrophages or eosinophils)

Question 5

What is the most common way of maintaining tolerance?

Answer 5

Level of T cells - removing the self reactive helper T cells which cause the cascade

Question 6

What is the process of thymic education?

Answer 6

Two stages: Positive and negative

1st Round Positive: Select T cell that interact with thymus epithelial cells - T cells can recognise MHCI and MHCII at this point (CD8 & CD4) so are checked to make sure their TCR can recognise OWN MHC, if they can then signal sent into cell which prevents apoptosis

2nd Round Negative - Select T cells which don’t recognise all MHC - T cells interact with dendritic and macrophages, default pathway switched to cell survival, apoptosis induced in T cells which have high affinity for MHC, if TCR interacts with MHCI then CD4 switched off, if interacts with MHCII CD8 switched off

So they become single positive T cells which don’t recognise own antigens

Question 7

How does the expression of CD4/CD8 of T cells vary throughout the process of thymic education?

Answer 7

T cells start off double negative (CD4- CD8-), then go to double positive (CD4+ CD8+), then go to single positive

Question 8

How does the default pathway change from positive to negative selection?

Answer 8

In positive selection the default pathway is apoptosis whereas in negative selection the default pathway is cell survival

Question 9

Where does positive/negative selection of T cells occur? Describer the organ in question

Answer 9

In the thymus

Single organ in thoracic cavity overlapping the heart/lung, consists of lobules each with an outer cortex and inner medulla

Question 10

What is the name of T cells which develop in the thymus?

Answer 10

THYMOCYTES

Question 11

Where does positive/negative selection occur in the thymus?

Answer 11

Positive selection of cells occurs when binding to MHC cells in the cortex. Negative selection occurs when T cells migrate from cortex to medulla and interact with macrophages/dendritic cells (and die if they have affinity for own antigen)

Massive amounts of cell death goes on in the thymus.

Question 12

What is the AIRE? What is it responsible for?

Answer 12

The Autoimmune Regulator - central tolerance

Binds to DNA in thymus and switches on expression of most self-genes (but not all - peripheral tolerance also helps) so T cells can mature with all the self antigens present. IF a defective thymus/AIRE is present then people will have lots of auto reactive cells

Question 13

What are the two methods of central tolerance of B cells (badly worded but ygm)?

Answer 13

1. Clonal Deletion

2. Receptor editing - if receptor is against own body proteins then receptor may be replaced

Question 14

What is the role of peripheral tolerance? What are it’s processes?

Answer 14

Deals with self-reactive lymphocytes that escape central tolerance.

Uses clonal anergy and suppression

Question 15

Describe the process of clonal anergy in peripheral tolerance

Answer 15

Removes lymphocytes by inactivating them (but not killing them) when there is not appropriate co-stimulation

Question 16

Describe the process of suppression in peripheral tolerance

Answer 16

Suppress unwanted immune responses using two types of regulatory cells: Natural and induced. Natural regulatory cells always express FoxP3 and CD25 whereas induced express FoxP3 and CD25 when stimulated by self-antigen. These release IL-10/TGF-beta, cytotoxic granules or mop up IL-2 (so can’t be used by other cells)

Treg’s can also use CTLA-4 on their surface to grab CD80/CD86 and rip them off the APC (antigen presenting cell) preventing the APC from co-stimulating.

Question 17

How do autoimmune diseases occur?

Answer 17

Breakdown in immunological tolerance - may break down at birth or later on in life. Strong genetic component.

Question 18

How may autoimmune diseases will be split? Give examples of each type

Answer 18

1. Organ specific - antigen only found in one organ (e.g. multiple sclerosis)
2. Non-organ specific - antigen found throughout body (e.g. lupus, rheumatoid arthritis)

Even if non-organ specific some tissues may be affected more than others. For lupus immune complexes build and become trapped in small areas like skin and kidneys

Question 19

What area of the body does Graves and rheumatoid arthritis affect? How?

Answer 19

Graves - thymus - TSH receptor overstimulated - overproduction of thyroid hormones

Rheumatoid arthritis - IgG antibodies recognise the Fc chain of other IgG antibodies

Question 20

What percentage of individuals does autoimmune disease affect?

Answer 20

5%

Question 21

What is Aetiology?

Answer 21

The study of causation/origin

Question 22

What two things affect autoimmune disease?

Answer 22

Genes - MHC and CTLA-4 important - more common in females than males - if one twin has AID than 50% chance other will

Environment - infection (molecular mimicry - make antibody against pathogen which is similar to your own)

Question 23

How does rheumatic fever cause autoimmune disease?

Answer 23

Streptococcal M protein from fever has a similar sequence to heart muscle cells, so antibodies developed against it, but then also attack own heart muscle cells.

Fuck that