Autoimmunity

Question 1

What are two examples of organ- specific autoimmune diseases?

Answer 1

Graves’ disease - TSH receptors in thyroid

Type 1 diabetes - insulin producing cells of pancreas

Question 2

What is systemic lupus erythrematosus (SLE)?

Answer 2

Multi system disease

Characterised by autoantibodies to nuclear antigens

Eg. Double stranded DNA

Question 3

What is auto immunity?

Answer 3

Immune attack or host components

Question 4

What is immune tolerance?

Answer 4

Immune system does not attack self proteins or cells - its tolerant to them

Question 5

Define central tolerance

Answer 5

Destroy self reactive T cell or B cells before they enter the circulation

Question 6

Define peripheral tolerance

Answer 6

Destroy or control any self reactive T or B cells which do enter the circulation

Question 7

What is central tolerance in terms of B cells?

Answer 7

If immature B cells in bone marrow encounter antigen in a form which can cross link their igM apoptosis is triggered

Any immature B cell will undergo apoptosis

Question 8

What is central tolerance in term of T cells?

Answer 8

T cells recognise antigens that are presented to them by MHC - use be able to recognise foreign peptides that are bound to self-MHC

Question 9

What is the correlation between T cell receptor and MHC binding?

Answer 9

If self MHC binding is too weak, my not be enough to allow signalling when bound with foreign peptides

If self MHC binding is too strong, may allow signalling irrespective of whether self or foreign is bound

Question 10

When is a T cell determined as bing useless and what happens?

Answer 10

When the T cell doesn’t bind to any self-MHC at all

Death by neglect (apoptosis)

Question 11

When is a T cell determined to be dangerous (NEGATIVE SELECTION)?

Answer 11

Binds to self-MHC too strongly

Apoptosis triggered - negative selection of T cell in thymus

Question 12

When is a T cell determined as useful (POSITIVE SELECTION)?

Answer 12

Binds self MHC weakly

Signal to survive - positive selection

Question 13

How can a developing T cell in the thymus encounter MHC bearing peptides expressed in other parts of the body?

Answer 13

A. Specialised transcription factor allows thymidine expression of genes that are expressed in peripheral tissues

Autoimmune regulator (AIRE)

Question 14

What is the autoimmune regulator (AIRE)?

Answer 14

A Transcription factor that Promotes self tolerance by allowing the thymidine expression of gees from other tissues

Mutations in AIRE result in multi-organ autoimmunity

Question 15

What are the three areas of peripheral tolerance?

Answer 15

Ignorance

Anergy

Regulation

Question 16

What is the IGNORANCE of peripheral tolerance?

Answer 16

Antigen may be present in to low a concentration to reach the threshold. For T cell receptor triggering

Immunologically privalidged sites eg. Eye, brain - no T cells can enter this compartment

Question 17

What is the ANERGY of peripheral tolerance?

Answer 17

Naive T cells need costimulatory signals in order to become activated

Most cells lack costimulatory proteins and MHC class 2 - if a naive T cell sees it MHC peptide without appropriate costimulatory protein it becomes anergic

Question 18

What is the REGULATION of peripheral tolerance?

Answer 18

A subset of helper T cells known as Treg inhibit other T cells

Question 19

What is expressed by Treg cells?

Answer 19

Transcription factor FOXP3

Mutation in this gene leads to severe and fatal autoimmune disorder - IPEX syndrome

Crucial in the CD4 T cell function

Question 20

REVISION ACTIVITY

Answer 20

DRAW TREE DIAGRAM FROM LECTURE TO MAKE MINDMAP

Question 21

What genetic factors can increase the chance of autoimmune disease?

Answer 21

Endocrine factors - some conditions are more common in one gender than another

MHC - highly polymorphic

Question 22

What enviormental factors increase the risk of autoimmune disease?

Answer 22

Hygiene hypothesis - the environment no exposure to different pathogens - migration

Smoking and rheumatoid arthritis - study showed link

Question 23

What might trigger a breakdown of self-tolerance?

Answer 23

Loss of/problem with regulatory cells

Release of sequestered antigen

Modification of self proteins

Molecular mimicry - autoimmune response to molecule

Question 24

Describe what occurs during modification of self in citrullination

Answer 24

Citrullin is a amino acid not coded for by DNA

Arginine can be converted to citruline as a post-translational modification by PAD enzymes

Cirullinaation may be increased by inflammation

Autoantibodies to citrullinated proteins seen in rheumatoid arthritis - used for clinical diagnosis

Question 25

Describe what occurs during modification of self in rheumatic fever

Answer 25

Disease is triggered by infection with streptococcus pyogenes Antibodies to step cell wall antigens may cross react with cardiac muscle

Question 26

What occurs during Graves’ disease?

Answer 26

Auto-antibodies bind thyroid stimulating hormone (TSH) receptor and stimulate it, resulting in hyperthyroidism Disease can be transferred with igG antibodies

Question 27

What occurs during myasthenia gravis?

Answer 27

Autoantibodies find to acetylcholine receptor and block ability of acetyl choline to bind Lead to receptor internalisation and degradation Results in muscle weakness

Question 28

What occurs in SLE and vasculitis?

Answer 28

Autoantibodies to soluble antigens form immune complexes Deposited in tissue (eg. blood vessels, joints) Can lead to activation of compliance and phagocytosis cells Immune complexes depositing in kidney can lead to entail failure

Question 29

How can newborn infants be cured from Graves’ disease?

Answer 29

Mother with Graves’ disease has anti-TSHR antibodies Transfer of antibodies that mediate autoimmune diseases travel across placenta into fetus Newborn infant also suffers from Graves’ disease Plasmapheresis removed me tar all antibodies and cures the disease

Question 30

How do T cells play a role in autoimmune pathology?

Answer 30

Direct killing of cells by CD8 + CTL Self destruction induced by cytokines such as TNFalpha Recruitment and activtion of macrophages leading to bystander tissue destruction CD4 cells providing help for Ab and cytotoxicity Multiple sclerosis Insulin depends diabetes mellitus

Question 31

What are TH7 cells?

Answer 31

Helper T cells that produce the cytokine IL-17 Implicate in autoimmune diseases including spondyloarthropathy, MS and diabetes Highly inflammatory Produce cytokines which are involved in the recruitment, migration and activation of immune cells

Question 32

What are some therapeutic strategies to deal with autoimmune disease?

Answer 32

Anti inflammatories - NSAID, corticosteroids T and B cell depletion Therapeutic antibodies Antigen specific therapies, in development - increases Tregs