Autoimmunity

Question 1

Organ-specific autoimmune diseases

Answer 1

Graves disease – TSH receptors in thyroid

Type 1 Diabetes – insulin producing cells of the pancreas

Question 2

HLA B27-associated spondyloarthropathies - describe effects/associations

Answer 2

Ankylosing spondylitis, undifferentiated spondyloarthropathy, reactive arthritis, psoriatic arthritis, urethritis, iritis

Spectrum of severity and HLA B27 association

Associated with bowel inflammation

Question 3

Systemic autoimmune pathologies – Systemic lupus erythematosus (SLE) - describe

Answer 3

Multi-system disease

characterised by autoantibodies to nuclear antigens eg double stranded DNA

Relapse and remission

Question 4

What is autoimmunity?

Answer 4

What is autoimmunity?
The immune system has various regulatory controls to prevent it from attacking self proteins and cells.

Failure of these controls will result in immune attack of host components – known as autoimmunity.

Question 5

Central tolerance - define

Answer 5

Central tolerance – destroy self-reactive T or B cells before they enter the circulation

Question 6

Peripheral tolerance - define

Answer 6

Peripheral tolerance – destroy or control any self reactive T or B cells which do enter the circulation

Question 7

Explain the effect on B cells if immature

Answer 7

If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered

Question 8

T cell receptor and MHC binding - explain effects if too weak/strong

Answer 8

Need to select for T cell receptors which are capable of binding self MHC

BUT

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

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

Question 9

T cell selection in the thymus - is it useless?

Answer 9

Is it useless?
Doesn’t bind to any self-MHC at all
Death by neglect (apoptosis)

Question 10

T cell selection in the thymus - is it dangerous?

Answer 10

Is it dangerous?
Binds self MHC too strongly
Apoptosis triggered – negative selection

Question 11

T cell selection in the thymus - is it useful

Answer 11

Is it useful?
Binds self MHC weakly
Signal to survive – positive selection

Question 12

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

Answer 12

A specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissues

Question 13

AutoImmune REgulator (AIRE) - function

Answer 13

promotes self tolerance by allowing the thymic expression of genes from other tissues

Question 14

Mutations in AIRE result in

Answer 14

Mutations in AIRE result in multi-organ autoimmunity

Autoimmune Polyendocrinopathy Syndrome type 1

Question 15

Peripheral tolerance - Ignorance - describe

Answer 15

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

Immunologically privileged sites e.g. eye, brain

Question 16

Peripheral tolerance - anergy - describe

Answer 16

Naive T cells need costimulatory signals in order to become activated

Most cells lack costimulatory proteins and MHC class II

If a naive T cell sees it’s MHC/peptide ligand without appropriate costimulatory protein it becomes anergic – i.e. Less likely to be stimulated in future even if co-stimulation is then present

Question 17

Peripheral tolerance - regulation - desribe

Answer 17

A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells

Question 18

Treg express what and describe the effect of a mutation in this

Answer 18

Treg express transcription factor FOXP3

Mutation in FOXP3 leads to severe and fatal autoimmune disorder - Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.

Question 19

The major histocompatibility complex - characteristics

Answer 19

Each copy of chromosome 6 carries 3 different MHC class I and 3 different MHC class II genes

High levels of genetic variation (polymorphism)

MHC is associated with more disease than any other region of the genome

Question 20

What might trigger a breakdown of self tolerance?

Answer 20

Loss of/problem with regulatory cells
Release of sequestered antigen
Modification of self
Molecular mimicry

Question 21

Modification of self - Citrullination, describe how it is formed and what is it increased by

Answer 21

Citrullin is an amino acid, not coded for by DNA
Arginine can be converted to citrulline as a post-translational modification by peptidylarginine deiminase (PAD) enzymes
Citrullination may be increased by inflammation

Question 22

Explain molecular mimicry with an example

Answer 22

Disease is triggered by infection with Streptococcus pyogenes
Antibodies to strep cell wall antigens may crossreact with cardiac muscle

Question 23

Immune complexes in SLE and vasculitis - describe the steps that lead to them depositing

Answer 23

Autoantibodies to soluble antigens form immune complexes

Deposited in tissue e.g. blood vessels, joints, renal glomerulus

Can lead to activation of complement and phagocytic cells

Immune complexes depositing in kidney can lead to renal failure

Question 24

T Cells in autoimmune pathology - direct killing by?

Answer 24

Direct killing by CD8+ CTL

Question 25

T Cells in autoimmune pathology - self destruction by?

Answer 25

Self-destruction induced by cytokines such as TNFα

Question 26

T Cells in autoimmune pathology - role of macrophages

Answer 26

Recruitment and activation of macrophages leading to bystander tissue destruction

Question 27

T Cells in autoimmune pathology - role of CD4 cells

Answer 27

CD4 cells providing help for Ab and cytotoxicity

Question 28

Th17 - define

Answer 28

Th17 cells are helper T cells that produce the cytokine IL-17

Question 29

Th17 - characteristics

Answer 29

Highly inflammatory

Produce cytokines which are involved in the recruitment, migration and activation of immune cells

Question 30

Th17 - implicated in which diseases

Answer 30

Implicated in autoimmune diseases including spondyloarthropathy, MS and diabetes

Question 31

Describe therapeutic strategies for AI diseases

Answer 31

Anti-inflammatories: NSAID, corticosteroids
T & B cell depletion (RA: anti-CD4, anti-CD20)
Therapeutic antibodies (anti-TNF; anti-VLA-4 (blocks adhesion))
Antigen specific therapies, in development. Glatiramer acetate, increases T-regs.