L25: Autoimmunity

Question 1

Give examples of organ specific autoimmune diseases

Answer 1

→Graves disease (thyrotoxicosis)

→Type 1 diabetes

Question 2

What is Graves disease?

Answer 2

→Disease which manifests due to having stimulatory antibodies against thyroid-stimulating hormones (TSH) receptors in thyroid

→Antibodies cause overproduction of TSH

→symptoms: bulging red eyes

Question 3

Why do people with Graves have bulging eyes?

Answer 3

→fibroblasts in the eye may express TSH leading to inflammation

Question 4

Give examples of HLA B27-associated spondyloarthropathies

Answer 4

→reactive arthritis
→psoriatic arthritis
→bowel inflammation
→urehtritis

Question 5

What molecule is implicated in ankolysing spondylitis?

Answer 5

→HLA B27

Question 6

What is systemic lupus erythematosus (SLE) characterised by?

Answer 6

→by autoantibodies to nuclear antigens eg double stranded DNA
→relapse and remission

→Multi-system disease

Question 7

What is central tolerance?

Answer 7

→destroy self-reactive T or B cells before they enter the circulation

Question 8

What is peripheral tolerance?

Answer 8

→destroy or control any self reactive T or B cells which do enter the circulation (and have avoided the central tolerance)

Question 9

Describe the mechanism of central tolerance

Answer 9

→If immature B cells in bone marrow encounter antigen in a form which can cross-link their IgM, apoptosis is triggered

so any immature B cell that gives rise to autoantibody in the form of IgM is removed.

Question 10

What are rheumatoid factors?

Answer 10

→autoantibodies of IgM,IgG, IgA

Question 11

What mutations can result in multi-organ autoimmunity?

Answer 11

→mutations in AIRE

Question 12

What syndrome can be caused by mutations in AIRE?

Answer 12

→Autoimmune Polyendocrinopathy Syndrome type 1

Question 13

What is involved in peripheral tolerance?

Answer 13

→ignorance
→anergy
→regulation

Question 14

What is ignorance in peripheral tolerance?

Answer 14

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

→immune privilege sites

Question 15

What is involved in anergy of peripheral tolerance?

Answer 15

→If a naive T cell sees it’s MHC/peptide ligand without appropriate costimulatory protein it becomes anergic –

→Less likely to be stimulated in future even if co-stimulation is then present

Question 16

What is regulation in peripheral tolerance?

Answer 16

→Tregs inhibit other Tcells

→IL-10 and TGF-beta

Question 17

What transcription factor do Tregs express?

Answer 17

→FOXP3

Question 18

What can mutations in FOXP3 result in?

Answer 18

→Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome

→autoimmune disorder

Question 19

Which gender is SLE more common in?

Answer 19

→females

Question 20

Which gender is MS more common in?

Answer 20

→females

Question 21

Which gender is diabetes more common in?

Answer 21

→females

Question 22

Which gender is ankylosing spondylitis more common in?

Answer 22

→males

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

→Molecular mimicry

Question 24

What is citrullin?

Answer 24

→amino acid

→not coded for by DNA

Question 25

How is citrullin is genrated?

Answer 25

→Arginine can be converted to citrullin as a post-translational modification by peptidylarginine deiminase (PAD) enzymes

Question 26

What charge does arginine have?

Answer 26

→positive

Question 27

What charge does citrullin have?

Answer 27

→neutral →more susceptible to proteolytic degradation

Question 28

How is citrullin implicated in rheumatoid arthritis?

Answer 28

→Autoantibodies to citrullinated proteins

Question 29

How is rheumatic fever triggered?

Answer 29

→Antibodies to strep cell wall antigens may cross react with cardiac muscle

Question 30

Which pathogen is implicated in rheumatic fever?

Answer 30

→Streptococcus pyogenes

Question 31

Which Ab is pathogenic in arthritis?

Answer 31

→IgG

Question 32

Describe mechanism of Myasthenia Gravis

Answer 32

→Autoantibodies bind to acetylcholine receptor and block the ability of acetyl choline to bind →lead to receptor internalisation and degradation →Results in muscle weakness

Question 33

Describe the mechanism of SLE

Answer 33

→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 34

How do babies rid themselves of autoimmune Abs?

Answer 34

→plasmapheresis removes maternal anti-TSHR and antibodies

Question 35

Which antibody aids in autoimmune disease transfer to babies?

Answer 35

→IgG

Question 36

Examples of autoimmune disease transferred across placenta

Answer 36

→Myasthenia gravis →Graves →thrombocytoenic purpura

Question 37

Which cytokines induce self destruction of cytokines?

Answer 37

→TNF-alpha

Question 38

What is the role of CD4 cells in Tcell autoimmune pathology?

Answer 38

→providing help for Ab and cytotoxicity

Question 39

What is the role of CD8 cells in Tcell autoimmunity?

Answer 39

→Direct killing by CD8+ CTL

Question 40

Examples of Tcell implicate autoimmunity

Answer 40

→Multiple sclerosis →Insulin dependent diabetes mellitus

Question 41

Which cytokines do Th17 cells produce?

Answer 41

→IL-17

Question 42

Which autoimmune diseases is TH17 implicated in?

Answer 42

→spondyloarthropathy, →MS →diabetes

Question 43

What are the therapeutic strategies for autoimmune disease?

Answer 43

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

Question 44

What do B cells produce?

Answer 44

→Initially IgM →Under influence of T cells IgG or other isotopes of antibody (development of humoral response)