Autoimmune Diseases

Question 1

What are self-MHC presented by in positive selection?

Answer 1

Cortical thymic epithelial cells (cTECs)

Question 2

What does APECED stand for?

Answer 2

Autoimmune polyendocrinopathy candidiasis ecotdermal dystrophy

Question 3

What does APS1 stand for?

Answer 3

Autoimmune polyendocrine syndrome type 1

Question 4

What 2/3 diseases do you need for APECED?

Answer 4

Candidiasis, Addison’s disease, autoimmune hypoparathyroidism

Question 5

What happens when central tolerance fails?

Answer 5

APECED

Question 6

How do nTregs work?

Answer 6

Inhibitory cytokines (IL10, TGFB and IL35).

Cytolysis using granzyme A or B to make a perforin pore.

Metabolic dsirubtion by deprivating cytokines.

Targeting DCs and inhibition their maturation and function.

Question 7

What causes IPEX?

Answer 7

Foxp3 mutation that is X-linked.

Means that there are no natural Treg cells.

Question 8

Can you cure APECED or IPEX with a bone marrow transplant?

Answer 8

APECED you cannot, IPEX you can.

Question 9

How do you keep autoimmunity in check?

Answer 9

Ignorance, anergy, negative co-stimulation, activation induced cell death and T regulatory cells.

Question 10

What is ignorance?

Answer 10

Immune priveleged sites do not spark immune responses, they have varriers that exclude naive T cells, and produce anti-inflammatory cytokines like TGFB. Lymphocytes which do eneter are killed by Fas.

Question 11

What is anergy?

Answer 11

Anergy is failure to proliferate or produce IL-2 following presentation of the cognate antigen.

IL-2 is the main cytokine they need to proliferate, it is when there is failure of co-stimulation.

Question 12

How is negative stimulation brought about?

Answer 12

CTLA4 is the major negative regulatory.

Initally intracellular and moves to cell surface after TCR signalling.

It binds all the CD80/86 - has a higher affinity than CD28 - prevents the co-stimulation.

Question 13

What is AICD?

Answer 13

Activation induced cell death. After the T cells have activated other cells or killed their targets they must be removed.

Apoptosis is controlled by the levels of pro- and anti-apoptotic proteins.

Also with Fas - they expressed this when activated, FasL+ then binds and activates the apoptosis pathway.

Question 14

What is autoimmune lyphoproliferative syndrome (ALPS) caused by?

Answer 14

Mutations in Fas or downstream pathway from there - caspases.

Question 15

How are self-reactive B cells removed in periphery?

Answer 15

Most self-reactive B cells need a T cell to be activated and mature in the germinal centres, is highly unlikely to also have a self reactibe T cell - most die by apoptosis.

Anergy occurs if there is a large amount of antigen present - IgM down regulated.

Fas ligand triggering also leads to death of B cells.

Question 16

How can self tolerance fail?

Answer 16

Genetics
Molecular mimicry
Epitope spreading
Bystander activation
Cryptic antigens

Question 17

What is molecular mimicry?

Answer 17

Steptococcus pyogenes infection can trigger cardiac pathology as they look similar to some cardiac antigens in the heart.

T cells can recognise heart-specifc proteins and strep.

Question 18

What is bystander activation?

Answer 18

Bystander T cells can be activated in the case of high cytokines/co-stimulatory molecule expression.

Some of these may be auto-reactive T cells, the inflammation caused by cytokines also temproarily suppresses Treg.

Question 19

What is Hashimoto’s Thyroiditis?

Answer 19

Autoreactive antibodies and T cells that attack the thyroid causing inflammation, enlargement of the thyroid and gradual destruction of follicles.

Genetics issue with HLA-DR5 and CTLA4 and is often misdiagnosed as depression.

Question 20

How to treat Hashimoto’s thyroiditis?

Answer 20

Blocking antibodies, TSH receptor, thyroid peroxidase or thyroglobulin, inadequate iodine uptake, thyroid hormone production and secretion.

Question 21

What is Grave’s disease?

Answer 21

Hyperthyroidism with the overproduction of thyroxine. Autoimmune B cells make antibodies against TSH receptor that also stimulates thyroid hormone production. Thyroid hormones shut down TSH production, but have no effect on autoantibody production, which continues to cause excesssive thyroid hormone production.

Question 22

What is Systemic Lupus Eryhtematosus?

Answer 22

Autoimmune disease that attacks many tissues. Autoanitbodies to DNA, histones, RBCs…

Symptoms are fever, arthritis, skin rash, pleurisy, kidney function.

Has immune complex formation and complement activation leading to vasculitis.

Question 23

How to treat lupus?

Answer 23

Steroids, symptomatic treatment, induce anergy - block T cell costimulation, shut off T cell activation with PD1 or CTLA4, suppressive cytokines or infuse Treg.

Question 24

What is Crohn’s Disease?

Answer 24

Chronic relapsing inflammatory bowel disease characterised by overwhelming inflammation in the ileum and colon.

Symptoms - diarrhoea, pain and damage to the epithelial lining - can result in surgery becoming necessary.

Question 25

What T cells are involved in maintenane of inflammation?

Answer 25

Th1 and Th17

Question 26

Treatment for Crohn’s disease?

Answer 26

Corticosteroids are used for flares - short-term. They reduce inflammation by inducing lymphocyte death and reducing T cell activation and cytokine production. BUT they suppress the entire immune system and have significant side effects.

Question 27

What does Anti-TNF do?

Answer 27

e.g. Infliximab

Induces and maintains remission as it prevents the release of TNF, the key pro-inflammatory cytokine, but this blocks all TNF so patients are at risk of infections.

Question 28

How does inhibition by S1P receptor agonists treat Crohn’s?

Answer 28

Blocks all T cells from leaving all lymph nodes. But you develop cancers and fatal cryptococcal meningitis.

e.g. Fingolimod

Question 29

How does inhibition by alpha4beta7 blockers help?

Answer 29

Blocks only T cells moving into the gut - fewever severe side effects but only works on 50% of patients, there are potentially other mechanisms for migration.

e.g. Vedolizumab