Autoimmunity

Question 1

What are some examples of some organ specific autoimmune diseases?

Answer 1

Graves disease – having antibodies against TSH receptors in thyroid. Antibodies cause the overproduction of thyroid hormones

Type 1 Diabetes – manifests from the production of insulin producing cells of the pancreas

Question 2

What is autoimmunity?

Answer 2

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 3

What is immune tolerance? What is tolerance broken down into?

Answer 3

Immune tolerance is knowing what to attack and what not to attack. Immune system does not attack self proteins or cells – it is tolerant to them.

Tolerance is broken down into:

1. Central tolerance – destroy self-reactive T or B cells before they enter the circulation
2. Peripheral tolerance – destroy or control any self reactive T or B cells which do enter the circulation

Question 4

What occurs with regards to B cells in central tolerance?

What about T cells?

Answer 4

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

T cells recognise antigens that are presented to them by MHC proteins. They are crucial for determining how a B cell develops.
T cells need to be able to recognise foreign peptides that are bound to self-MHC

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

T CELL SELECTION IN THE THYMUS:

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

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

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

just a note:
B cells produce IgM initially but only under the influence of T cells can they produce IgG or other isotypes etc

Question 5

What does Autoimmune Regulator (AIRE) do?

Answer 5

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

SO essentially AIRE allows a T cell to recognise any protein expressed in the body and to allow those that bind too strongly to be deleted.

Mutations in AIRE result in multi-organ autoimmunity

(Autoimmune Polyendocrinopathy Syndrome type 1)

Question 6

What happens to autoreactive T cells that survive central tolerance control?

Answer 6

Peripheral tolerance comes into play, which can be broken down into 3 areas:(in which peripheral tolerance can be maintained)

Ignorance

Anergy

Regulation

Question 7

What is involved in the 3 areas that peripheral tolerance can be broken down into?

Answer 7

1. IGNORANCE:
   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

2.ANERGY
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

3.REGULATION:
A subset of helper T cells known as Treg (T regulatory cells) inhibit other T cells

Question 8

What is a consequence of a mutation in FOXP3?

Answer 8

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

Question 9

What may trigger a breakdown of self tolerance?

Answer 9

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

Question 10

What do autoimmune mechanisms act through?

Answer 10

Autoimmune mechanisms can act through antibody or T cell responses (or a combination of both)