0526 - Self tolerance - CS

Question 1

Define self-tolerance

Answer 1

• The immune system’s capacity to prevent clonal expansion of self-reactive lymphocytes
• Function is to prevent immune system from attacking self antigens, as in autoimmune diseases
• Involves mechanisms such as deletion of lymphocytes that bind antigen early in development, ie while still in bone marrow (as antigens lymphocytes are exposed to at this stage are likely to be self)

Question 2

Where was the clonal selection theory formulated?

Answer 2

Melbourne. Woo!

Question 3

Explain clonal selection theory?

Answer 3

1. Lymphocytes bind antigen and produce antibody
2. Each lymphocyte can produce only one type of antibody
3. The repertoire of natural antibodies is generated by somatic mutation of the genes of antibody forming cells
4. Antigen selects for expansion of specific antibody within the natural antibody repertoire
5. The lymphocyte is the unit of selection. Thus, antigen binding leads to clonal expansion of antigen-specific lymphocytes (producing specific antibody)
6. Self tolerance is acquired

Question 4

Is self tolerance acquired or genetically encoded? Explain.

Answer 4

Acquired. It can’t be genetically encoded because our diverse repertoire of antibodies are generated in the bone marrow, not in the germ line. BDJ segments are present in the germ line but the recombination takes place in the lymphocytes

Question 5

How does the body achieve its diversity of antibodies?

Answer 5

Via V(D)J recombination. This occurs in the early stages of immunoglobulin and T cell receptor production, taking place in the bone marrow and thymus. V(D)J recombination nearly randomly combines Variable, Diverse and Joining gene segments in lymphocytes and because of its randomness in choosing different gene segments, is able to generate a huge repertoire of antibodies to match most antigens.

Question 6

Explain how clonal deletion occurs

Answer 6

Clonal deletion depends on timing of antigen exposure. If lymphocytes react to antigen early in development - while still in the primary lymphoid organs, there is a high likelihood that this antigen is self, so mechanisms are triggered that prevent this lymphocyte from undergoing clonal expansion (eg it may be deleted, made anergic or rearranged).

Question 7

What are three possible ways self-reactive lymphocytes can be eliminated in order to achieve self tolerance?

Answer 7

1. Deletion - by apoptosis
2. Anergy (cell downregulated and ‘paralysed’ but not deleted)
3. Receptor editing - RAG reactivation, Lc rearrangement

Question 8

Explain two mechanism that the body has for preventing activation of self-reactive lymphocytes once they enter the periphery

Answer 8

Eg 1. Two-signal model.

Multiple signals are required before a lymphocyte becomes activated and clonal expansion is triggered. Eg. T cells require activation of it’s receptor by an antigen (signal 1) as well as receive signal from an antigen presenting cell such as a dendritic cell (DC) (signal 2). Antigen presenting cells have mechanisms for recognising non-self antigen (eg recognising PAMPs and DAMPs) which enables them to provide signal 2 (or prevents signal 2 if DC does not recognise non-self patterns in the antigen).

Eg 2. Regulatory T cells

Make up about 10% of CD4+ T cells in the periphery. Function to maintain self tolerance to organ specific self antigens. Down regulate responses to innocuous environmental antigens, allergens and gut commensals. FoxP3 is a protein that acts as a master regulator (transcription factor) and plays a role in the development and function of regulatory T cells.

Question 9

What is a possible trigger that can over-ride peripheral tolerance and induce self-reactivity?

Answer 9

Infection