4.

How is the immune response to self-antigen regulated

Introduction
 Why do we need to regulate the immune response? → Autoimmune disease
 What response?
 B-cell mediated → antibody destruction and complex formation
 T-cell mediated → causing apoptosis, tissue damage, inflammation.
 Tolerance to self-antigen is acquire – not hard wired.

Central Tolerance → During lymphocyte development in the primary lymphoid organs.

T-cells
 Occurs by negative selection in the medulla of the thymus
 Exposes TCR on the developing thymocyte to Self MHC + self peptide → those that bind
too strongly are forced to undergo apoptosis.
 Mediated by the cells on the thymus, mainly the bone derived dendritic cells and
macrophages but also by medullary epithelial cells (mTECs).
 mTECs express AIRE → transcription factor → up-regulates many peripheral genes so
many more peptides available to test.
 Killing is believed to be carried out by 'veto cells' many of which are activated CD8+
lymphocytes.
 Dead thymocytes are cleared by macrophages.

B-cells
 In theory shouldn't need tolerance because must be activated by T-cells. This is the case for
some self antigens. (split tolerance)
 However, tolerising B-cells helps protect against a response mediated by a pathogen
expressing antigen mimicking the host.
 Occurs in bone marrow
 B-cells that react with membrane bound self antigen will eventually undergo apoptosis →
clonal deletion.
 This process is slow to give the B-cell a chance to rearrange its receptor chain to a non-
reactive form. During this process the expressed IgM is down-regulated.

 B-cells can also be induced to become anergic by large quantities of uncross-linked antigen
in solution, if it is above a critical threshold.
 This process down-regulates IgM on the surface as well as CD28. The cell can be
reactivated in response to CD40 co-stimulation with expressed IgD or by cytokines.
 Anergised B-cells have a shorter half-life in the circulation than active cells.
 It takes about 100-1000 times more antigen to tolerise a B-cell to self antigen than a T-cell.

Peripheral tolerance
 Acts a back up in case of a failure of central tolerance mechanisms
 Split tolerance → quite common.
 Ignorance → inaccessible area (eye, testes, brain), no MHC class I
 Anergy in T-cells → induced if a peptide is presented without co-stimulation. Cell remains
alive but inactive.
 Suppression by Tregs, specialised T cells expressing IL 2-R (CD25+). They bind to self-
antigen expressed on MHC and release IL4, IL10 and TGF β to down-regulate auto-reactive
T-cells. Tregs come in inducible or natural classes.
Conclusion
 Regulation of the immune response to self-antigen is absolutely essential. If the process fails
then autoimmune diseases result which are often chronic and debilitating.
 The numerous overlapping systems put in place to prevent autoimmunity indicate its
importance. For the most part the system works very well and the vast majority of self-
antigens do not generate an immune response.
 However, if something does go wrong we can regulate the response through use of drugs →
corticosteroids , antibodies against T-cell markers or receptors and antibodies against
cytokines have all been used to control to reaction of the immune response to self antigen
but they also suppress the rest of the immune system.
 Ideally we would like to specifically block the T-cell producing the response and leave the
rest intact. It is possible this could be achieved by co-receptor blockade, which tolerises the
T-cells and then induces Treg mediated suppression of immunity towards the self-antigen.