Cell stress response is individually tuned

Personalised immune response to stress antigens may explain the differences between patients in tumour control, transplant rejection and inflammation.

MICA, a stress antigen, is expressed on the surface of cells under stress from infection or early events of carcinogenesis (becoming a cancer cell) such as DNA damage, where it is recognised by particular immune cells. This can activate the immune cells, causing an immune response. Activation was expected to be ‘dose-dependent’ (ie the higher the levels of MICA, the stronger the immune response). However, researchers have now shown that this is not the case.

They found that the immune response is highly personalised, with some people responding to low levels of MICA and others responding to high levels.

The research

MICA is very polymorphic, which means that there are variations between individuals – much more so than other stress-related molecules. The research shows that these variations affect how much MICA is expressed.

Immune cells from different people were tested against 4 variants of MICA. All reacted differently.

This diversity is best explained by differences in ’tuning’, ie:

• Immune cells from different donors respond to different ranges of MICA levels
• To a lesser extent, some donors respond preferentially to specific variants, irrespective of expression levels

"The immune response is highly personalised; there are huge differences from person to person. There is no ‘normal’ range across the population. This discovery explains a lot of things – including why groups disagree on MICA’s role in stress response – but we still don’t know the molecular basis of personal thresholds,” says Dr Pierre Vantourout, the study’s co-lead author.

How

A likely explanation for this personalised immune response is that during their development, a person’s immune cells get used to the particular level of MICA expression there is at that time.

This level becomes fixed as being ‘normal’ for that person, with anything above sensed as abnormal. However, the failure of some people to detect a very high MICA level is probably because their immune cells are focused on the most common MICA variants, rather than the rare ones.

Implications

If we understand how MICA expression is regulated and how it affects immune responses it would help us understand:

• How cells respond to chemical and physical stress
• How cells respond to infection and inflammation
• Patients’ response to cancer
• Graft rejection
• Autoimmune diseases

Reference

S Shafi, P Vantourout et al, Sci Trans Med, 30 Nov 2011 (early online access)