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Despite more than a decade of research, many aspects of variant Creutzfeldt-Jakob disease (vCJD) remain a mystery. Now research from Priority scientists at The Roslin Institute is helping us to understand why vCJD appears to mainly affect the young.

 

This fatal neurodegenerative disease, often referred to as the human form of bovine spongiform encephalopathy (BSE), known to most as ‘mad cow disease’, was first described in 1996. Proteins known as prions are believed to be the causative agent. A build-up of ‘misfolded’ prions in the brain causes the progressive death of neurons, for which there is no cure.
Once a misfolded prion enters a healthy person – potentially by eating infected food – it converts correctly-folded proteins into the disease-associated form. Nobody knows quite how this happens.
Variant CJD is rare. There have been 177 definite or probable cases reported in the UK to date (September 2014). Although research published recently in the British Medical Journal suggests that up to 493 people per million in the UK could have abnormal prions levels. It is by no means the only form of prion disease that affects people. Sporadic CJD (sCJD) is the most common, causing around 1-2 deaths per million people in the UK each year, generally in those over the age of 60. However, unlike sCJD, the majority of those affected by vCJD are young (~26 years old).
Initially, this age discrepancy was thought to be related to dietary habits, with young people more likely to be eating food with a high risk of contamination. No strong evidence for this was found (older people eat pies and burgers, too). Interestingly, having a healthy immune system seems to be central to vCJD development.

The immune system relay

In a new study, published in the Journal of General Virology, researchers at The Roslin Institute, which is strategically-funded by BBSRC, have shown that mice without a functional immune system have a lower susceptibility to prion disease. The misfolded prions appear to hijack the defence system that protects against bacterial and viral infection, using it to gain access to the nervous system and, ultimately, the brain.
Dr Neil Mabbott, one of the authors of the study, describes the movement of the prions as ‘a relay’, which begins in the small intestine.
In order to ascertain whether there are any pathogens in the small intestine and, if so, what response needs to be mounted, the body uses an ‘antigen sampling’ system (like a built-in dipstick) to see what is present. This system is the point of entry for the misfolded prions, allowing them to slip into the body’s lymphatic system. Once there, they attach to the surface of immune cells known as follicular dendritic cells (FDCs), and replicate by causing normal prion proteins to misfold into the disease-causing version.
Through mechanisms unknown, the misfolded prions escape the surface of the FDCs, moving into the nerves, and spread through the spinal cord and vagus nerve to the brain where the real damage begins.

Dropping the baton?

The new research studied two groups of mice: 32 between six and eight weeks of age and 29 around ninety weeks old (very old for a mouse). These two groups of mice were injected with prions from a cow known to have been infected with BSE.
Within a few weeks, prions had accumulated in the lymph nodes and spleen of the young mice, although they did not show any clinical signs of disease. Over a year later, the majority of those tested showed classic signs of prion neurodegeneration.
In contrast, none of the old mice developed any clinical disease, all died of natural age-related diseases. Only one of the 29 older aged mice showed any sign of having prions in its brain and this was only in a small, localised area. Given that most of these adult mice died before the time it takes to develop prion disease, it can’t be ruled out that they would not have developed an infection if they’d lived long enough.
Despite there being no evidence of prions in the elderly mice’s brains, there were detectable levels in their spleens, albeit at lower levels than in the younger mice. Dr Mabbott suggests that this may be because one of the relay steps is missing, or working less efficiently, in the older mice.
The findings build on previous work that showed how the microarchitecture of the mouse spleen – part of the antigen sampling system – deteriorates with age, as do the numbers of FDCs, leaving fewer for the prions to replicate on.
This work also provides a more general understanding of the effects of ageing on the immune system. Dr Mabbott has recently been awarded a grant from BBSRC to further investigate the mechanisms that cause the immune system to break down, which may ultimately help to improve people’s health as they get older.

Figure below shows the follicular dendritic cells (FDC) in the spleen which are important sites of prion replication in lymphoid tissues

A0014 follicular dendritic cells (FDC)
Figure below shows the boundary of the marginal zone in the spleens of young and aged mice.  Our data suggest that the aging related disturbances to the marginal zone impede the delivery of prions to follicular dendritic cells, reducing disease susceptibility in aged animals

A0014 follicular dendritic cells (FDC)

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