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Research suggests that the production of misshaped proteins ...

- like the ones associated with neurodegenerative diseases – can affect the immune system

The formation of misshaped proteins - a process suggested to be behind neurodegenerative diseases such as Parkinson’s and Alzheimer’s – can affect an important molecule of the immune system (MHC class I) says a group of Portuguese scientists in an article to be published on the 15th March issue of the "Journal of Immunology".

The researchers have been studying Hereditary Hemochromatosis (HH) – which is also associated with a misshaped/misfolded protein – and discovered that the anomalies in MHC class I molecules observed in some HH patients were linked to a mechanism involved in the elimination of aberrant misfolded proteins. The discovery helps to understand better HH, the most common genetic disease among people of North Europeans ancestry, but also raises important questions on possible immune defects and their role in the many disorders associated with anomalous protein production.

HH is caused by mutations in the HFE gene - which regulates the movement of iron into the cells – and is characterised by excessive absorbance and storage of this metal in the body tissues and organs that can lead, if not treated, to organ failure and even death. Additionally, some HH patients can show anomalies in the numbers of lymphocytes whose development is associated with MHC-I molecules (MHC-I) and which are generally crucial to a proper immune response. Recent research has also shown that HH patients can have abnormal MHC class I molecules what helps to explain the other immune defects observed in these patients.

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However, the connection between mutated HFE proteins and abnormal MHC-I molecules has remained a mystery until recent research on a virus of the herpes family suggested that a cellular mechanism used to get rid of misfolded proteins could also affect MHC class I. This observation has led Sergio F. de Almeida, Maria de Sousa and colleagues at Porto University and Lisbon University, Portugal to hypothesise that maybe cellular stress, induced by the production of mutated misfolded HFE proteins, could be behind the MHC-I abnormalities found in HH patients.

In fact, proteins after being produced in the nucleus are delivered to their target sites through a system of “channels” where they also undergo through constant quality controls that, if not passed, result in cellular stress and ultimately in the activation of mechanisms to eliminate the abnormal proteins. The unfolded protein response (UPR) is, like the name indicates, one of such mechanisms specifically responsible for the destruction of misshaped/misfolded proteins. And in the herpes virus study UPR also seemed to be able to affect MHC-I expression.

To test the hypothesis that UPR activation was behind the immune alterations observed in HH patients, de Almeida, de Sousa and colleagues used cells expressing MHC-I molecules but no HFE and genetically manipulated them into expressing normal or mutated (misfolded) HFE proteins. The cells were then analysed for MHC-I expression and UPR activation and compared with non-manipulated cells.

It was found that cells that expressed mutated misfolded HFE proteins showed higher levels of UPR and lower MHC-I expression (due to the production of aberrant MHC-I molecules) in comparison with cells with no HFE or cells with normal HFE proteins. Further supporting the link “misfolded HFE - UPR activation - aberrant MHC-I”, blood cells from HH patients were shown to have UPR activated. Finally, the team of researchers blocked UPR in cells with mutated HFE and this led to increased MHC-I expression further confirming the role of UPR activation behind the MHC-I problems. It was also shown that non-specific UPR activation equally affected MHC-I expression suggesting that this effect may occur in any disease where misfolded proteins are produced and is not specific to HFE

De Almeida, de Sousa and colleagues’ results establish for the first time a link between UPR activation in response to protein misfolding and abnormalities in the immune response. Their work helps the understanding of HH, a disease that affects as many as 1 in 200-300 individuals in the world, but also raises new questions for a range of other disorders, including neurodegenerative illnesses, such as Alzheimer’s, prion’s or Parkinson’s disease, and also type II diabetes and some cancers, all of which are known to be associated with misfolded proteins. The question now is to confirm and understand the possible significance of these alterations in other diseases.

Finally, de Almeida, de Sousa and colleagues’ work also might explain the reason why some viruses induce the production of aberrant misfolded proteins in their infected host as this will affect MHC class I molecules, which are crucial in the immune response against viral infections.

Piece researched and written by: Catarina Amorim (

Catarina Amorim | alfa
Further information:

Further reports about: Almeida HFE MHC MHC-I Sousa UPR abnormal misfolded mutated

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