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Study in Nature points to a role for the adaptive immune system in Alzheimer’s disease

Wednesday 08 January 2020

On 8 January, Dr David Gate and colleagues published a paper in Nature, showing for the first time that clonally-expanded T cells are present in cerebrospinal fluid and brain samples from people with Alzheimer’s disease (AD). Our immune systems protect our bodies using two different approaches. The first approach, termed “innate immunity”, involves immune cells such as macrophages, scavenger cells that indiscriminately destroy a broad range of pathogens, such as bacteria. The second type of immune response, termed “adaptive immunity”, involves cells called “leukocytes”, immune footsoldiers which only recognise specific pathogens.  When T leukocytes, also known as “T cells”, encounter and recognise a specific pathogen (for example, a measles virus), they undergo clonal expansion, proliferating extensively to generate thousands or even millions of identical T cells that can track down and destroy the pathogen in question.  Unlike the innate immune system, the adaptive immune system can create long-lasting immunological memories. Immunological memory is at the heart of most vaccination strategies, which rely on the fact that the adaptive immune system “remembers” what specific pathogens look like, and can mount a protective response to them before they do any damage. 

Although many studies have now shown that the innate immune system goes off-track in AD, causing neuroinflammation, little is known about the adaptive immune response. Do T cells enter the brain and, if so, what do they do while they’re there? To answer this question, Dr Gate and colleagues first studied blood samples from groups of people with AD, mild cognitive impairment (MCI) or healthy controls. They observed that people with AD or MCI had a higher abundance of CD8+ TEMRA cells, which are also known as cytotoxic or “killer” T cells due to their ability to trigger the death cascade in target cells. In a separate cohort of individuals, the researchers assessed the relationship between cognition and the presence of different T cell subtypes.  They identified a negative correlation between TEMRA cells and cognition in people with AD & MCI: in other words, the presence of these cells is associated with cognitive impairment.  Interestingly, they noted that TEMRA cells from people with AD and MCI showed signs of antigenic stimulation, suggestive of prior activation in response to a pathogen.

Next, the researchers asked whether these CD8+ T cells were present in the brains and CSF of people with AD. Using a small number of post-mortem brain samples, they localised T cells to amyloid plaques and AD-affected areas of the hippocampus.  Importantly, using state-of-the art sequencing technology they showed that CSF from a small number of people with MCI or AD contained higher numbers of clonally-expanded CD8+ T cells compared to CSF from healthy individuals. As this was indicative of an adaptive immune response to a pathogen, the researchers then performed further studies to assess the antigen specificity of the CD8+ T cells in CSF from people with AD. Although there was some variation between individuals, there was a shared antigen motif for a protein that belongs to the Epstein-Barr virus (EBV), an extremely common virus that can cause infectious mononucleosis.

Together, these results are a first demonstration that there is an adaptive immune response in AD, associated with neurodegeneration and cognitive impairment – although researchers caution that there is no evidence of a causal link between EBV and AD, stating that several different antigens may be responsible for T cell activation in people with AD.  To confirm the results of this study, more large-scale investigations involving additional disease stages and longer follow-up durations are now required. Link to article: https://www.nature.com/articles/d41586-019-03892-8

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