Multiple sclerosis enters a grey area

Studies of multiple sclerosis have long focused on the white matter of the brain. Insights into how immune cells target the brain’s grey matter now illuminate the stage of the disease at which neurodegeneration occurs.
Jenna L. Pappalardo is in the Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA.

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David A. Hafler is in the Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA, and at The Broad Institute of MIT and Harvard University, Cambridge, Massachusetts.

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Multiple sclerosis is an autoimmune disease with a genetic origin. The condition is characterized by an attack on the brain mediated by the immune system, leading to diverse symptoms caused by damage to neurons1. Animal models are available for the early stage of the disease, which is called relapsing–remitting multiple sclerosis. However, the progressive forms of multiple sclerosis associated with neurodegeneration and disability are comparatively under-studied, and what shapes the course of disease progression is largely unknown. Insights into the later stage of the condition could help the development of clinical approaches that tackle the underlying causes. Writing in Nature, Lodygin et al.2 shed light on the progressive stage of the disease. Using a rat model and blood samples from people who had multiple sclerosis, the authors identify the protein target of an immune cell that attacks the brain region called grey matter.

Multiple sclerosis is usually diagnosed at the relapsing–remitting stage, in which people have periods of symptoms and then remission when the symptoms subside. There is growing evidence that relapsing–remitting multiple sclerosis originates from inflammation that is driven by immune cells3. A hallmark of this disease stage is a targeted attack by immune cells, including T cells and macrophages, on the brain region called white matter, which contains parts of neurons known as axons or nerve fibres Fig. 1). Myelin, a mixture of lipids and proteins that covers and protects nerve cells in the white matter, is thought to be the T-cell target in this destructive process4. Much progress has been made in understanding how this process occurs57, particularly from studies of a mouse model called experimental autoimmune encephalomyelitis.

Figure 1 | Immune cells and multiple sclerosis. a, The myelin sheath (a mixture of lipids and proteins) covers and protects the axonal region of nerve cells in the part of the brain called white matter. Immune cells called T cells that recognize myelin have a key role in initiating an autoimmune destructive attack on myelin that is the hallmark of the early-stage disease — relapsing–remitting multiple sclerosis. b, Lodygin et al.2 shed light on later-stage, progressive multiple sclerosis, which is associated with disability. Progressive disease is characterized by destruction of the part of nerve cells that contains the nucleus and is located in the brain’s grey-matter region. Studying a rat model of the disease and blood samples from people who had multiple sclerosis, the authors report that progressive disease is characterized by the presence of T cells that recognize the protein β-synuclein, which is present in grey matter.

Relapsing–remitting multiple sclerosis often leads to the progressive stage of the disease. If this progression occurs, people stop experiencing remission periods and have a gradual loss of nerve-cell function that might be linked to destruction in the brain’s grey-matter region8,9; grey matter harbours the parts of nerve cells called cell bodies, which contain the nucleus. Immunosuppressive treatment for relapsing–remitting multiple sclerosis can help to decrease the chance of progressive disease developing10, but what causes this switch is not understood.

The destruction of material in white and grey matter in people with multiple sclerosis might arise from distinct inflammatory processes8. What drives immune-system cells to infiltrate and damage these different brain regions is therefore a key question. Lodygin and colleagues investigated this using a rat model to compare the migration into the brain of T cells that target myelin and those that recognize the protein β-synuclein, which is present in grey matter and is a possible target11 for autoimmune attack. It was thought that immune cells might be drawn to different brain regions on the basis of the cells’ expression of receptors for inflammatory chemokine molecules that can influence immune-cell movement.

The authors reveal that T-cell specificity for its target protein, rather than the expression of chemokine receptors on T cells, influences the location of these cells in the brain. Myelin-reactive T cells were found in myelin-rich white-matter regions of the rat brain and did not substantially infiltrate or damage the grey matter. By contrast, T cells that recognize β-synuclein caused damage mainly in the grey matter, where they released cytokines and induced tissue damage in neurons and neuron-supporting glial cells. The grey-matter damage was permanent, mirroring neurodegenerative processes that occur in multiple sclerosis and other neurodegenerative diseases, such as Parkinson’s disease, in which the grey matter is mainly affected.

By identifying T cells that are linked to damage in grey matter in a model of multiple sclerosis, Lodygin and colleagues’ work suggests a new way to study disease progression. This is particularly useful because the understanding of molecules targeted in grey matter has lagged behind knowledge of those targeted in white matter.

The authors assessed the levels of myelin-reactive and β-synuclein-reactive T cells in blood samples from people with multiple sclerosis and healthy controls. People who had relapsing–remitting multiple sclerosis had more myelin-reactive T cells than did the healthy controls, whereas people who had progressive multiple sclerosis had more β-synuclein-reactive T cells than did the healthy controls. The number of β-synuclein-reactive T cells was highest in people who had had the disease for a longer time. This suggests that β-synuclein might be a late-stage autoimmune target that arises through a process called epitope spreading, in which an initial immune response that targets a particular protein is followed by a diversified immune response that targets other proteins.

Variability is often observed in the presence and degree of white-matter and grey-matter destruction in relapsing–remitting and progressive multiple sclerosis, which might reflect the action of T cells of differing protein specificities. This issue could be examined by using magnetic resonance imaging to determine whether there is a correlation between the frequency of myelin-reactive compared with β-synuclein-reactive T cells and the location and extent of the brain damage observed. Moreover, analysing T cells linked to grey-matter destruction to determine their role and function might improve our understanding of progressive disease and enable the development of new monitoring and treatment strategies for multiple sclerosis.

The authors’ identification of β-synuclein-reactive T cells in people who have multiple sclerosis is particularly interesting because T cells that recognize another protein called α-synuclein have been found in blood samples from people with Parkinson’s disease12. Both α-synuclein and β-synuclein are present in junctions between nerve cells, called synapses, are broadly expressed throughout the nervous system, and fulfil similar functions of binding lipid membranes and regulating an intracellular transport process called endocytosis13. The emerging appreciation of the synuclein family of proteins as immune-cell targets suggests that grey-matter proteins might have a role in chronic, inflammatory neurodegenerative diseases, and that perhaps there is a connection between the development of Parkinson’s disease and that of multiple sclerosis.

Future studies into synuclein-reactive T cells — including an analysis of how they function and change in number after immune-targeted therapies, and an investigation into whether they have a role in other neurological diseases — might unveil previously unknown mechanisms that cause multiple sclerosis or other types of neurodegeneration. Moreover, such studies might aid the development of animal models for investigating progressive multiple sclerosis.

Nature 566, 465-466 (2019)

doi: 10.1038/d41586-019-00563-6


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Competing Financial Interests

D.A.H. has received funding from Bristol-Myers Squibb, Novartis and Genentech. D.A.H. has been a consultant for Compass Therapeutics, EMD Serono, Novartis Pharmaceuticals, Sanofi Genzyme and Versant Venture, Genentech and Proclara Bioscience.

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