In this instalment of LIMS Explains, Associate Professor Orian tells us what we know about MS, the role platelets play in the early stages of the disease, and how this could lead to new, more effective treatments, and eventually even block progression.
What is Multiple Sclerosis – also known as MS?
MS is a common but poorly understood neurodegenerative condition which affects over 2.9 million individuals worldwide. Although its causes are still unclear, we do know that it’s an autoimmune disease where the immune system mistakenly attacks the brain and the spinal cord. This causes a wide range of physical and psychological symptoms such as blurred vision, loss of balance, incontinence, physical and mental fatigue, pain, and depression. The symptoms can have a serious impact on the quality of life for those living with MS, and can result in social isolation and loss of financial independence.
MS is the second most common neurological disorder which affects young adults. In more than 80 per cent of cases, the age of onset ranges from 18 – 35 years; of this group, it affects three times more women than men. However, the disease can occur at other ages as well. In a minority of cases, onset occurs in middle age – men and women are equally affected in this age group – and there are other extremely rare forms of the disease, which include paediatric MS where the age of onset is under 16 years.
The age of onset changes the patterns of the disease and how it manifests. Younger people with MS initially experience periods of neurological symptoms which are interrupted by periods of no symptoms – this is called “relapsing-remitting MS”. By middle age, this transitions to constant symptoms without remissions, called “progressive MS”. Later onset of MS is also characterized by this relentless progression, while those who have paediatric MS subsequently develop relapsing-remitting MS.
How is MS treated at the moment?
MS is extremely difficult to treat, as we don’t yet know its root cause. As well as this, it is difficult for researchers and clinicians to see the immune system’s attack on the whole brain and spinal cord and analyse the full extent of the damage.
Current treatments for MS focus on “immunomodulation” - that is, by moderating the immune system’s behaviour. There are about fifteen types of medication which help to ease symptoms by limiting the number of immune cells – the ‘B’ cells, ‘T’ cells, and other rapidly-dividing cells which usually help our bodies to fight infection when the immune system is working correctly. Immunomodulation medication can relieve symptoms and help improve quality of life for those living with MS, and can somewhat slow – but not stop or reverse – the disease’s progression. Some lifestyle changes, like specialised exercises, can also help relieve symptoms.
Epidemiologists have also identified certain risk factors for MS, which include the western diet, smoking, lack of exposure to sunlight, childhood obesity, and imbalances in gut bacteria. But in terms of better treatment and prevention there are still crucial questions for which we don’t yet have answers. What comes first, the brain tissue damage, or the autoimmune attack? What damage happens in the very early stages of MS, before a person seeks medical advice - and when they do receive a diagnosis, what is the prognosis, and at what speed will the condition progress? We hope that finding answers to these questions might lead to better and more detailed diagnosis, more effective treatments, and strategies to prevent its onset.
A key area of your research is examining the relationship between the onset of MS and unusual platelet behaviour, which sees these tiny cells leaking through the blood-brain barrier and invading the brain. First of all, some definitions: what are platelets, and what is the blood-brain barrier?
Platelets are tiny cells which are historically known for their ability to clot blood. However, they’re now also recognized as part of the array of specialized cells which make up the immune system.
The blood-brain barrier (BBB) is a highly organized structure made up of several layers of cells, membranes and spaces which protects the brain by separating it from the circulatory system that transports blood around our bodies. The way it works can be compared with how a moat isolates a castle from surrounding lands, protecting it from attack. The brain is a highly sensitive organ which needs a stable environment to stay healthy, which the blood-brain barrier helps provide by isolating the brain from the rest of the body and strictly controlling everything which tries to enter. Disruption to this structure can have highly detrimental effects on the brain environment’s stability, which in turn can change how the brain functions as well as make it vulnerable to attack - not only from infection-causing pathogens like bacteria, viruses or fungi, but also from our body’s own systems.
What relationship did you find between MS, the blood-brain barrier, and unusual platelet behaviour?
Our research showed how platelets play a key role in the immune attack, by being one of the earliest immune cells to become switched on in autoimmune disease. It is already known that B and T cells which cross the blood-brain barrier contribute to the neurological damage in MS; however, using models we observed how some platelets exhibit unusual behaviour and rapidly cross the blood-brain barrier well before B and T cells. The research also showed that once inside the brain tissue, these rogue platelets attach to neurons – the nerve cells which send signals around the body. This causes physiological stress to the neurons, and we observed that from very early in the disease process neurons began to die.
We believe that this is an early and critical step in the signalling process in MS which focuses self-reactive B and T cells to attack the brain and spinal cord. The details of how the different types of immune cells communicate are still poorly understood; but what we’ve seen in our research suggests that this association of platelets with neurons sends signals that trigger autoimmune processes in those who already have a highly reactive immune system. This then leads to immune cells’ repeated attacks on the brain, and the accumulation of dying neurons – both hallmarks of MS at a cellular level.
What do you hope the impact of your research will be?
The findings in our research have shed important, new light on some of the earliest events which cause the blood-brain barrier to break down in MS. In the past, the understanding of neurodegeneration in MS was that it began with the invasion and accumulation of B and T cells in the brain – and there was no hypothesis as to why these immune cells would cross the blood-brain barrier in the first place. Through our research, we now know that rogue platelets cross the blood-brain barrier and cause damage before B and T cells invade, which paves the way for scientists to investigate whether drugs that target platelets might be a more effective treatment for MS, and block this early damage.
Our research also opens new avenues of investigation to answer a more fundamental question: What causes platelets to go rogue in the first place? The literature is now rich in evidence that platelets play a role not only in MS, but across a broad range of autoimmune conditions and other diseases such as cancer. We hope that deepening our understanding of platelet immunology in health and disease will in the future bring benefits across multiple complex conditions.
--
Associate Professor Jacqueline Orian leads the Neurodegenerative Diseases Research Group at the La Trobe Institute for Molecular Science (LIMS) and the School of Agriculture, Biomedicine and Environment (SABE) at La Trobe University, and is the head of the LIMS Histology Facility.
From 2021 – 2024, her research “Blood platelets as a novel therapeutic target for MS” was supported by MS Australia. You can learn more about MS and access resources at MS Australia, and to find out more about World MS Day, visit worldmsday.org.
