“The brain and the immune system have a close dialogue, which is important not only for the defense of the brain, but also for its functioning. Over the last decade it has gradually become more and more evident.” Gabriela Constantin, professor of General Pathology and Immunology at the University of Verona and coordinator of Spoke 7 “Neuroimmunology and Neuroinflammation” of the Mnesys project for the study of the brain, explains it, illustrated at the First Neuroscience Forum, which opens today in Naples. “We are working precisely to understand the involvement of the immune system in neurodegenerative diseases, such as multiple sclerosis and Alzheimer’sthat is, all the pathologies for which inflammation of the brain has a role that has only recently been identified”, highlights the expert. An important line of research to shed light on diseases that are still ‘puzzle’.
I study
The role of T lymphocytes, fundamental immune cells, in the induction of multiple sclerosis is being investigated by the research ‘Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis’, conducted by the University of Tor Vergata in Rome and recently accepted for publication in ‘Frontiers in Immunology’. In this neurodegenerative autoimmune disease of the central nervous system, which affects approximately 2.8 million people worldwide, of which almost 130,000 in Italy, T lymphocytes are activated in an abnormal manner. They go beyond the autoimmune response and thus damage the tissues of the central nervous system, causing a disturbance in the activity of neuronal synapses and, therefore, brain dysfunction.
Drugs
“The study confirms that the worsening of the disease, from a mild phase with periods of remission to a progressive chronic phase, is accompanied by a functional alteration of the neurons at the synapse level, where contacts between neurons occur and transmission of the nervous impulse, caused precisely by the immune cells – clarifies Diego Centonze, professor of Neurology at the University of Rome Tor Vergata and director of the Complex Operational Unit of Neurology and of the Stroke Unit at the Irccs Neuromed of Pozzilli – We have also managed to highlight how this alteration is attenuated by treatment with Siponimid, a drug already in use in patients with multiple sclerosis, thus emphasizing the role of immune mechanisms in the induction of cognitive deficit in neuroinflammatory and neurodegenerative diseases”. The drug “traps lymphocytes in lymphoid organs and prevents their entry into the nervous system where they would cause damage, including to synapses.”
Another drug that significantly reduces the neurotoxic effects induced by inflammatory processes at the synapse level is Interleukin-9, as demonstrated by another Spoke 7 study, published in the ‘Journal of Neuroinflammation’ in May 2024. “Research proves that in multiple sclerosis the administration of this molecule produced by a particular category of cells of the immune system – continues Centonze – reduces the harmful inflammation characteristic of the disease induced by microglial cells, i.e. those cells that deal with the first and main immune defense active in the central nervous system, and improves disease symptoms in experimental models”.
Alzheimer’s disease
Not just multiple sclerosis. The immune system also plays a fundamental role in Alzheimer’s disease, as emerges from studies conducted by the University of Verona, not yet published. “Our research is demonstrating how the white blood cells that circulate naturally in the blood migrate into the brain and position themselves near the neurons, in the areas important for memory – says Constantin – We have highlighted that this phenomenon of leukocyte migration has a fundamental role in the disease Alzheimer’s and its blockade has a therapeutic effect, reducing brain inflammation and improving memory.” In in vitro studies “we have in fact detected how immune cells ‘attack’ neurons, inducing cellular damage and the alteration of neuronal circuits. This research indicates that white blood cells can induce direct damage to brain cells and contribute to the development of cognitive deficits”. An unexpected twist.
And again, within Spoke 7, predictive biomarkers of neurodegenerative diseases are being researched, as emerges from the studies led by Massimiliano Calabrese, professor of Neurology at the University of Verona, which will soon be published in the journal ‘Neurology Neuroimmunology & Neuroinflammation’ . Researchers have identified two proteins that may be associated with multiple sclerosis, present in the cerebrospinal fluid that surrounds the central nervous system and which allows the diffusion of nutrients and chemicals. “Osteopontin is a protein involved in bone remodeling with relevant pro-inflammatory actions, an indicator of the numerical and functional decline of neurons and their connections and of the progression of the disease in patients with multiple sclerosis in the early phase. Furthermore, the presence of a Another protein, parvalbumin, at the onset of the disease, has been identified as an indicator capable of anticipating the development of brain damage 4 years later. In particular, increased levels of parvalbumin in the cerebral fluid predicted the risk of developing atrophy brain, cognitive deficits, physical disability and chronic fatigue in patients with multiple sclerosis”, Calabrese comments.
The research, published in ‘Frontiers in Cellular Neuroscience’ in June 2023, focused on the role of ferroptosis, a new type of programmed cell death caused by iron accumulation, in the induction of epilepsy. “The increase in ferroptosis in the brain is related to a dysfunction of the immune system – highlights Enrico Cherubini, scientific director of the European Brain Research Institute Rita Levi–Montalcini (Ebri) and coordinator of the joint Ebri – Bambino Gesù pediatric hospital laboratory on the forms of drug-resistant epilepsy in children – and is characterized by an inflammatory reaction that could contribute to the onset of epilepsy. It has in fact been shown that ferroptosis is involved in this disease, particularly in drug-resistant forms, and understanding its mechanism. It therefore opens new avenues for the treatment of epilepsy.”
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