Elucidating the beneficial and harmful elements of the BAFF/APRIL system in multiple sclerosis
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Multiple Sclerosis (MS) is a chronic neuroinflammatory disease of the brain and spinal cord that is a common cause of serious physical disability in young adults. This disease is considered an autoimmune condition as autoreactive lymphocytes mount aberrant responses against the central nervous system (CNS).
Current treatments focus on reducing immune cell activity and their entry into the CNS, but these therapies are often associated with side effects and are not suitable for all patients. None of the available treatments cure MS, and we still do not fully understand the exact nature of the immune anomaly leading to pathology. While remitting/relapsing MS can be reasonably controlled in some patients, progressive MS remains a very important clinical challenge resulting in disability and death with no effective treatment to date.
Recently, some contradicting results have emerged from clinical trials. Indeed, clinical trials using a depleting antibody directed at the molecule CD20 used as a specific agent depleting B-lymphocytes showed efficacy of this treatment in patients with MS. This success sparked the development of another antibody blocking the cytokine BAFF, which prevents BAFF-mediated B cell survival, with the expectation that this agent, which also reduced B cell numbers, would be as good as anti-CD20. To everyone’s surprise blocking BAFF in patients with MS made the disease worse, and forced clinical researchers to abandon this trial.
We believe we have an explanation for these conflicting results in the clinic, which possibly could be attributed to regulatory B cells or Bregs. Bregs are characterised by the production of IL-10 and are an immunosuppressive subset of B lymphocytes. Many studies have shown that Bregs are essential for the prevention of MS severity. We have data confirming that the BAFF system is important to maintain Bregs. This project aims to understand the role of BAFF and Bregs by using a murine model of MS called Experimental Autoimmune Encephalopathy (EAE).
This project will dissect the role of the cytokines BAFF/APRIL and their receptors in the development of MS. We will analyse how the genetic deficiency of BAFF, its related ligand APRIL or their respective receptors (BAFF-R, TACI, and BCMA) affects Breg numbers in the EAE model of MS. Bregs can be measured by in vitro activation followed by intracellular staining for IL-10 and flow cytometry analysis. Additionally, spinal chord pathology and inflammation will be studied using histology. We will also assess how the lack of a member from the BAFF/APRIL system affects the ratio of Bregs versus inflammatory cells such as effector Th17 T cells.
This work is likely to provide information on how we can better harness the regulatory function of Bregs to treat MS.
Professor Fabienne Mackay, Lab Head
Dr Beatriz Garcillan, Postdoctoral Researcher
This research project is available to PhD, Honours students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.
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