Laboratory of Neuroimmunology

Primarily devoted to the research in Multiple Sclerosis (MS), our Laboratory studies the interaction between the immune response - with a focus on CD8+ T cells - and environmental factors. In particular, we have investigated the mechanism by which Epstein-Barr virus (EBV) might be implicated in the pathogenesis of MS. We have found that EBV-specific CD8+ T cells are dysregulated in the blood and the cerebrospinal fluid (CSF) of MS patients. In order to examine whether EBV-specific CD8+ T cells would cross-react with central nervous system (CNS) cells, we have established a program of human induced pluripotent stem cells (hiPSC). We have thus set up an in vitro human model allowing to study, in a fully autologous way, the interaction between peripheral immune cells and CNS cells. Thanks to this potent tool, several opportunities opened to us and are leading to fruitful collaborations.

We also have a long-standing interest in the immunopathogenesis of progressive multifocal leukoencephalopathy (PML), a disease mediated by the polyomavirus JC (JCV). Our hiPSC technology offers a beautiful opportunity to modelize this complex disease in vitro. Indeed, up to now, there is no animal models of PML and in vitro cultures were done on tumoral CNS cells, thus poorly reflecting the real brain environment.  

The Laboratory of neuroimmunology run by Prof Renaud Du Pasquier is linked to other laboratories of research in immunology, in particular the Laboratory of Cellular Immunology and AIDS Immunopathology (Prof. Giuseppe Pantaleo) and the Laboratory of experimental neuroimmunology (Prof Caroline Pot). Lab’s main research topic is the study of the immune- and neuro-pathogenesis of demyelinating illnesses, including:

1. Multiple Sclerosis (MS)
2. Progressive multifocal encephalopathy (PML).

1. Multiple Sclerosis (MS)

MS is a disease that encompasses two phases: the inflammatory and the neuro-degenerative ones. Whereas major improvements to tame the inflammatory phase have been achieved thanks to the famous disease-modifying therapies (DMTs), MS remains without cure. We believe that only a full understanding of the immunopathogenesis of MS will allow to find a curative (or preventive) treatment. This theme is explored through the following lines of research:

• Growing evidences strongly suggest that Epstein-Barr virus (EBV) is a key environmental factor in MS. However, how precisely EBV would contribute to the pathogenesis of MS remains unknown. Over the past years, we have shown that there was a dysregulated EBV-specific CD8+ T cell response in patients with MS, in particular at the early stages of the disease, suggesting that EBV may be instrumental in triggering MS. We also found that B lymphocytes, which are the targets of EBV, exhibit an increased expression of HLA-DR and CD40 ex-vivo.
• This set of studies has contributed to better explain the immunopathogenesis of MS. However, we are left with a crucial question: does this dysregulated immunity plays a role in the pathogenesis of MS or it is just a surrogate marker of EBV infection? To deepen our understanding of the link between the peripheral immunity and the CNS, we decided to establish the technique of hiPSC. We have set up protocols to differentiate hiPSCs into neurons, astrocytes, oligodendrocytes (unpublished) and brain endothelial-like cells (Figure 1).

This program opens major perspectives. Indeed, it will be possible to:

• study the effect of the inflammatory environment
• determine whether CNS auto-antigens would be recognized by peripheral auto-reactive T cells and secreted auto-antibodies
• develop a highly-sophisticated pre-clinical in vitro method to screen candidate neuroprotective compounds
• tackle the question of molecular mimicry between EBV and CNS antigens leading to CNS-autoreactive immune response in MS 

2. Progressive multifocal encephalopathy (PML)

JC virus (JCV)  is the causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system (CNS) that results in the widespread formation of lesions across the brain parenchyma ¹². JCV is an opportunistic virus that resides in a latent state in the kidneys of more than half of the adult population ¹³. However, in rare cases of severe immune suppression, the virus establishes infection in the brain where it infects oligodendrocytes and astrocytes. The infection of oligodendrocytes is lytic and results in demyelination, the hallmark of the disease ¹⁴. Since there exist no antiviral therapies against JCV, the only way to halt disease progression is to reconstitute an adequate immune response, which is often impossible ¹⁵.

To better understand the pathogenesis of PML, our lab is involved in the following lines of research:

• Improving our understanding on immunomodulatory treatment associated with an increase in PML incidence in MS patients (e.g. natalizumab, fingolimod, dimethyfumarate)^16-20
• Collecting detailed clinical and biological samples from patient suffering from PML in collaboration with Dr Raphaël Bernard-Valnet (CORPUS cohort)²¹
• Developing a unique human-based in vitro model of JCV infection to assess the role of CNS cells in JCV propagation based on CNS cells derived from human induced pluripotent stem cells (hiPSCs). Indeed, because of its human selective nature and tissue specificity, there is a lack of proper animal models and culture systems to study JCV infection. Being able to infect human iPSC-derived glial cells with JCV will be a tremendous tool, a model which could further be used to pave the way to the development of new early biomarkers and new therapeutic agents able to block JC virus propagation.