IL-2 Signaling and Polarization of Regulatory LBs: Involvement in Multiple Sclerosis
- Conditions
- Multiple Sclerosis
- Interventions
- Biological: Blood samplingBiological: CSF sampling
- Registration Number
- NCT04697407
- Lead Sponsor
- Rennes University Hospital
- Brief Summary
Multiple sclerosis (MS) has long been considered a disease mediated primarily by CD4+ T cells. However, recent clinical trials demonstrating significant efficacy of B-lymphocyte depletive therapies have highlighted the major role of this cell population in the development of MS. Among B-Ls, regulatory ("anti-inflammatory") B-Ls (Bregs) have protective functions in autoimmune diseases including MS, however the mechanisms that regulate the development and function of Bregs are poorly characterized. In our research laboratory (INSERM UMR1236), one of the lines of research focuses on the role of interleukin-2 (IL-2) signaling in the fate of the B lymphocyte. Numerous studies conducted in both human and mouse models of MS demonstrate the major role of this IL-2/IL2R signaling pathway in the pathogenesis of autoimmune diseases.
The hypothesis is that IL-2/IL2R pathway could contribute, by a mechanism intrinsic to B lymphocytes, to the development of autoimmune diseases such as MS.
While a defect in IL-2 signaling plays a critical role in the pathogenesis of MS, the impact of this defective signaling on regulatory B lymphocyte populations, which has been shown to play a protective role in the development of the disease, has never been studied. This study could help establish a new mechanism predisposing patients to develop the disease.
- Detailed Description
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is the leading cause of non-traumatic disability in young adults. Pathophysiopathologically, MS has long been considered a disease mediated primarily by CD4+ T cells. However, recent clinical trials demonstrating significant efficacy of B-lymphocyte (B-lymphocyte) depletive therapies have highlighted the major role of this cell population in the development of MS. Thus, it has been shown that these cells, in addition to their ability to secrete pathogenic antibodies, produce pro-inflammatory cytokines in this disease, and an imbalance between these potentially pathogenic pro-inflammatory B-Ls and regulatory ("anti-inflammatory") B-Ls (Bregs) has been suggested.
Bregs have protective functions in autoimmune diseases including MS, however the mechanisms that regulate the development and function of Bregs are poorly characterized. In our research laboratory (INSERM UMR1236), one of the lines of research focuses on the role of interleukin-2 (IL-2) signaling in the fate of the B lymphocyte. Our team has thus demonstrated that this cytokine, essentially produced by CD4+ T lymphocytes, triggers the differentiation of naïve human B cells in vitro into plasma cells. And, more recently, the analysis of the early response of BLs in mice disabled for the IL-2 receptor specifically in mature BLs (Il2rbfl/flCD19cre/+) suggests a role of IL-2 in the acquisition of suppressive/regulatory functions. In addition, numerous studies conducted in both human and mouse models of MS demonstrate the major role of this IL-2/IL2R signaling pathway in the pathogenesis of autoimmune diseases.
The hypothesis is that IL-2 signaling induces the polarization and/or regulatory function of Bregs in vivo and that deregulation of this IL-2/IL2R pathway could contribute, by a mechanism intrinsic to B lymphocytes, to the development of autoimmune diseases such as MS.
While a defect in IL-2 signaling plays a critical role in the pathogenesis of MS, the impact of this defective signaling on regulatory B lymphocyte populations, which has been shown to play a protective role in the development of the disease, has never been studied. This study could help establish a new mechanism predisposing patients to develop the disease.
The objective of this study is the analysis of the Bregs population in the blood of MS patients (at the diagnostic stage and in different forms) who are untreated compared to controls who are healthy in various aspects.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 95
Not provided
For all groups
- Pregnancy ;
- Breastfeeding ;
- Persons of full age subject to legal protection (safeguard of justice, curatorship, guardianship), persons deprived of liberty.
Healthy volunteers :
- Absence of autoimmune pathologies
- Without immunomodulating or immunosuppressive background treatment for at least 3 months;
- Without systemic corticosteroid treatment for at least 3 months.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description MS Patients Blood sampling Patients with MS at any stage and for any type of MS : MS at the onset of the disease, Clinically isolated syndrome (CIS), Relapsing-remitting MS (RRMS), Primary progressive MS (PPMS), Secondary progressive MS (SPMS) Healthy volunteers Blood sampling - non MS Patients Blood sampling Patients with a neurological and immunological disease except MS. non MS Patients CSF sampling Patients with a neurological and immunological disease except MS. MS Patients CSF sampling Patients with MS at any stage and for any type of MS : MS at the onset of the disease, Clinically isolated syndrome (CIS), Relapsing-remitting MS (RRMS), Primary progressive MS (PPMS), Secondary progressive MS (SPMS)
- Primary Outcome Measures
Name Time Method Frequency of Bregs in blood of MS patients 1 month Comparison of the frequency of Bregs in the blood of untreated MS patients (at the diagnostic stage and in different forms of MS: Relapsing-remitting (RR), Primary Progressive (PP) and Secondary Progressive (SP)) compared to healthy controls matched for age and gender.
- Secondary Outcome Measures
Name Time Method Frequency of Bregs in the CSF of MS patients 1 month Comparison of the frequency of Bregs in the CSF of early MS patients to the frequency of Bregs in the CSF of patients with other non-MS inflammatory neurological diseases.
Comparison of IL-2, soluble IL2RA, IL-10, IL-21 and IL-5 protein concentrations 1 month Comparison of IL-2, soluble IL2RA, IL-10, IL-21 and IL-5 protein concentrations in blood and/or CSF of MS patients to protein concentration of patients with inflammatory neurological non MS disease and to protein concentration in blood of healthy volunteers
Comparison of the concentrations in Igs 1 month Comparison of the concentrations in immunoglobulins in blood and/or CSF of MS patients to protein concentration of patients with inflammatory neurological non MS disease and to immunoglobulin concentration in blood of healthy volunteers
Trial Locations
- Locations (1)
CHU Rennes
🇫🇷Rennes, France