IL-2 Signaling and Polarization of Regulatory LBs: Involvement in Multiple Sclerosis (BREGS)

BREGS - IL-2 Signaling and Polarization of Regulatory LBs: Involvement in Multiple Sclerosis

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.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Biological: Blood sampling; Biological: CSF sampling

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.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Laure Michel, Md; Phone Number: +33 2.99.28.43.21; Email: laure.michel@chu-rennes.fr
• Study Contact Backup: Name: Marie-Laure Gervais, PhD; Phone Number: +33 2.99.28.25.91; Email: marie-laure.gervais@chu-rennes.fr

Study Locations

• France
  • Rennes, France
    • CHU Rennes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

About the patients,Inclusion Criteria :

• Patients at the onset of illness :
• With a strong suspicion of MS requiring an LP to confirm the diagnosis (suggestive neurological symptoms AND more than two typical lesions on MRI) ; OR
• MS patients (untreated RR, SP or PP) :
• With MS that meets the MacDonald 2017 criteria;
• With relapsing-remitting (RR), secondary-progressive (SP) or primary-progressive (PP) MS; OR
• Non-MS patients :
• Presenting a non MS neurological inflammatory disease (meningitis, neurolupus, neurosarcoidosis, autoimmune encephalitis, acute polyradiculoneuritis);
• Benefiting from an LP for diagnostic or monitoring purposes;

AND

• At least 18 years old;
• Without immunomodulating or immunosuppressive background treatment for at least 3 months;
• Without systemic corticosteroid treatment for at least 3 months;
• Having signed a free, informed and written consent.
• Affiliated with a social security system

About healthy volunteers, inclusion criteria :

• At least 18 years old;
• Having signed a free, informed and written consent.
• Affiliated with a social security system

Exclusion Criteria:

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Healthy volunteers	Biological: Blood sampling; In all groups, 80 ml of blood will be collected. For patients, this will be done during routine cares.
Experimental: MS Patients; 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)	Biological: Blood sampling; In all groups, 80 ml of blood will be collected. For patients, this will be done during routine cares.; Biological: CSF sampling; Only in both patients groups whom will have a CSF sampling in routine care, some CSF will be collected for the study in addition, with a limit of 5 ml for routine care and study.
Active Comparator: non MS Patients; Patients with a neurological and immunological disease except MS.	Biological: Blood sampling; In all groups, 80 ml of blood will be collected. For patients, this will be done during routine cares.; Biological: CSF sampling; Only in both patients groups whom will have a CSF sampling in routine care, some CSF will be collected for the study in addition, with a limit of 5 ml for routine care and study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Bregs in blood of MS patients	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.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Bregs in the CSF of MS patients	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.	1 month
Comparison of IL-2, soluble IL2RA, IL-10, IL-21 and IL-5 protein concentrations	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	1 month
Comparison of the concentrations in Igs	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	1 month

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Principal Investigator: Laure Michel, Md, Rennes University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2021
• Primary Completion (Actual): May 23, 2023
• Study Completion (Actual): May 23, 2023

Study Registration Dates

• First Submitted: January 4, 2021
• First Submitted That Met QC Criteria: January 4, 2021
• First Posted (Actual): January 6, 2021

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: May 23, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis
• Other Study ID Numbers: 35RC20_9867_BREGS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No