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Laatste wijziging: 24 January 2022
The role of regulatory T-cells in B-cell autoreactivity in multiple sclerosis
Principal Investigator: Prof. Dr. Niels Hellings, Researcher: Dr. Tessa Dhaeze
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. MS is characterized by auto-reactive myelin-specific T-cells and autoantibodies. In addition, MS is characterized by impaired function of regulatory T-cells (Tregs). Due to the increased presence of auto-antibodies in MS the role of Tregs in the regulation of auto-reactive antibodies can be an important aspect in the pathogenesis of MS. Recent studies have identified a new type of Treg who expresses CXCR5, a chemokine receptor. This gives this Tregs the ability to migrate to the germinal centers where they may regulate the resulting antibody reaction. Furthermore, in a recent GWAS study, CXCR5 gene was identified to be strongly associated with MS. The ligand of CXCR5, CXCL13, has been found in the cerebrospinal fluid of RR-MS patients and in ectopic lymphoid follicular structures in the meninges of patients with SP-MS.
This project will further investigate the role of Tregs in the pathogenesis of MS and focus more specifically on the correlation with increased autoantibodies. To test the hypothesis that a Treg-deficiency may be linked to the B- cell autoreactivity, Treg function and B-cell autoreactivity will be correlated: measuring IgG levels against common autoantigens and using co-cultures. For this purpose blood of individuals with and without MS will be analyzed. Plasma will be used to analyze auto-antibodies and cell isolation will be used for the phenotyping of different types of T-cells and for the determination of B-cell maturation. In addition, the genetic effect of a SNP in CXCR5 on the function of the different Tregs will be examined. The liquor will be used for the phenotyping of the cells to determine the migration of Tregs and auto-antibodies.
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. MS is characterized by auto-reactive myelin-specific T-cells and auto-antibodies. In addition, MS is characterized by impaired function of regulatory T-cells (Tregs). Due to the increased presence of auto-antibodies in MS the role of Tregs in the regulation of auto-reactive antibodies can be an important aspect in the pathogenesis of MS. Recent studies have identified a new type of regulatory T-cells expressing CXCR5, a chemokine receptor. Upregulation of this receptor gives these Tregs the ability to migrate into the germinal centers where they affect the strength and the character of the resulting antibody response by limiting the number of follicular T-helper cells (TFH) and/or through direct inhibition of the selection of B-cells.
To investigate these regulatory T-cells in MS a vaccination study (Influenza and Hepatitis B) will be performed. The purpose of this study is to investigate the effect of a vaccine on the frequency of follicular regulatory T-cells and antibodies in the peripheral blood of healthy persons. A vaccine will lead to an immune response in which antibodies are produced against the vaccine. This could have an impact on the follicular regulatory T cells, which are mainly located in the secondary lymphoid organs where selection of antibody producing cells occurs. The objective is to investigate whether an immunological reaction that takes place at the level of the secondary lymphoid organs can be measured in the peripheral blood. In this way, the peripheral blood could be regarded as a reflection of the secondary lymphoid organs. This could result in the use of peripheral blood of MS patients to study the function and frequency of these follicular regulatory T-cells.
Dhaeze T, Peelen E, Hombrouck A, Peeters L, Van Wijmeersch B, Lemkens N, Lemkens P, Somers V, Lucas S, Broux B, Stinissen P, Hellings N. Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis. J Immunol. 2015;195(3):832-40.