The role of regulatory B cell properties in multiple sclerosis - future therapeutic implications
by Roxanne Alice Bianca Pretzsch
Date of Examination:2024-09-24
Date of issue:2024-09-23
Advisor:Prof. Dr. Martin Weber
Referee:Prof. Dr. Ralf Dressel
Referee:Prof. Dr. Francesca Odoardi
Persistent Address:
http://dx.doi.org/10.53846/goediss-10760
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Description:Medical thesis - Roxanne Pretzsch
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Abstract
English
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which affects 2.8 million people worldwide. Most likely, B cells play an important role in its immunopathogenesis, however, they also possess important immune regulatory functions. This thesis consists of three independent projects which all aim to a better understanding of regulatory B cell properties in MS. In the first project, I found that the production of the anti-inflammatory cytokine interleukin 10 (IL-10) of human B cells is context-dependent and cannot be solely attributed to a specific B cell phenotype. Importantly, stimulation via the toll-like receptor 9 led to an overall enhanced level of cytokine production in predominantly antigen-experienced B cells, while specific stimulation via the B cell receptor led to a significant increase of IL-10 production in naïve B cells in contrast to antigen-experienced B cells. Interestingly, the production of IL-10 was preserved in patients with MS. These findings are important as they reveal the necessity of a function-related instead of cell-based approach for the promotion of immunoregulatory B cell properties as possible treatment strategy in patients with MS. The second project investigated the expression level of Bruton’s tyrosine kinase (BTK) in B cells isolated from patients with MS in comparison to healthy controls and found no significant difference. The inducibility of phosphorylated BTK, however, differed significantly regarding maturation and differentiation states of human B cells. Importantly, more maturated and differentiated B cells showed significantly higher levels of inducibility of phosphorylated BTK than naïve B cells. This might result in a differential effect of BTK inhibition in more maturated B cells than naïve ones. Furthermore, I found inhibitory, but reversible effects of BTK inhibition via evobrutinib on cytokine production in human B cells. Considering the current phase III studies of various BTK inhibitors in patients with MS, this study gives mechanistic insights into the role of BTK inhibition in human B cells. The third project evaluated the potential of incomplete Freund’s adjuvants (IFA) as an adjuvant in the myelin oligodendrocyte glycoprotein (MOG)-peptide experimental autoimmune encephalitis (EAE) model for the induction of IL-10 producing B cells. We found that IFA-induced MOG peptide EAE did not result in enhanced production of IL-10 in B cells in comparison to complete Freund’s adjuvants (CFA)-induced MOG peptide EAE. We concluded that a strong activation of the immune system as seen in CFA-MOG peptide EAE is necessary to induce IL-10 production in B cells in mice. Altogether, this thesis elucidates the complex regulation of IL-10 production in murine and human B cells.
Keywords: multiple sclerosis; regulatory B cell properties; Bruton's tyrosine kinase; evobrutinib; incomplete Freund's adjuvants
Schlagwörter: multiple sclerosis
