Antibody-mediated recognition of central nervous system antigen as therapeutic target
by Jacqueline Thode
Date of Examination:2025-03-19
Date of issue:2025-04-04
Advisor:Prof. Dr. Martin Weber
Referee:Prof. Dr. Martin Weber
Referee:Prof. Dr. Jürgen Wienands
Persistent Address:
http://dx.doi.org/10.53846/goediss-11182
Files in this item
Name:Dissertation Jacqueline Thode.pdf
Size:6.56Mb
Format:PDF
This file will be freely accessible after 2026-03-18.
Abstract
English
The discovery of autoantibodies directed against myelin oligodendrocyte glycoprotein (MOG) in a proportion of patients diagnosed with multiple sclerosis (MS) led to the definition of MOG antibody-associated disease (MOGAD) as a separate disorder. Although the pathogenesis of this demyelinating disorder of the central nervous system (CNS) is not yet fully understood, it is becoming increasingly clear that the mechanisms involved are different from those of MS. The discovery of the CNS lymphatic network together with the detection of myelin in cervical lymph nodes (cLN) of MS patients and healthy controls led to the hypothesis that degraded myelin might be drained to cLN, where antigen presentation and activation of autoreactive CNS-specific T cells through myeloid cells takes place. Furthermore, in an animal model mimicking MOGAD, where mice contain MOG-specific T cells, the addition of anti-MOG antibodies triggers the development of inflammatory CNS demyelination probably caused by enhanced antigen recognition by myeloid cells through opsonization. To date, there is no approved therapeutic option for the treatment of MOGAD available. Emerging strat-egies are mainly focused on reducing anti-MOG antibodies in order to reduce their pathogenic function. However, to have a more lasting therapeutic effect, it might be important to interfere with pathogenic B cells before they differentiate into antibody-producing plasma cells. Furthermore, targeting antigen-presenting myeloid cells to reduce the activation of CNS-specific T cells might also be an interesting therapeutic approach. Hence, the inhibition of the Bruton´s tyrosine kinase (BTK) is an emerging treat-ment strategy that has been shown to fulfill a pleiotropic immunomodulatory effect on both antibody-producing B cells and antibody-recognizing myeloid cells. Based on this, its immunomodulatory effects were investigated as a therapeutic option for antibody-mediated diseases such as MOGAD. The modulatory effects of the BTK inhibitor evobrutinib was evaluated both in an in vivo setting with and without an inflammatory environment. The obtained results showed a general modulatory effect on BTK-expressing B cells by preventing their maturation while fostering regulatory properties. Furthermore, evobrutinib treatment limited the pro-inflammatory activity of monocytes and macrophages. These im-mune modulatory effects were also maintained in the inflammatory context. Furthermore, we were interested in understanding the underlying mechanisms of BTK inhibition. Anti-bodies enhance antigen internalization by myeloid cells in a Fc receptor (FcR)-dependent manner via a BTK-dependent signaling pathway. Therefore, the impact of various BTK inhibitors on the phenotype and function of human monocyte-derived macrophages were investigated following FcR-stimulation. Indeed, all BTK inhibitors reduced the production of the pro-inflammatory cytokines TNF-α and IL-6, while in our setting no effect could be observed on the expression of molecules associated with antigen presentation. In conjunction, our findings highlight BTK inhibitors as a promising therapeutic approach for MOGAD, especially by limiting IL-6 production while fostering regulatory properties in B cells.
Keywords: BTK inhibition; MOGAD
