Investigating how peripheral myelin-specific antibodies contribute to central nervous system demyelination – implications for future therapeutical approaches
by Marie Freier
Date of Examination:2022-06-20
Date of issue:2022-07-14
Advisor:Prof. Dr. Martin Weber
Referee:Prof. Dr. Martin Weber
Referee:Prof. Dr. Holger Reichardt
Files in this item
This file will be freely accessible after 2023-06-30.
EnglishThe discovery of peripheral autoantibodies against myelin oligodendrocyte glycoprotein (MOG) allowed the delineation of MOG antibody-associated disease (MOGAD) from other central nervous system (CNS) demyelinating disorders, such as multiple sclerosis. Although the mechanisms and site of disease initiation are unknown in MOGAD, rising evidence indicates that peripheral MOG-specific antibodies may harbor pathogenic functions. In this regard, anti-MOG antibody-mediated opsonization of endogenous MOG was previously suggested to trigger inflammatory CNS demyelination in mice. However, it remains elusive if this can also occur in MOGAD patients. Hence, the first project of the present study focused on investigating the opsonizing capacity of MOG-reactive antibodies isolated from MOGAD patients. Using an in vitro setting with human myeloid antigen-presenting cells, the study on hand demonstrated that patient-derived anti-MOG antibodies opsonized soluble and membrane-bound MOG, thus facilitating antigen recognition and uptake by in vitro differentiated antigen-presenting cells presumable via Fc gamma receptor III. These findings support the hypothesis that anti-MOG antibody-mediated opsonization represents a disease-triggering mechanism in MOGAD patients. Based on this, targeting peripheral anti-MOG antibodies and their effector mechanisms may be an efficient strategy for the treatment of MOGAD. Since Bruton’s tyrosine kinase (BTK) is crucially involved in Fc gamma receptor signaling in myeloid cells, its inhibition may prevent activation of myeloid cells induced by anti-MOG antibody-mediated opsonization. Thus, the second project of the study addressed the therapeutic potential of BTK inhibitor evobrutinib in anti-MOG antibody-triggered CNS demyelination. In a set of in vivo experiments, it was first observed that evobrutinib did not affect the phenotype of myeloid cells in the absence of inflammation. In anti-MOG antibody-induced CNS inflammation however, evobrutinib was found to prevent the clinical manifestation of experimental autoimmune encephalomyelitis (EAE) by significantly reducing inflammatory CNS demyelination in the spinal cord. Analysis of immune cells in secondary lymphoid organs showed that BTK inhibition diminished the expression of Fc gamma receptors on monocytes and macrophages, but did not alter the phenotype of T cells in the chronic phase of EAE. Taken together, these results indicate that BTK inhibition by evobrutinib can be a promising strategy to counteract anti-MOG antibody-mediated CNS demyelination. However, the underlying immunological mechanisms need to be further investigated.
Keywords: anti-MOG antibodies; MOGAD; BTK