009 – The role of autoreactive antibodies in initiation and propagation of central nervous system demyelinating disorders

19 Lug 2019
9:10 - 9:20
Auditorium
IMMUNOLOGY, ORAL

009 – The role of autoreactive antibodies in initiation and propagation of central nervous system demyelinating disorders

Marie Freier (1) – Silke Häusser-Kinzel (1) – Wolfgang Brück (1) – Martin Weber (1, 2)
Department of Neuropathology, University Medical Centre, Georg August University Gšttingen (1) – Department of Neurology, University Medical Centre, Georg August University Gšttingen (2)


Over the last decade, B cells were identified as important contributors in multiple sclerosis and related demyelinating disorders. The role of antibodies mainly consisted in amplifying ongoing demyelination by complement fixation. However, evidence condensed that autoreactive antibodies may likewise foster central nervous system (CNS) inflammation. Deciphering the precise function of CNS-specific antibodies would be of particular significance for a subgroup of patients with CNS demyelinating disorder, which show antibodies against myelin oligodendrocyte glycoprotein (MOG), an important component of the myelin sheath, in their blood. We hypothesize that MOG-reactive antibodies are capable of opsonizing endogenous MOG protein, thus triggering CNS inflammation and demyelination in these patients. In this regard, we showed that whole immunoglobulin G from patients with anti-MOG antibody-associated CNS demyelination promoted internalization of human MOG protein by murine bone marrow-derived macrophages in an Fc gamma receptor dependent manner. We next wanted to validate these preliminary results using human myeloid antigen-presenting cells instead of murine macrophages. For this purpose, we generated dendritic cells and macrophages by culturing CD14+ monocytes isolated from human peripheral blood mononuclear cells in the presence of distinct cytokines. Flow cytometry analysis of the generated cells revealed that macrophages highly expressed the activating Fc gamma receptors I and III as well as the inhibitory Fc gamma receptor II. By contrast, dendritic cells only expressed Fc gamma receptor II, suggesting that these cells may not be able to bind opsonized MOG protein. Furthermore, we could demonstrate that the generated antigen-presenting cells produced proinflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha. Both dendritic cells and macrophages were capable of internalizing soluble human MOG protein in a concentration-dependent manner. In ongoing experiments, we investigate the effect of whole immunoglobulin G from patients with anti-MOG antibody-associated CNS demyelination on phagocytosis of human MOG protein by myeloid antigen-presenting cells. If it can be confirmed that MOG-reactive antibodies indeed opsonize endogenous MOG protein and subsequently trigger CNS inflammation in anti-MOG antibody positive patients, pathogenic antibodies may be a new target for medications.