Pathomechanisms in demyelination and astrocytopathy: autoantibodies to AQP4, MOG, GFAP, GRP78 and beyond

Abstract

Purpose of reviewThe purpose of this review is to highlight the recently emerging pathomechanisms of diseases associated with autoantibodies to AQP4, MOG, GFAP, GRP78 and further novel targets. We discuss novel biomarkers and therapeutic approaches.Recent findingsAlthough complement-mediated cytotoxicity (CDC) is regarded as the major effector mechanism for AQP4-IgG in neuromyelitis optica spectrum disorders (NMOSD), recent studies helped to understand the relevance of complement-independent effector mechanisms. For MOG-IgG mediated diseases the role of CDC is less clear. MOG-IgG may trigger a tightly controlled FcR and BTK-driven microglia proliferative response in MOG-antibody-associated diseases. Differences of antibody-mediated tissue damage may reflect differential response to therapy. In addition, antibodies to GFAP, GRP78 and further novel targets have been implicated in demyelination and astrocytopathy.SummaryElucidating the whole spectrum of effector functions in diseases mediated by AQP4-IgG and MOG-IgG and understanding the role of additional novel autoantibodies involved in demyelination and astrocytopathy may guide further novel treatment decisions.

Anti-glial fibrillary acidic protein antibody and anti-aquaporin-4 antibody double-positive neuromyelitis optica spectrum disorder: A case report

“…The exact role of GFAP-IgG in NMOSD remains a topic of debate and ongoing research. Some studies argue that they are epiphenomenal and do not directly contribute to the disease, while others suggest their pathogenic involvement in its development or progression[ 13 ].…”

Case report: Granzyme-B expression by T- and B- cells during severe AQP4-positive Neuromyelitis Optica spectrum disorder with fatal venous thromboembolism outcome

“…However, resembling data from MS ( 6 , 11 , 20 ) and recent evidence obtained in NMOSD ( 4 ), it is possible to speculate that arising/continuous cytotoxic T- and B- subsets may impact the clinical severity (due to constant EDSS 8.0) and poor response to rituximab observed in our patient. Mechanistically, GzmB is known to cause damage to the blood-brain barrier ( 26 ), possibly allowing the entry of inflammatory subsets and AQP4-IgG into the CNS during NMOSD ( 27 , 28 ) (summarized in Figure 2B ).…”

“…(B) Th17 subsets (expressing IL-17), innate cells, and complement system may promote peripheral inflammation, eventually disrupting the blood-brain barrier (BBB) during AQP4-positive NMOSD pathogenesis ( 2 , 30 , 31 ). Considering well-established pathophysiological mechanisms during disease, approved monoclonal antibodies used to treat NMOSD are shown ( 28 ). We hypothesize that cytotoxic (CD8 + and CD4 + ) T- and B- subsets may also support BBB damage by expressing and releasing serine-protease granzyme-B (GzmB).…”