Biogen

Author Of 1 Presentation

Pathogenesis – Role of Glia Poster Presentation

P0941 - Anti-myelin oligodendrocyte glycoprotein autoantibodies trigger an Fc-Receptor and BTK-dependent proliferative response in microglia (ID 1382)

Speakers
Presentation Number
P0941
Presentation Topic
Pathogenesis – Role of Glia

Abstract

Background

Autoantibodies are a hallmark feature of numerous neurologic disorders, including multiple sclerosis (MS) and Neuromyelitis optica (NMO) even though the exact pathogenic role(s) and mechanism(s) associated with these autoantibodies are not fully understood. Within the CNS, antibodies can bind to both activating and inhibitory Fc-Receptors (FcRs) that are expressed on barrier-associated macrophages, microglia and other trafficking immune subsets. While well understood in peripheral myeloid cells, the pathophysiological significance of autoantibody-induced FcR signaling in microglia remains unknown, in part due to the lack of a robust in vivo model.

Objectives

Develop an in vivo model to assess Fc Receptor (FcR) and Bruton's tyrosine kinase (BTK) dependent antibody-induced microglia activation.

Methods

Anti-Myelin oligodendrocyte glycoprotein (MOG) monoclonal antibodies (mAbs) were generated and injected peripherally. Anti-MOG CNS target engagement and microglia activation were measured by immunohistochemistry and flow cytometry. Microglia transcriptomics were assessed by RNAseq.

Results

Here, we report that peripheral injection of anti-Myelin oligodendrocyte glycoprotein (MOG) monoclonal antibodies (mAbs) triggers a rapid and tightly regulated microglia Ki-67+ proliferative burst in both brain and spinal cord. This microglia activation was FcR-dependent as only Fc effector-competent but not Fc effectorless aglycosylated antibodies triggered the proliferative response. Accordingly, anti-MOG induced microglia proliferation was fully abrogated in FcR knockout mice. The anti-MOG driven microglia proliferative response was associated with a transient and tightly-regulated gene expression signature of largely proliferation-associated genes. Moreover, we determined that anti-MOG-induced microglia activation in vivo was dependent on BTK, a signaling node downstream of FcRs. Specifically, we found that anti-MOG microglia response was amplified in BTKe41K knock-in mice that express a constitutively active form of BTK and was blunted in mice treated with ibrutinib, a CNS penetrant small molecule BTK inhibitor.

Conclusions

Together, these results demonstrate the first report of an in vivo physiological function for FcR and BTK signaling in microglia and we propose that this model provides a novel tool to further dissect the roles of microglia-specific FcR and BTK driven responses to antibodies in CNS homeostasis and disease.

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