Anti-MOG autoantibodies trigger a tightly-controlled FcR- and BTK-dependent microglia proliferative response.

Autoantibodies are a hallmark feature of numerous neurologic disorders, including multiple sclerosis (MS) and neuromyelitis optica (NMO). While well understood in peripheral myeloid cells, the pathophysiological significance of autoantibody-induced Fc receptor (FcR) signaling in microglia remains unknown, in part due to the lack of a robust in vivo model. Here, we describe a novel in vivo experimental paradigm that allows for selective engagement of Fc receptors within the CNS by peripherally injecting anti-myelin oligodendrocyte glycoprotein (MOG) monoclonal antibodies (mAbs) in normal wild-type mice. MOG antigen-bound immunoglobulins were detected throughout the CNS and triggered a rapid and tightly regulated proliferative response in both brain and spinal cord microglia. This microglial response was abrogated when anti-MOG antibodies were deprived of Fc effector function or injected into FcR knockout mice and was associated with the downregulation of FcRs in microglia, but not peripheral myeloid cells, establishing that this response was dependent on central FcR engagement. Downstream of FcRs, Bruton's tyrosine kinase (BTK) was a required signaling node for this response, as microglia proliferation was respectively amplified and blunted in BTKE41K knock-in mice expressing a constitutively active form of BTK and in mice treated with a CNS penetrant small molecule inhibitor of BTK. Finally, this response was associated with transient and tightly regulated changes in gene expression predominantly related to cellular proliferation, which markedly differed from transcriptional programs typically associated with FcR engagement in peripheral myeloid cells. Together, these results establish an important physiological function for FcR and BTK signaling in microglia while providing a novel in vivo tool to further dissect the roles of microglia-specific FcR and BTK-driven responses to both pathogenic and therapeutic antibodies in CNS homeostasis and disease.