MOGAD patient autoantibodies induce complement, phagocytosis, and cellular cytotoxicity
Soumya S. Yandamuri, Beata Filipek, Abeer H. Obaid, Nikhil Lele, Joshua M. Thurman, Naila Makhani, Richard J. Nowak, Yong Guo, Claudia F. Lucchinetti, Eoin P. Flanagan, Erin E. Longbrake, Kevin C. O’Connor
Soumya S. Yandamuri, Beata Filipek, Abeer H. Obaid, Nikhil Lele, Joshua M. Thurman, Naila Makhani, Richard J. Nowak, Yong Guo, Claudia F. Lucchinetti, Eoin P. Flanagan, Erin E. Longbrake, Kevin C. O’Connor
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Research Article Neuroscience

MOGAD patient autoantibodies induce complement, phagocytosis, and cellular cytotoxicity

Abstract

Myelin oligodendrocyte glycoprotein (MOG) antibody–associated disease (MOGAD) is an inflammatory demyelinating CNS condition characterized by the presence of MOG autoantibodies. We sought to investigate whether human MOG autoantibodies are capable of mediating damage to MOG-expressing cells through multiple mechanisms. We developed high-throughput assays to measure complement activity (CA), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC) of live MOG-expressing cells. MOGAD patient sera effectively mediate all of these effector functions. Our collective analyses reveal that (a) cytotoxicity is not incumbent on MOG autoantibody quantity alone; (b) engagement of effector functions by MOGAD patient serum is bimodal, with some sera exhibiting cytotoxic capacity while others did not; (c) the magnitude of CDC and ADCP is elevated closer to relapse, while MOG-IgG binding is not; and (d) all IgG subclasses can damage MOG-expressing cells. Histopathology from a representative MOGAD case revealed congruence between lesion histology and serum CDC and ADCP, and we identified NK cells, mediators of ADCC, in the cerebrospinal fluid of relapsing patients with MOGAD. Thus, MOGAD-derived autoantibodies are cytotoxic to MOG-expressing cells through multiple mechanisms, and assays quantifying CDC and ADCP may prove to be effective tools for predicting risk of future relapses.

Authors

Soumya S. Yandamuri, Beata Filipek, Abeer H. Obaid, Nikhil Lele, Joshua M. Thurman, Naila Makhani, Richard J. Nowak, Yong Guo, Claudia F. Lucchinetti, Eoin P. Flanagan, Erin E. Longbrake, Kevin C. O’Connor

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Figure 4

Neuropathology in frontal lobe biopsy of patient with MOGAD with paired serum effector functions.

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Neuropathology in frontal lobe biopsy of patient with MOGAD with paired ...
Right frontal lobe biopsy was undertaken in a symptomatic patient with MOGAD based on MRI findings. (A–C) Histology was performed and indicated active demyelinating lesions with loss of (A) MAG, (B) MOG, and (C) PLP. (D and E) Complement deposition in lesions indicated by (D) C9neo (red), with higher magnification on right (E). (F and G) CD68+ (brown) macrophage/microglia infiltration detected in lesions and (G) macrophages appear foamy and myelin-laden upon higher magnification of MOG staining. Scale bar: 500 μm (A–D and F) and 50 μm (E and G). (H) The patient’s serum was collected at 4 time points: during relapse (MOG t1), 2 days thereafter (MOG t2), and twice during remission (MOG t3, t4). The serum was tested for MOG binding IgG in comparison to serum from 4 HD in a live MOG-CBA. These samples were then tested for induction of CDC and ADCP effector functions. (I–L) Resultant (I) MAC formation and (J) dead MOG+ cells in CDC assay and (K) phagocytosis and (L) MOG+ out of total HEK cells in ADCP assay. Experiments shown in H–L were performed in duplicate, shown as dots, with bar showing their mean.