Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination.

Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein(MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Abdetection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Abis required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Abin a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Abresponse was of immunoglobulin G1isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Abwere detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Abtargeted a dominant extracellular antigenic region around Proline42. MOG Abtiters fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Abresponse, a feature that may be harnessed for predicting relapse. Higher titers of MOG Abwere observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Abseropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies.