Localized on the outermost lamellae of CNS myelin, exposure to the extracellular space has placed MOG in the spotlight as a prime target of autoimmune demyelination. The single extracellular MOG domain adopts a folded immunoglobulin (Ig) variable topology formed by two anti-parallel β-sheets surrounding a hydrophobic core. Myelin oligodendrocyte glycoprotein (MOG) is a myelin transmembrane protein exclusively expressed by oligodendrocytes within the central nervous system (CNS). Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin.
MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in 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). While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. 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.
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