Age-Dependent B Cell Autoimmunity to a Myelin Surface Antigen in Pediatric Multiple Sclerosis

Abstract

Multiple sclerosis (MS) typically manifests in early to mid adulthood, but there is increasing recognition of pediatric-onset MS, aided by improvements in imaging techniques. The immunological mechanisms of disease are largely unexplored in pediatric-onset MS, in part because studies have historically focused on adult-onset disease. We investigated autoantibodies to myelin surface Ags in a large cohort of pediatric MS cases by flow cytometric labeling of transfectants that expressed different myelin proteins. Although Abs to native myelin oligodendrocyte glycoprotein (MOG) were uncommon among adult-onset patients, a subset of pediatric patients had serum Abs that brightly labeled the MOG transfectant. Abs to two other myelin surface Ags were largely absent. Affinity purification of MOG Abs as well as competition of binding with soluble MOG documented their binding specificity. Such affinity purified Abs labeled myelin and glial cells in human CNS white matter as well as myelinated axons in gray matter. The prevalence of such autoantibodies was highest among patients with a very early onset of MS: 38.7% of patients less than 10 years of age at disease onset had MOG Abs, compared with 14.7% of patients in the 10- to 18-year age group. B cell autoimmunity to this myelin surface Ag is therefore most common in patients with a very early onset of MS.

Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases

“…Anti-MOG antibodies occur more frequently in children than in adults and have been described (using different assays which, as noted above, may affect findings) in pediatric patients with a variety of autoimmune demyelinating disease phenotypes, including those of ADEM, MS, 32,[35][36][37] relapsing ADEM, relapsing ON, 38,39 relapsing ADEM-ON, 40 and relapsing ON-longitudinally extensive TM (NMO-like). 36,37 The normal function of MOG, which resides at the cell surface of oligodendrocytes, is not well understood.…”

“…There is a dominant epitope involved in MOG IgG binding on the extracellular domain 13 and evidence of MOG IgG pathogenicity including alteration of oligodendrocyte cytoskeleton, 38 as well as implication in both complement-dependent and cell-based cytotoxicity. 35,41,42 A recent pathology report demonstrated antibody and complement deposition in an adult case of anti-MOG antibody-associated demyelination. 43 Compared to AQP4 IgG-associated disease, CBA seropositivity for MOG IgG appears to be associated with less severe disease, including better resolution and less likelihood to relapse, 44 and may also be associated with a non-MS disease phenotype.…”

Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis

“…[14][15][16][17][18] In contrast, the clinical relevance of MOG antibodies in adults is unclear, as only a minority of patients with MS and NMO/NMOSD are seropositive. 16,[18][19][20][21][22][23][24] Herein, we provide evidence that MOG antibodies are a clinical biomarker of bilateral and/ or recurrent optic neuritis (BON) in adults and describe the characteristic clinical course, response to therapy, and visual outcomes of this condition.…”

“…11 In particular, flow cytometry has emerged as a sensitive detection method, 6,14,16,21,32 with recent confirmation of the surface expression of the dominant MOG epitopes. 33 We describe that surface MOG IgG antibodies have a strong association with BON in adults.…”

Multi-Stage Mass Spectrometry Analysis of Sugar-Conjugated β-Turn Structures to be Used as Probes in Autoimmune Diseases

“…Multiple sclerosis is one of the most known inflammatory, demyelinating diseases of the central nervous system (CNS) possibly triggered by an autoimmune reaction against different CNS myelin components, like myelin basic protein (MBP) [6], proteolipid protein, and myelin oligodendrocyte glycoprotein [7].…”