Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders

Abstract

BackgroundSerum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved.ResultsWe analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels.ConclusionsWe could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.

Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases

“…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.…”

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

“…The case for AQP4-IgG-negative NMO is more complex, as these patients form a heterogeneous group with demographic and clinical characteristics different from seropositive patients [11]. Autoantibodies targeting the myelin oligodendrocyte glycoprotein have been reported in some AQP4-IgG-negative patients with a classical clinical presentation of NMO [12,13], however, anti-myelin oligodendrocyte glycoprotein-antibodies are not specific for NMO and occur in a variety of other demyelinating diseases [14]. Recently, new diagnostic criteria were published that present a uniform concept combining NMO and NMOSD [15], which is why the term "NMOSD" will be used throughout this review.…”