Coexistence of Myelin Oligodendrocyte Glycoprotein and Aquaporin-4 Antibodies in Adult and Pediatric Patients | Demyelinating Disorders | JAMA Neurology | JAMA Network
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Figure 1.  Flowchart of Cohort Selection and Identification of Glial Antibodies Within the Tested Population
Flowchart of Cohort Selection and Identification of Glial Antibodies Within the Tested Population

The frequency of detection of antibodies in 13 736 adults and 1862 children. AQP4-IgG indicates aquaporin-4 immunoglobulin G; MOG-IgG, myelin oligodendrocyte glycoprotein immunoglobulin G.

Figure 2.  Frequency of Myelin Oligodendrocyte Glycoprotein (MOG)–IgG and Aquaporin-4 (AQP4)–IgG Serum Titers on Flow Cytometry Assay
Frequency of Myelin Oligodendrocyte Glycoprotein (MOG)–IgG and Aquaporin-4 (AQP4)–IgG Serum Titers on Flow Cytometry Assay

A-D, sex ratio of glial antibodies in adults and children; E, AQP4-IgG–positive cohort; F, MOG-IgG–positive cohort; G, AQP4-IgG in individuals with dual positivity; and H, MOG-IgG in individuals with dual positivity.

1.
Pittock  SJ, Lucchinetti  CF.  Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies: a decade later.  Ann N Y Acad Sci. 2016;1366(1):20-39. doi:10.1111/nyas.12794PubMedGoogle ScholarCrossref
2.
Hyun  J-W, Woodhall  MR, Kim  S-H,  et al.  Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory diseases.  J Neurol Neurosurg Psychiatry. 2017;88(10):811-817. doi:10.1136/jnnp-2017-315998PubMedGoogle ScholarCrossref
3.
Höftberger  R, Sepulveda  M, Armangue  T,  et al.  Antibodies to MOG and AQP4 in adults with neuromyelitis optica and suspected limited forms of the disease.  Mult Scler. 2015;21(7):866-874. doi:10.1177/1352458514555785PubMedGoogle ScholarCrossref
4.
Waters  PJ, Komorowski  L, Woodhall  M,  et al.  A multicenter comparison of MOG-IgG cell-based assays.  Neurology. 2019;92(11):e1250-e1255. doi:10.1212/WNL.0000000000007096PubMedGoogle Scholar
5.
Quek  AML, McKeon  A, Lennon  VA,  et al.  Effects of age and sex on aquaporin-4 autoimmunity.  Arch Neurol. 2012;69(8):1039-1043. doi:10.1001/archneurol.2012.249PubMedGoogle ScholarCrossref
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    Research Letter
    October 28, 2019

    Coexistence of Myelin Oligodendrocyte Glycoprotein and Aquaporin-4 Antibodies in Adult and Pediatric Patients

    Author Affiliations
    • 1Department of Neurology, Mayo Clinic, Rochester, Minnesota
    • 2Department Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
    • 3Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota
    • 4Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota
    JAMA Neurol. 2020;77(2):257-259. doi:10.1001/jamaneurol.2019.3656

    Myelin oligodendrocyte glycoprotein (MOG)–IgG is a biomarker associated with central nervous system–demyelinating disorders termed MOG-IgG–associated disorders. These disorders have overlapping clinical features, including optic neuritis and myelitis, with aquaporin-4 (AQP4)–IgG–positive neuromyelitis optica spectrum disorders. These disorders are hypothesized to be biologically distinct; AQP4-IgG–positive neuromyelitis optica spectrum disorders are autoimmune astrocytopathies, whereas MOG-IgG–associated disorders are postulated to be autoimmune oligodendrocytopathies.1 Despite their immunopathogenic differences, there are rare reports of patients with dual positivity of MOG-IgG and AQP4-IgG.2,3 We aimed to determine the frequency, sex ratio, and coexistence of glial antibodies (AQP4-IgG and MOG-IgG) in adults and children undergoing evaluation for suspected central nervous system–demyelinating diseases.

    Methods

    This is a retrospective cohort study approved by the Mayo Clinic institutional review board and ethics committee with a waiver of informed consent because of the restricted, deidentified nature of the data used. All patients who had serum samples tested for AQP4-IgG and MOG-IgG from October 2017 to May 2019 were evaluated using a clinically validated flow cytometric assay (BD FACSCanto II [BD Biosciences]).4 All samples were repeated to confirm positivity. We have used basic demographic data (age and sex) provided through the clinical testing request forms. We used χ2 tests to compare the proportions of female and male individuals within the antibody-positive groups. All tests were 2-sided, and P values less than .05 were considered significant. The statistical software R version 3.5.1 (R Foundation for Statistical Computing) was used.

    Results

    Over a 20-month period, 15 598 patients (1862 children [<18 years] and 13 736 adults) were tested for both AQP4-IgG and MOG-IgG (Figure 1). In 1291 patients (8.3%), MOG-IgG was detected; AQP4-IgG was detected in 387 patients (2.3%).

    Of the adults, 899 (6.5%) were MOG-IgG positive, and 351 (2.6%) were AQP4-IgG positive (Figure 2A). Of the adults with MOG-IgG, 546 were female (60.7%); 303 of the adults with AQP4-IgG (86.3%) were female (P < .001) (Figure 2C). Of the children, 392 were MOG-IgG positive (21.1%), and 36 were AQP4-IgG positive (1.9%) (Figure 2B). Of all children with MOG-IgG, 214 were female (54.6%) vs 21 (58.3%) of all children with AQP4-IgG (P = .79) (Figure 2D).

    In the subgroup of patients with serum testing completed on the same sample (n = 8276), similar proportions of antibody positivity were observed as in those with separate samples tested (Figure 1). The median serum titers for the cohort were 1:10 000 (range, 1:5 to 1:100 000) for AQP4-IgG and 1:100 (range, 1:20 to 1:100 000) for MOG-IgG (Figure 2E and F). The adult and children subgroups had the same median titers.

    Of 15 598 patients, 10 patients (0.06%) had dual positivity. All 10 patients with dual positivity had high-titer AQP4-IgG (median, 1:10 000; range, 1:100 to 1:100 000) and low-titer MOG-IgG (median, 1:40; range, 1:20 to 1:100) (Figure 2G and H). All of the patients with dual positivity were adults (median age, 47 years [range, 30-61 years]), and 9 of the 10 patients were female (90%).

    Conclusions

    In this large cohort of patients undergoing evaluation for suspected central demyelinating diseases, MOG-IgG were detected almost 3 times as often as AQP4-IgG in adults; in children, MOG-IgG was detected more than 11 times as often as AQP4-IgG. In this study, MOG-IgG and AQP4-IgG rarely coexisted in a single patient (0.06%).

    We have confirmed the previously described female predominance in adults who are positive for AQP4-IgG.5 Furthermore, we have demonstrated that there is a distinct difference in the female predominance in adults with AQP4-IgG compared with MOG-IgG. Together, these sex differences and the greater detection of MOG-IgG, especially in children, suggests that central demyelinating diseases associated with these biomarkers may have different drivers of autoimmunity.

    The rare coexistence of these 2 antibody biomarkers also points to distinct immunopathogeneses of these diseases. It has been postulated that MOG-IgG is an epiphenomenon, occurring with exposure of antigen in the AQP4-IgG disease. However, the rarity of dual positivity is this large cohort is evidence against an epiphenomenon. All individuals with dual positivity had high titers of AQP4-IgG and low titers of MOG-IgG, suggesting the disease phenotype may be more compatible with AQP4-IgG–positive neuromyelitis optica spectrum disorders.

    These findings suggest that MOG-IgG may occur more frequently than AQP4-IgG in patients tested for central demyelinating diseases, particularly in children. However, because the study population was derived from patients who had undergone a central demyelinating disease serological evaluation, these data should not be interpreted as representing seroprevalence in the general population. Further population-based studies are required to determine the prevalence and incidence of MOG-IgG–associated disorders. That MOG-IgG and AQP4-IgG rarely coexist highlights the immunopathogenic distinction of these biomarkers.

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    Article Information

    Accepted for Publication: August 26, 2019.

    Corresponding Author: Sean J. Pittock, MD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905-0001 (pittock.sean@mayo.edu).

    Published Online: October 28, 2019. doi:10.1001/jamaneurol.2019.3656

    Author Contributions: Drs Kunchok and Pittock had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Kunchok, Pittock.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Kunchok, Pittock.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Kunchok.

    Administrative, technical, or material support: McKeon, Mills.

    Supervision: Pittock.

    Conflict of Interest Disclosures: Dr Kunchok has received research funding from Biogen. Dr McKeon has received research funding from Alexion, Grifols, and Medimmune and reported grants from Euroimmun outside the submitted work. Dr Flanagan is a site principal investigator in a randomized placebo-controlled clinical trial of inebilizumab (a CD-19 inhibitor) in neuromyelitis optica spectrum disorders funded by MedImmune/Viela Bio and has served on that organization’s advisory board. Dr Pittock reports grants, personal fees, and nonfinancial support from Alexion Pharmaceuticals Inc and Guthy Jackson Charitable Foundation; consulting fees from Euroimmun; grants from Grifols, the National Institutes of Health (grant RO1 NS065829-01), and Autoimmune Encephalitis Alliance; grants, personal fees, nonfinancial support, and honoraria from MedImmune Inc; and a patent (#9,891,219; application #12-573942). Drs Pittock and McKeon have patents pending for various IgG as biomarkers of autoimmune neurological disorders (septin-5, Kelch-like protein 11, glial fibrillary acidic protein, phosphodiesterase 10A, and microtubule‐associated protein 1B). No other disclosures were reported.

    Additional Contributions: We would like to acknowledge the Mayo Clinic Neuroimmunology Laboratory research administrative and laboratory staff: James Fryer, myelin oligodendrocyte glycoprotein–IgG flow cytometry assay testing and development, Thomas Hartman, MBA, laboratory manager, Jade Zbacnik, laboratory specialist, Jessica Sagen, MA, research coordinator, and Mary Curtis, laboratory secretary. Compensation was as per normal employment practices only.

    References
    1.
    Pittock  SJ, Lucchinetti  CF.  Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies: a decade later.  Ann N Y Acad Sci. 2016;1366(1):20-39. doi:10.1111/nyas.12794PubMedGoogle ScholarCrossref
    2.
    Hyun  J-W, Woodhall  MR, Kim  S-H,  et al.  Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory diseases.  J Neurol Neurosurg Psychiatry. 2017;88(10):811-817. doi:10.1136/jnnp-2017-315998PubMedGoogle ScholarCrossref
    3.
    Höftberger  R, Sepulveda  M, Armangue  T,  et al.  Antibodies to MOG and AQP4 in adults with neuromyelitis optica and suspected limited forms of the disease.  Mult Scler. 2015;21(7):866-874. doi:10.1177/1352458514555785PubMedGoogle ScholarCrossref
    4.
    Waters  PJ, Komorowski  L, Woodhall  M,  et al.  A multicenter comparison of MOG-IgG cell-based assays.  Neurology. 2019;92(11):e1250-e1255. doi:10.1212/WNL.0000000000007096PubMedGoogle Scholar
    5.
    Quek  AML, McKeon  A, Lennon  VA,  et al.  Effects of age and sex on aquaporin-4 autoimmunity.  Arch Neurol. 2012;69(8):1039-1043. doi:10.1001/archneurol.2012.249PubMedGoogle ScholarCrossref
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