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March 2023; 10 (2) Diagnostic & Treatment ChallengesOpen Access

MOG Antibody–Associated Disease and Thymic Hyperplasia

From the National Multiple Sclerosis Society Case Conference Proceedings

Brigitte Hurtubise, Elliot M. Frohman, Steven Galetta, Laura J. Balcer, Teresa C. Frohman, Robert P. Lisak, Scott D. Newsome, Jennifer S. Graves, Scott S. Zamvil, Lilyana Amezcua
First published December 14, 2022, DOI: https://doi.org/10.1212/NXI.0000000000200077
Brigitte Hurtubise
From the Department of Neurology (B.H., L.A.), University of Southern California (USC), Keck School of Medicine; Distinguished Senior Fellows (Sabbatical) Neuroimmunology Laboratory of Professor Lawrence Steinman (E.M.F., T.C.F.), Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (S.G., L.J.B.), Population Health (L.J.B.) and Ophthalmology (L.J.B., S.G.), New York University Grossman School of Medicine; Department of Neurology (R.P.L.), Wayne State University, Detroit MI; Department of Neurology (S.D.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurosciences (J.S.G.), University of California, San Diego; and Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco.
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Elliot M. Frohman
From the Department of Neurology (B.H., L.A.), University of Southern California (USC), Keck School of Medicine; Distinguished Senior Fellows (Sabbatical) Neuroimmunology Laboratory of Professor Lawrence Steinman (E.M.F., T.C.F.), Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (S.G., L.J.B.), Population Health (L.J.B.) and Ophthalmology (L.J.B., S.G.), New York University Grossman School of Medicine; Department of Neurology (R.P.L.), Wayne State University, Detroit MI; Department of Neurology (S.D.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurosciences (J.S.G.), University of California, San Diego; and Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco.
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Steven Galetta
From the Department of Neurology (B.H., L.A.), University of Southern California (USC), Keck School of Medicine; Distinguished Senior Fellows (Sabbatical) Neuroimmunology Laboratory of Professor Lawrence Steinman (E.M.F., T.C.F.), Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (S.G., L.J.B.), Population Health (L.J.B.) and Ophthalmology (L.J.B., S.G.), New York University Grossman School of Medicine; Department of Neurology (R.P.L.), Wayne State University, Detroit MI; Department of Neurology (S.D.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurosciences (J.S.G.), University of California, San Diego; and Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco.
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Laura J. Balcer
From the Department of Neurology (B.H., L.A.), University of Southern California (USC), Keck School of Medicine; Distinguished Senior Fellows (Sabbatical) Neuroimmunology Laboratory of Professor Lawrence Steinman (E.M.F., T.C.F.), Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (S.G., L.J.B.), Population Health (L.J.B.) and Ophthalmology (L.J.B., S.G.), New York University Grossman School of Medicine; Department of Neurology (R.P.L.), Wayne State University, Detroit MI; Department of Neurology (S.D.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurosciences (J.S.G.), University of California, San Diego; and Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco.
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Teresa C. Frohman
From the Department of Neurology (B.H., L.A.), University of Southern California (USC), Keck School of Medicine; Distinguished Senior Fellows (Sabbatical) Neuroimmunology Laboratory of Professor Lawrence Steinman (E.M.F., T.C.F.), Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (S.G., L.J.B.), Population Health (L.J.B.) and Ophthalmology (L.J.B., S.G.), New York University Grossman School of Medicine; Department of Neurology (R.P.L.), Wayne State University, Detroit MI; Department of Neurology (S.D.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurosciences (J.S.G.), University of California, San Diego; and Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco.
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Robert P. Lisak
From the Department of Neurology (B.H., L.A.), University of Southern California (USC), Keck School of Medicine; Distinguished Senior Fellows (Sabbatical) Neuroimmunology Laboratory of Professor Lawrence Steinman (E.M.F., T.C.F.), Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (S.G., L.J.B.), Population Health (L.J.B.) and Ophthalmology (L.J.B., S.G.), New York University Grossman School of Medicine; Department of Neurology (R.P.L.), Wayne State University, Detroit MI; Department of Neurology (S.D.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurosciences (J.S.G.), University of California, San Diego; and Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco.
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Scott D. Newsome
From the Department of Neurology (B.H., L.A.), University of Southern California (USC), Keck School of Medicine; Distinguished Senior Fellows (Sabbatical) Neuroimmunology Laboratory of Professor Lawrence Steinman (E.M.F., T.C.F.), Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (S.G., L.J.B.), Population Health (L.J.B.) and Ophthalmology (L.J.B., S.G.), New York University Grossman School of Medicine; Department of Neurology (R.P.L.), Wayne State University, Detroit MI; Department of Neurology (S.D.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurosciences (J.S.G.), University of California, San Diego; and Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco.
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Jennifer S. Graves
From the Department of Neurology (B.H., L.A.), University of Southern California (USC), Keck School of Medicine; Distinguished Senior Fellows (Sabbatical) Neuroimmunology Laboratory of Professor Lawrence Steinman (E.M.F., T.C.F.), Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (S.G., L.J.B.), Population Health (L.J.B.) and Ophthalmology (L.J.B., S.G.), New York University Grossman School of Medicine; Department of Neurology (R.P.L.), Wayne State University, Detroit MI; Department of Neurology (S.D.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurosciences (J.S.G.), University of California, San Diego; and Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco.
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Scott S. Zamvil
From the Department of Neurology (B.H., L.A.), University of Southern California (USC), Keck School of Medicine; Distinguished Senior Fellows (Sabbatical) Neuroimmunology Laboratory of Professor Lawrence Steinman (E.M.F., T.C.F.), Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (S.G., L.J.B.), Population Health (L.J.B.) and Ophthalmology (L.J.B., S.G.), New York University Grossman School of Medicine; Department of Neurology (R.P.L.), Wayne State University, Detroit MI; Department of Neurology (S.D.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurosciences (J.S.G.), University of California, San Diego; and Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco.
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Lilyana Amezcua
From the Department of Neurology (B.H., L.A.), University of Southern California (USC), Keck School of Medicine; Distinguished Senior Fellows (Sabbatical) Neuroimmunology Laboratory of Professor Lawrence Steinman (E.M.F., T.C.F.), Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (S.G., L.J.B.), Population Health (L.J.B.) and Ophthalmology (L.J.B., S.G.), New York University Grossman School of Medicine; Department of Neurology (R.P.L.), Wayne State University, Detroit MI; Department of Neurology (S.D.N.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurosciences (J.S.G.), University of California, San Diego; and Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco.
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Citation
MOG Antibody–Associated Disease and Thymic Hyperplasia
From the National Multiple Sclerosis Society Case Conference Proceedings
Brigitte Hurtubise, Elliot M. Frohman, Steven Galetta, Laura J. Balcer, Teresa C. Frohman, Robert P. Lisak, Scott D. Newsome, Jennifer S. Graves, Scott S. Zamvil, Lilyana Amezcua
Neurol Neuroimmunol Neuroinflamm Mar 2023, 10 (2) e200077; DOI: 10.1212/NXI.0000000000200077

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    Figure 1 MRI Images of Orbit and Brain

    (A) MRI orbits with and without contrast showing longitudinal hyperintensity and enhancement along the left optic nerve and perineural sheath. (B) MRI brain with and without contrast showing meningeal contrast enhancement and T2 fluid‐attenuated inversion recovery (FLAIR) hyperintensities seen over frontal and parietal lobes, including extension in the right parietal parenchyma, consistent with meningeal inflammation.

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    Figure 2 Thymic Imaging

    PET with CT scan showing a 37 × 28-mm thymic bed mass with homogenous fluorodeoxyglucose uptake, circled.

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    Figure 3 Thymic Selection of T Cells and Their Potential Role in Promoting MOGAD Pathogenesis

    Precursor (pre)-T cells emerge from the bone marrow and migrate to the thymus. Pre-T cells (CD4 and CD8 double negative) enter the cortex, undergo T-cell receptor gene rearrangement and become double positive for CD4 and CD8 molecules. There, CD4+CD8+ thymocytes are exposed to cortical epithelial cells (cTECs) that express major histocompatibility complex (MHC) I and II molecules that bind self-antigen peptides. CD4+CD8+ thymocytes that recognize MHC/peptides on cTECs with low affinity undergo apoptosis. CD4+CD8+ thymocytes that exhibit intermediate or high affinity for MHC I/peptide or MHC II/peptide on cTECs are believed to be positively selected to become single positive CD8+ T cells or CD4+ T cells, respectively, and then migrate to the medulla. Medullary thymic epithelial cells (mTECS), which also express MHC I and MHC II, regulate negative selection (i.e., deletion) of CD8+ and CD4+ T cells that exhibit high affinity to self (tissue-specific) antigens. This process of thymic education first ensures adequate binding to the MHC molecules on antigen-presenting cells (APCs) (positive selection, cortex) and subsequent deletion of those that have a high affinity for self-antigen (negative selection, medulla). Approximately 2% of T cells survive thymic education and exit as mature T cells. A small number of T cells that recognize self-antigen may escape deletion, even in the normal thymus of healthy individuals. In MOGAD, as in certain other autoimmune diseases such as myasthenia gravis, the self-reactive T cells are believed to be more active and lead to disease pathogenesis. This may reflect failure of deletion of high-affinity MOG-reactive T cells or failure to regulate MOG-reactive T cells peripherally. MOG-reactive T cells may have distinct roles in MOGAD. First, it is known from animal models that proinflammatory MOG-reactive T cells (Teff) can induce encephalomyelitis and optic neuritis independent of MOG-specific antibodies.21 Second, MOG-specific antibodies in MOGAD are IgG1, a T-cell–dependent Ig subtype.22 As T follicular helper (Tfh) cells are required for maturation of B cells into Ab-secreting plasmablasts and plasma cells, it is believed that MOG-specific Tfh promote maturation of MOG-specific B cells into IgG1-secreting plasma cells. Therefore, MOG-specific Teff along with MOG-specific antibodies may enter the CNS causing damage to myelin and oligodendrocytes. The extent to which complement participates in this inflammatory process is not clear. Figure art created by Xavier Studio. MOGAD = myelin oligodendrocyte glycoprotein antibody–associated disease.

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    Figure 4 Thymic Pathology

    Here demonstrated are the 2 most likely thymic pathologies to exist in our patient and normal thymic tissue. (A) Gross: Triangular shape, as seen in our patient, is more frequently observed with thymic hyperplasia (left), whereas more rounded enlargement favors thymoma (right). (B) Low magnification: Lobular architecture is preserved in thymic hyperplasia (left), whereas thymoma has increased numbers of lobules (right). (C) High magnification: (Left) B-cell germinal centers with surrounding thymocytes characterize thymic hyperplasia. (Center) Hassall corpuscles are groups of concentrically arranged eosinophilic epithelial cells in the normal thymic medulla that are believed to support thymocyte development; they mark thymic tissue apart from other lymphoid tissues and may be seen in the normal as well as pathologic thymus. (Right) Neoplastic thymic epithelial cells with increased reactive thymocytes are seen in thymoma. Figure art created by Xavier Studio.

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