MOG Antibody–Associated Disease and Thymic Hyperplasia

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

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.