Aberrant Encounter of Acetylcholine Receptor-Expressing Cells with the Lymphoid Infiltrates in the Thymus of Myasthenia Gravis Patients

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The muscle weakness in myasthenia gravis (MG) is clearly mediated by autoantibodies to the acetylcholine receptor (AChR). Their production depends on helper T cells, the induction of which must be a crucial step in autosensitization [1]. MG patients with onset of the disease before 40 years of age (early onset MG-EOMG) typically show a characteristic thymic hyperplasia (reviewed in [1]). This is largely due to invasion of the extraparenchymal perivascular spaces by lymphoid infiltrates with germinal centers (GC) and T cell areas [2–4]. In parallel, the true thymic parenchyma also shows alterations, with rearrangement of the medullary epithelium into bands (medullary epithelial bands-MEB) [3, 4]. In normal thymus, the two compartments are separated by a laminin+ basement membrane. By contrast, in the EOMG thymus, this barrier is frequently fenestrated [3, 4], and thymic epithelial cells (TEC) are occasionally seen protruding toward the lymphoid infiltrates. Such TEC are intermingled with abundant deposits of extracellular matrix (ECM) proteins (e.g. laminin) that are continuous with an analogous network in T cell areas. Furthermore, they express high levels of ECM protein receptors (integrins) and epidermal growth factor receptor (EGFR) [5], which could synergize in leading to TEC proliferation and migration. As a result, in the EOMG thymus, a considerable proportion of TEC is aberrantly exposed to the lymphoid infiltrates. Interestingly, it has been previously noticed that GC are frequently localized at sites of basement membrane fenestrations [3, 4]. There is also recent evidence that TEC express AChR subunits [6], though not whole AChR.