Myasthenia gravis thymus: complement vulnerability of epithelial and myoid cells, complement attack on them, and correlations with autoantibody status.
In early-onset myasthenia gravis, the thymus contains lymph node-type infiltrates with frequent acetylcholine receptor (AChR)-specific germinal centers. Our recent evidence/two-step hypothesis implicates hyperplastic medullary thymic epithelial cells (expressing isolated AChR subunits) in provoking infiltration and thymic myoid cells (with intact AChR) in germinal center formation. To test this, we screened for complement attack in a wide range of typical generalized myasthenia patients. Regardless of the exact serology, thymi with sizeable infiltrates unexpectedly showed patchy up-regulation of both C5a receptor and terminal complement regulator CD59 on hyperplastic epithelial cells. These latter also showed deposits of activated C3b complement component, which appeared even heavier on infiltrating B cells, macrophages, and especially follicular dendritic cells. Myoid cells appeared particularly vulnerable to complement; few expressed the early complement regulators CD55, CD46, or CR1, and none were detectably CD59(+). Indeed, when exposed to infiltrates, and especially to germinal centers, myoid cells frequently labeled for C1q, C3b (25 to 48%), or even the terminal C9, with some showing obvious damage. This early/persistent complement attack on both epithelial and myoid cells strongly supports our hypothesis, especially implicating exposed myoid cells in germinal center formation/autoantibody diversification. Remarkably, the similar changes place many apparent AChR-seronegative patients in the same spectrum as the AChR-seropositive patients.
Leite
Maria I
MI
Department of Clinical Neurology, University of Oxford, Oxford, United Kingdom.
Jones
Margaret
M
Ströbel
Philipp
P
Marx
Alexander
A
Gold
Ralf
R
Niks
Erik
E
Verschuuren
Jan J G M
JJ
Berrih-Aknin
Sonia
S
Scaravilli
Francesco
F
Canelhas
Aurea
A
Morgan
B Paul
BP
Vincent
Angela
A
Willcox
Nick
N
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D003165:Complement System Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D006801:Humans; D009157:Myasthenia Gravis / Q000276:immunology* / Q000473:pathology; D011951:Receptors, Complement / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000473:pathology
D015703:Antigens, CD; D001323:Autoantibodies; D011951:Receptors, Complement; D003165:Complement System Proteins