Myasthenia gravis thymus: complement vulnerability of epithelial and myoid cells, complement attack on them, and correlations with autoantibody status.

• Autor(a) principal: LEITE, M.I.
• Data de Publicação: 2007
• Outros Autores: JONES, M., STRÖBEL, P., MARX, A., GOLD, R., NIKS, E., VERSCHUUREN, J.J., BERRIH‐AKNIN, S., SCARAVILLI, F., CANELHAS, A., MORGAN, B.P., VINCENT, A., WILLCOX, N.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.16/554

Am J Pathol. 2007 Sep;171(3):893-905. Epub 2007 Aug 3. Myasthenia gravis thymus: complement vulnerability of epithelial and myoid cells, complement attack on them, and correlations with autoantibody status. Leite MI, Jones M, Ströbel P, Marx A, Gold R, Niks E, Verschuuren JJ, Berrih-Aknin S, Scaravilli F, Canelhas A, Morgan BP, Vincent A, Willcox N. Department of Clinical Neurology, University of Oxford, Oxford, United Kingdom. Abstract 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. PMID: 17675582 [PubMed - indexed for MEDLINE]PMCID: PMC1959483Free PMC Article Images from this publication.See all images (6) Free text Figure 1 Distribution of complement receptors C3aR, C5aR, and CR1 (receptor for C3b and C4b) (all in red) in epithelial areas and/or infiltrates in thymi from non-MG controls (A and B), AChRAb+ (C–E), or SNMG (F) MG patients. A and B: In control thymi, occasional mTECs are weakly C5aR+, as in some areas in MG thymi, bu... Myasthenia Gravis Thymus Am J Pathol. 2007 September;171(3):893-905.Figure 2 Distribution of complement regulators CD46, CD55, and CD59 (all in red) in epithelial areas and infiltrates in control (A and D) and MG thymi (B, C, and E–I). Cytokeratin (CK, green). A: In controls, CD46 (A) and CD55 (not shown) expression is minimal; in MG, both are much stronger in the MEBs than in the nMe... Myasthenia Gravis Thymus Am J Pathol. 2007 September;171(3):893-905.Figure 3 Labeling for C1q and C3b complement fragments (both in red) in epithelial areas and infiltrates in MG and control thymi. Cytokeratin (CK, green). A and B: In MG, there is extensive patchy labeling for C1q in mTECs and other cells in MEBs and in infiltrates and GC in AChRAb+ (A) or SNMG (B) samples. C: In co... Myasthenia Gravis Thymus Am J Pathol. 2007 September;171(3):893-905.Figure 4 Rarity of complement regulators on myoid cells. In both control (not shown) and MG thymi (A), myoid cells (MC) are uniformly CD59− (red), even when exposed to infiltrates, but ∼5% of the latter express detectable CD55 (red) (B, inset). (Donors both female: A, 20 years of age; B, 16 years of age). Desmin (De, ... Myasthenia Gravis Thymus Am J Pathol. 2007 September;171(3):893-905.Figure 5 Labeling for C1q, C3b, or C9 (all in red) on exposed myoid cells (MC) in MG thymi. Desmin (De, green). A and B: Some exposed myoid cells label for C1q in AChRAb+ (A) or SNMG (B) MG samples, in which many of them label for C3b (C and D; enlarged in insets) and some for C9 in AChRAb+ (E) or SNMG (F) samples. Note aggr... Myasthenia Gravis Thymus Am J Pathol. 2007 September;171(3):893-905.Figure 6 Percentages of myoid cells exposed to the infiltrates in non-MG controls and MG patient subgroups. Their rarity in the control and MuSKAb+ samples reflects the paucity of infiltrates. There were significantly fewer myoid cells/mm2 in the AChRAb+ group than in the controls (see mini-table below; *P < 0.0... Myasthenia Gravis Thymus Am J Pathol. 2007 September;171(3):893-905.