Failure to down-regulate Bcl-2 protein in thymic germinal center B cells in myasthenia gravis.
The most unusual characteristic of myasthenia gravis (MG) is that the thymus has germinal centers (GC). Cultured thymic lymphocytes from MG patients spontaneously produce anti-acetylcholine receptor antibodies, indicating that autoreactive B cells have escaped negative selection. To investigate the underlying mechanism, we examined the expression of the apoptosis-related protein Bcl-2 in GC B cells (defined as CD19+ CD38+ cells) in the thymus in 14 MG patients using three-color flow cytometry. GC in MG patients did not show the normal down-regulation of Bcl-2 (the frequency of Bcl-2+ GC B cells in the MG thymus and in control tonsils 54.3 +/- 16.2% versus 20.6 +/- 8.0%; mean +/- SD. p < 0.0001). In contrast, Bcl-2 in GC in the mediastinal lymph nodes from four patients was down-regulated to a relatively normal level. Using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method to detect DNA fragmentation in situ, the frequency of TUNEL+ cells in GC in the MG thymus was lower than in control tonsils. These results suggest that autoreactive B cells which normally undergo apoptosis in GC may survive because of Bcl-2 up-regulation in this unusual location.
Shiono
H
H
First Department of Surgery, Osaka University Medical School, Japan. shiono@surg1.med.osaka-u.ac.jp
Fujii
Y
Y
Okumura
M
M
Takeuchi
Y
Y
Inoue
M
M
Matsuda
H
H
D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D018858:Germinal Center / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D008482:Mediastinum; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000276:immunology* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*
D019253:Proto-Oncogene Proteins c-bcl-2