Interleukin-6 overproduction by cultured thymic epithelial cells from patients with myasthenia gravis is potentially involved in thymic hyperplasia.
Most patients with Myasthenia Gravis (MG) present a thymic hyperplasia characterized by the presence of lymphoid follicles. The acetylcholine receptor autoantigen, as well as autoantigen specific activated T and B cells found in the thymus, strongly suggest that auto-sensitization could take place in this organ. Since IL-6 is involved in T and B cell growth and differentiation, we thought that abnormal IL-6 expression by thymic epithelial cells (TEC) could be related to thymic hyperplasia in MG. In this paper, IL-6 protein and gene expression by cultured TEC from patients with MG were examined. TEC from patients presented a dramatic IL-6 hyperproduction phenotype as compared to controls when stimulated by exogenous signals such as LPS and cytokines (IL-1 beta, TNF-alpha) alone or in combination. Moreover, we observed a similar effect with a physiological signal such as the syngeneic lympho-epithelial cell contact. Autologous thymocytes stimulated normal and MG TEC IL-6 production in a time- and dose- dependent way, and with a higher magnitude in MG TEC compared to controls. In all stimulation conditions, induction of IL-6 production required protein synthesis and was associated with increased IL-6 mRNA level expression as assessed by computer-aided quantification after in situ mRNA hybridization. In addition, recombinant IL-6 induced in vitro growth of TEC, demonstrating that IL-6 is a possible autocrine growth factor for these cells. This deregulated IL-6 production as well as the ability of TEC to use it as a growth factor may be of pathophysiological relevance in MG. It provides an explanation for morphological changes of the thymus and may have a key role in initiation, exacerbation and ongoing of the autoimmune response in MG. Therefore this study extends our current understanding of the molecular pathophysiology of MG.
Cohen-Kaminsky
S
S
CNRS URA-1159, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
Devergne
O
O
Delattre
R M
RM
Klingel-Schmitt
I
I
Emilie
D
D
Galanaud
P
P
Berrih-Aknin
S
S
D000328:Adult; D002450:Cell Communication / Q000276:immunology; D002455:Cell Division; D002478:Cells, Cultured; D002675:Child, Preschool; D004848:Epithelium / Q000276:immunology / Q000473:pathology; D006801:Humans; D007223:Infant; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D009157:Myasthenia Gravis / Q000150:complications / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology; D013952:Thymus Hyperplasia / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha