The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis.
Myasthenia gravis (MG) is associated with ectopic germinal centers in the thymus. Thymectomy and glucocorticoids are the main treatments but they induce operative risks and side effects, respectively. The aim of this study was to propose new therapies more efficient for MG. We hypothesized that molecules dysregulated in MG thymus and normalized by glucocorticoids may play a key role in thymic pathogenesis. Using gene chip analysis, we identified 88 genes complying with these criteria, the most remarkable being the B-cell chemoattractant (CXCL13). Its expression was increased in thymus and sera of glucocorticoid-untreated patients and decreased in response to treatment in correlation with clinical improvement. Normal B cells were actively chemoattracted by thymic extracts from glucocorticoid-untreated patients, an effect inhibited by anti-CXCL13 antibodies. In the thymus, CXCL13 was preferentially produced by epithelial cells and overproduced by epithelial cells from MG patients. Altogether, our results suggest that a high CXCL13 production by epithelial cells could be responsible for germinal center formation in MG thymus. Furthermore, they show that this gene is a main target of corticotherapy. Thus, new therapies targeting CXCL13 could be of interest for MG and other autoimmune diseases characterized by ectopic germinal center formation.
Centre National de la Recherche Scientifique-Unité mixte de recherche CNRS-UMR 8162, Institut Paris-Sud Cytokines (IPSC), Université Paris XI, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
Amel
A
Meraouna
Geraldine
G
Cizeron-Clairac
Rozen Le
RL
Panse
Jacky
J
Bismuth
Frederique
F
Truffault
Chantal
C
Tallaksen
Sonia
S
Berrih-Aknin
D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000328:Adult; D016022:Case-Control Studies; D054382:Chemokine CXCL13; D019743:Chemokines, CXC / Q000235:genetics* / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000473:pathology; D006801:Humans; D009157:Myasthenia Gravis / Q000209:etiology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D013950:Thymus Gland / Q000473:pathology
D000305:Adrenal Cortex Hormones; C110663:CXCL13 protein, human; D054382:Chemokine CXCL13; D019743:Chemokines, CXC