CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myasthenia.
OBJECTIVE
Myasthenia gravis (MG), a neuromuscular disease mediated by anti-acetylcholine receptor (AChR) autoantibodies, is associated with thymic hyperplasia characterized by ectopic germinal centers that contain pathogenic antibody-producing B cells. Our thymic transcriptome study demonstrated increased expression of CCL21, a recruiter of immune cells. Accordingly, we are investigating its implication in MG pathogenesis.


METHODS
The expression of CCL21 and its CCR7 receptor was analyzed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting, respectively. Chemotaxis of T and B cells to CCL21 was measured by transwell assay. The nature of the thymic cells overexpressing CCL21 was investigated by immunochemistry and laser-capture microdissection combined with real-time PCR.


RESULTS
We demonstrate that CCL21 is overexpressed specifically in hyperplastic MG thymuses, whereas there is no variation in CCR7 levels on blood cells. We show that although CCL21 attracts both human T and B cells, it acts more strongly on naive B cells. CCL21 overexpression is normalized in corticoid-treated MG patients, suggesting that targeting this chemokine could represent a new selective treatment, decreasing the abnormal peripheral lymphocyte recruitment. Moreover, we locate protein and messenger RNA overexpression of CCL21 to specific endothelial vessels. Investigation of the nature of these vessels demonstrated different angiogenic processes in MG thymuses: high endothelial venule angiogenesis and lymphangiogenesis. Unexpectedly, CCL21 overexpression originates from afferent lymphatic endothelial vessels.


CONCLUSIONS
We postulate that thymic overexpression of CCL21 on specialized lymphatic vessels results in abnormal peripheral lymphocyte recruitment, bringing naive B cells in contact with the inflammatory environment characteristic of MG thymuses, where they can be sensitized against AChR.
Berrih-Aknin
Sonia
S
Centre National de la Recherche Scientifique-Unité Mixte de Recherche, Institut Paris-Sud Cytokines, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
Ruhlmann
Nathalie
N
Bismuth
Jacky
J
Cizeron-Clairac
Géraldine
G
Zelman
Einat
E
Shachar
Idit
I
Dartevelle
Philippe
P
de Rosbo
Nicole Kerlero
NK
Le Panse
Rozen
R
D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D016175:B-Lymphocyte Subsets / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D054421:Chemokine CCL21 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D042601:Lymphatic Vessels / Q000378:metabolism* / Q000473:pathology; D009157:Myasthenia Gravis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013952:Thymus Hyperplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
D001323:Autoantibodies; C515478:CCL21 protein, human; D054421:Chemokine CCL21