SDF-1/CXCL12 recruits B cells and antigen-presenting cells to the thymus of autoimmune myasthenia gravis patients.
Myasthenia gravis (MG), a neuromuscular disease mediated by autoantibodies against the anti-acetylcholine receptor, is often associated with thymic hyperplasia characterized by ectopic germinal centers that contain autoreactive T and B cells. The MG thymus is the site of active neoangiogenic processes including the abnormal development of high endothelial venules (HEVs). This study tested the hypothesis that thymic HEVs and associated chemokines participate in MG pathology by mediating peripheral cell recruitment to the MG thymus. We observed that the number of HEVs positively correlated with the degree of thymic hyperplasia. Testing various chemokines, we demonstrated that thymic HEVs selectively expressed SDF-1 mRNA and presented SDF-1 protein on the lumen side. Antigen presenting cells (APCs) such as monocytes/macrophages, dendritic cells (DCs) and B cells expressing SDF-1 receptor CXCR4 were detected inside and around thymic HEVs. In the periphery, CXCR4 expression was especially reduced on myeloid DCs (mDCs). In parallel, the number of mDCs was decreased suggesting a recruitment of these cells from the periphery to MG thymus. Corticosteroid treatment normalized the number of HEVs and may thus decrease the recruitment of peripheral cells. Indeed, it restored the level of CXCR4 on peripheral mDCs and the number of peripheral mDCs. Altogether, our results suggest that HEV development and engagement of SDF-1 contribute to MG pathology by recruitment of peripheral B cells and APCs to the MG thymus.
Unité Mixte de Recherche, CNRS UMR7215/INSERM U974/UPMC UM76/AIM, Thérapie des Maladies du Muscle Strié, Institut de Myologie, Paris, France.
Julia Miriam
JM
Weiss
Perrine
P
Cufi
Jacky
J
Bismuth
Bruno
B
Eymard
Elie
E
Fadel
Sonia
S
Berrih-Aknin
Rozen
R
Le Panse
D000328:Adult; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D009157:Myasthenia Gravis / Q000276:immunology*; D009389:Neovascularization, Pathologic; D019718:Receptors, CXCR4 / Q000378:metabolism; D013950:Thymus Gland / Q000473:pathology; D013952:Thymus Hyperplasia; D014699:Venules / Q000473:pathology
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4