title: Central role of interferon-beta in thymic events leading to myasthenia gravis.
abstract: The thymus plays a primary role in early-onset Myasthenia Gravis (MG) mediated by anti-acetylcholine receptor (AChR) antibodies. As we recently showed an inflammatory and anti-viral signature in MG thymuses, we investigated in detail the contribution of interferon (IFN)-I and IFN-III subtypes in thymic changes associated with MG. We showed that IFN-I and IFN-III subtypes, but especially IFN-β, induced specifically α-AChR expression in thymic epithelial cells (TECs). We also demonstrated that IFN-β increased TEC death and the uptake of TEC proteins by dendritic cells. In parallel, we showed that IFN-β increased the expression of the chemokines CXCL13 and CCL21 by TECs and lymphatic endothelial cells, respectively. These two chemokines are involved in germinal center (GC) development and overexpressed in MG thymus with follicular hyperplasia. We also demonstrated that the B-cell activating factor (BAFF), which favors autoreactive B-cells, was overexpressed by TECs in MG thymus and was also induced by IFN-β in TEC cultures. Some of IFN-β effects were down-regulated when cell cultures were treated with glucocorticoids, a treatment widely used in MG patients that decreases the number of thymic GCs. Similar changes were observed in vivo. The injections of Poly(I:C) to C57BL/6 mice triggered a thymic overexpression of IFN-β and IFN-α2 associated with increased expressions of CXCL13, CCL21, BAFF, and favored the recruitment of B cells. These changes were not observed in the thymus of IFN-I receptor KO mice injected with Poly(I:C), even if IFN-β and IFN-α2 were overexpressed. Altogether, these results demonstrate that IFN-β could play a central role in thymic events leading to MG by triggering the overexpression of α-AChR probably leading to thymic DC autosensitization, the abnormal recruitment of peripheral cells and GC formation.
authors.affiliation: INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institute of Myology, Paris, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Cufi
authors.affiliation: INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institute of Myology, Paris, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Dragin
authors.affiliation: INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ruhlmann
authors.affiliation: INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institute of Myology, Paris, France.
authors.forename: Julia Miriam
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Marie Lannelongue Hospital, Paris-Sud University, Le Plessis-Robinson, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.affiliation: Marie Lannelongue Hospital, Paris-Sud University, Le Plessis-Robinson, France; Jacques Cartier Hospital, Massy, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Serraf
authors.affiliation: INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institute of Myology, Paris, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Berrih-Aknin
authors.affiliation: INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institute of Myology, Paris, France. Electronic address: rozen.lepanse@upmc.fr.
authors.forename: Rozen
authors.initials: R
authors.lastname: Le Panse
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000235:genetics / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000235:genetics / Q000378:metabolism; D002675:Child, Preschool; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018858:Germinal Center / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia; D007223:Infant; D007231:Infant, Newborn; D016899:Interferon-beta / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009157:Myasthenia Gravis / Q000276:immunology*; D011070:Poly I-C / Q000008:administration & dosage; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D011950:Receptors, Cholinergic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology*; D055815:Young Adult
chemical_list: D053264:B-Cell Activating Factor; D054421:Chemokine CCL21; D054382:Chemokine CXCL13; D011950:Receptors, Cholinergic; C505719:TNFSF13B protein, human; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D011070:Poly I-C
keywords: Chemokines; Germinal centers; Glucocorticoids; Interferon; Thymus; Virus