Thymoma-associated myasthenia gravis: On the search for a pathogen signature.
Myasthenia gravis (MG) is an autoimmune disease mainly mediated by anti-acetylcholine receptor (AChR) antibodies. In the late onset, a thymoma, tumor of the thymus, is quite frequent. However, the events leading to thymoma and MG are not understood. As thymoma-associated MG (MG-T) patients also display anti-interferon type I (IFN-I) neutralizing antibodies, we investigated if MG-T could be associated with an anti-viral signature. RT-PCR analyses demonstrated huge increases of IFN-I subtypes, IFN-α2, -α8, -ω and -β, in thymoma-associated MG but not in thymomas without MG or in control thymuses. Next, we investigated if dsRNA signaling pathway involvement could be observed in MG-T, as recently observed in early-onset MG. We observed an abnormal regulation of dsRNA-sensing molecules with an increase of toll-like receptor 3 (TLR3), and a decrease of protein kinase R (PKR) and dsRNA helicases (RIG-I and MDA5) in thymoma from MG patients. We also detected a decreased expression of p53, the tumor suppressor that is known to be down-regulated by dsRNA. Altogether, these results strongly suggest that MG-T could be linked to a viral infection. As p16 (CDKN2A), a marker of HPV infections, was up-regulated in MG-T, we thus screened DNA from thymomas for human papillomavirus (HPV) by real-time PCR using HPV consensus SPF10 primers. RT-PCR results were negative for all samples tested. We confirmed the absence of HPV DNA detection by end point PCR using FAP primers to amplify a larger panel of HPV genotypes. Our data clearly demonstrate INF-I overexpression together with the activation of innate immunity pathways in thymoma-associated MG suggesting that MG might develop after a pathogen infection. We were not able to relate thymoma to HPV infections and the implication of other pathogens is discussed.
INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institut de myologie, Paris, France.
Perrine
P
Cufi
Service de Virologie, Hôpital Tenon, Paris, France; INSERM U845, Paris, France.
Patrick
P
Soussan
INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institut de myologie, Paris, France.
Frédérique
F
Truffault
Service de Virologie, Hôpital Tenon, Paris, France; INSERM U845, Paris, France.
Rachid
R
Fetouchi
INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institut de myologie, Paris, France.
Marieke
M
Robinet
Hôpital Marie Lannelongue, Université Paris-Sud, Le Plessis-Robinson, France.
Elie
E
Fadel
INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institut de myologie, Paris, France.
Sonia
S
Berrih-Aknin
INSERM U974, Paris, France; CNRS UMR 7215, Paris, France; UPMC Univ Paris 6, Paris, France; AIM, Institut de myologie, Paris, France. Electronic address: rozen.lepanse@upmc.fr.
Rozen
R
Le Panse
D000328:Adult; D000368:Aged; D052685:Alphapapillomavirus / Q000235:genetics / Q000276:immunology*; D000914:Antibodies, Viral / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism; D002478:Cells, Cultured; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D007223:Infant; D007231:Infant, Newborn; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology; D013945:Thymoma / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D013953:Thymus Neoplasms / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
D000914:Antibodies, Viral; D001323:Autoantibodies; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D007370:Interferon Type I; D011950:Receptors, Cholinergic
Innate immunity; Interferon type I; Myasthenia gravis; Thymoma; Toll-like receptors; Virus