A disease- specific convergence of host and Epstein-Barr virus genetics in multiple sclerosis

被引：0

作者：

Mechelli, Rosella ^{[1
,2
]}

Umeton, Renato ^{[3
,4
,5
]}

Bellucci, Gianmarco ^{[6
]}

Bigi, Rachele ^{[6
]}

Rinaldi, Virginia

Angelini, Daniela F. ^{[7
]}

Guerrera, Gisella ^{[7
]}

Pignalosa, Francesca C. ^{[1
,2
]}

Ilari, Sara ^{[2
]}

Patrone, Marco ^{[8
]}

Srinivasan, Sundararajan ^{[9
,10
]}

Cerono, Gabriel ^{[11
]}

Romano, Silvia ^{[6
]}

Buscarinu, Maria C. ^{[6
]}

Martire, Serena ^{[12
,13
,14
,16
]}

Malucchi, Simona ^{[15
]}

Landi, Doriana ^{[17
]}

Lorefice, Lorena ^{[18
]}

Steinman, Lawrence

Umeton, Raffaella Pizzolato ^{[19
,20
,21
]}

Anastasiadou, Eleni ^{[22
]}

Trivedi, Pankaj ^{[23
]}

Fornasiero, Arianna ^{[6
]}

Ferraldeschi, Michela ^{[6
]}

Di Sapio, Alessia ^{[12
,13
,15
,16
]}

Marfia, Gerolama ^{[17
]}

Cocco, Eleonora ^{[18
]}

Centonze, Diego ^{[24
,25
]}

Uccelli, Antonio ^{[26
,27
,28
]}

Di Silvestre, Dario ^{[29
]}

Mauri, Pierluigi ^{[29
]}

de Candia, Paola ^{[30
]}

D'Alfonso, Sandra ^{[31
]}

Battistini, Luca ^{[7
,8
]}

Farina, Cinthia ^{[9
,10
]}

Magliozzi, Roberta ^{[32
,33
]}

Reynolds, Richard ^{[33
]}

Baranzini, Sergio E. ^{[11
]}

Matarese, Giuseppe ^{[30
,34
]}

Salvetti, Marco ^{[6
,7
,25
]}

Ristori, Giovanni ^{[7
]}

机构：

[1] San Raffaele Roma Univ, Dept Promot Human Sci & Qual Life, Rome, Italy

[2] Ist Ricovero & Cura Carattere Sci San Raffaele, I-00166 Rome, Italy

[3] Weill Cornell Med, New York, NY 10021 USA

[4] MIT, Cambridge, MA 02139 USA

[5] Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA

[6] Sapienza Univ, Ctr Expt Neurol Therapies, Dept Neurosci Mental Hlth & Sensory Organs, I-00189 Rome, Italy

[7] Fdn Santa Lucia, Neuroimmunol Unit, Ist Ricovero & Cura Carattere Sci, I-00179 Rome, Italy

[8] Ist Ricovero & Cura Carattere Sci, San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, Biocrystallog Unit, I-20132 Milan, Italy

[9] Ist Ricovero & Cura Carattere Sci, Inst Expt Neurol, San Raffaele Sci Inst, I-20132 Milan, Italy

[10] Ist Ricovero & Cura Carattere Sci, San Raffaele Sci Inst, Div Neurosci, I-20132 Milan, Italy

[11] Univ Calif San Francisco, Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA

[12] Neurosci Inst Cavalieri Ottolenghi, Clin Neurobiol Unit, I-10043 Orbassano, Italy

[13] Univ Hosp San Luigi Gonzaga, Ctr Riferimento Reg Sclerosi Multipla Biobank, I-10043 Orbassano, Italy

[14] Univ Turin, Dept Neurosci Rita Levi Montalcini, I-10043 Turin, Italy

[15] Univ Hosp San Luigi Gonzaga, Dept Neurol, I-10043 Orbassano, Italy

[16] Univ Hosp San Luigi Gonzaga, Ctr Riferimento Reg Sclerosi Multipla, I-10043 Orbassano, Italy

[17] Tor Vergata Univ, Dept Syst Med, Multiple Sclerosis Clin & Res Unit, I-00133 Rome, Italy

[18] Univ Cagliari, Binaghi Hosp, Multiple Sclerosis Ctr, Dept Med Sci & Publ Hlth,Azienda Sanitaria Locale, I-09126 Cagliari, Italy

[19] Univ Massachusetts, Med Sch, Dept Neurol, Worcester, MA 01655 USA

[20] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[21] Harvard Med Sch, Boston, MA 02115 USA

[22] Sapienza Univ, Dept Clin & Mol Med, I-00189 Rome, Italy

[23] Sapienza Univ, Dept Expt Med, I-00161 Rome, Italy

[24] Tor Vergata Univ, Dept Syst Med, I-00133 Rome, Italy

[25] Ist Ricovero & Cura Carattere Sci, Ist Neurol Mediterraneo Neuromed, I-86077 Pozzilli, Italy

[26] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, I-16132 Genoa, Italy

[27] Univ Genoa, Ctr Excellence Biomed Res, I-16132 Genoa, Italy

[28] Osped Policlin San Martino, Ist Ricovero & Cura Carattere Sci, I-16132 Genoa, Italy

[29] CNR, Ist Tecnol Biomed, Elixir Prote Lab, I-20054 Milan, Italy

[30] Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Treg Cell Lab, I-80131 Naples, Italy

[31] Univ Piemonte Orientale, Interdisciplinary Res Ctr Autoimmune Dis, Dept Hlth Sci, I-28100 Novara, Italy

[32] Univ Verona, Dept Neurosci Biomed & Movement Sci, Neurol B, I-37134 Verona, Italy

[33] Imperial Coll London, Fac Med, Dept Brain Sci, London, W12 ONN, England

[34] CNR, Ist Endocrinol & Oncol Sperimentale, Lab Immunol, I-80131 Naples, Italy

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2025年 / 122卷 / 14期

关键词：

autoimmunity; Epstein-Barr virus; multiple sclerosis; B-CELLS; REVEALS; NETWORK; TOLERANCE; ANTIGENS; COMMON; EBV;

D O I：

10.1073/pnas.241878312

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Recent sero-epidemiological studies have strengthened the hypothesis that Epstein-Barr virus (EBV) may be a causal factor in multiple sclerosis (MS). Given the complexity of the EBV-host interaction, various mechanisms may be responsible for the disease pathogenesis. Furthermore, it remains unclear whether this is a disease-specific process. Here, we showed that genes encoding EBV interactors are enriched in loci associated with MS but not with other diseases and in prioritized therapeutic targets. Analyses of MS blood and brain transcriptomes confirmed a dysregulation of MS-associated EBV interactors affecting the CD40 pathway. Such interactors were strongly enriched in binding sites for the EBV nuclear antigen 2 (EBNA2) viral transcriptional regulator, often in colocalization with CCCTC binding factor (CTCF) and RNA Polymerase II Subunit A (POLR2A). EBNA2 was expressed in the MS brain. The 1.2 EBNA2 allele downregulated the expression of the CD40 MS-associated gene analogously to the CD40 MS-risk variant. Finally, we showed that the 1.2 EBNA2 allele associates with the risk of MS. This study delineates how host and viral genetic variability converge in MS-specific pathogenetic mechanisms.

引用

页数：11

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