A novel infection- and inflammation(_)associated molecular signature in peripheral blood of myasthenia gravis patients

作者：Barzago Claudia; Lum Josephine; Cavalcante Paola; Srinivasan Kandhadayar Gopalan; Faggiani Elisa; Camera Giorgia; Bonanno Silvia; Andreetta Francesca; Antozzi Carlo; Baggi Fulvio; Calogero Raffaele Adolfo; Bernasconi Pia; Mantegazza Renato; Mori Lucia; Zolezzi Francesca

来源：Immunobiology, 2016, 221(11): 1227-1236.

DOI：10.1016/j.imbio.2016.06.012

• Myasthenia gravis
• Peripheral blood mononuclear cells
• Whole-transcriptome sequencing
• Inflammation
• Viral infection
• microRNAs

Myasthenia gravis (MG) is a T-cell dependent autoimmune disorder of the neuromuscular junction, characterised by muscle weakness and fatigability. Autoimmunity is thought to initiate in the thymus of acetylcholine receptor (AChR)-positive MG patients; however, the molecular mechanisms linking intrathymic MG pathogenesis with autoreactivity via the circulation to the muscle target organ are poorly understood. Using whole-transcriptome sequencing, we compared the transcriptional profile of peripheral blood mononuclear cells from AChR-early onset MG (AChR-EOMG) patients with healthy controls: 178 coding transcripts and 229 long non-coding RNAs, including 11 pre-miRNAs, were differentially expressed. Among the 178 coding transcripts, 128 were annotated of which 17% were associated with the 'infectious disease' functional category and 46% with 'inflammatory disease' and 'inflammatory response-associated' categories. Validation of selected transcripts by qPCR indicated that of the infectious disease-related transcripts, ETF1, NEKB2, PLK3, and PPP1R15A were upregulated, whereas CLC and 1L4 were downregulated in AChR-EOMG patients; in the 'inflammatory' categories, ABCAI, FUS, and RELB were upregulated, suggesting a contribution of these molecules to immunological dysfunctions in MG. Data selection and validation were also based on predicted microRNA-mRNA interactions. We found that miR-612, miR-3654, and miR-3651 were increased, whereas miR-612-putative AICAp12 and HRH4 targets and the miR-3651-putative CRISP3 target were downregulated in AChR-EOMG, also suggesting altered immunoregulation. Our findings reveal a novel peripheral molecular signature in AChR-EOMG, reflecting a critical involvement of inflammatory-and infectious disease-related immune responses in disease pathogenesis.

• 出版日期2016-11