title: A novel infection- and inflammation-associated molecular signature in peripheral blood of myasthenia gravis patients.
abstract: 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 intra-thymic 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, NFKB2, PLK3, and PPP1R15A were upregulated, whereas CLC and IL4 were downregulated in AChR-EOMG patients; in the 'inflammatory' categories, ABCA1, 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 AKAp12 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.
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, 138648 Singapore; Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy. Electronic address: claudia.barzago@istituto-besta.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Barzago
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, 138648 Singapore. Electronic address: josephine_lum@immunol.a-star.edu.sg.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lum
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy. Electronic address: paola.cavalcante@istituto-besta.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Cavalcante
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, 138648 Singapore. Electronic address: srinivasan_kg@immunol.a-star.edu.sg.
authors.forename: Kandhadayar Gopalan
authors.initials: KG
authors.lastname: Srinivasan
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy. Electronic address: elisa.faggiani@istituto-besta.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Faggiani
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy. Electronic address: giorgia.camera@istituto-besta.it.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Camera
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy. Electronic address: silvia.bonanno@istituto-besta.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bonanno
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy. Electronic address: francesca.andreetta@istituto-besta.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Andreetta
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy. Electronic address: carlo.antozzi@istituto-besta.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Antozzi
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy. Electronic address: fulvio.baggi@istituto-besta.it.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Baggi
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy. Electronic address: raffaele.calogero@unito.it.
authors.forename: Raffaele Adolfo
authors.initials: RA
authors.lastname: Calogero
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy. Electronic address: pia.bernasconi@istituto-besta.it.
authors.forename: Pia
authors.initials: P
authors.lastname: Bernasconi
authors.affiliation: Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy. Electronic address: renato.mantegazza@istituto-besta.it.
authors.forename: Renato
authors.initials: R
authors.lastname: Mantegazza
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, 138648 Singapore. Electronic address: lucia.mori@unibas.ch.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mori
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, 138648 Singapore. Electronic address: francesca.zolezzi@galderma.com.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zolezzi
mesh_terms: D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D015415:Biomarkers; D016022:Case-Control Studies; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007239:Infections / Q000150:complications* / Q000209:etiology; D007249:Inflammation / Q000150:complications* / Q000209:etiology; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000097:blood / Q000175:diagnosis / Q000209:etiology*; D022661:RNA, Untranslated / Q000235:genetics; D011950:Receptors, Cholinergic / Q000378:metabolism; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D022661:RNA, Untranslated; D011950:Receptors, Cholinergic
keywords: Inflammation; Myasthenia gravis; Peripheral blood mononuclear cells; Viral infection; Whole-transcriptome sequencing; microRNAs