1. A novel infection- and inflammation-associated molecular signature in peripheral blood of myasthenia gravis patients
- Author
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Josephine Lum, Paola Cavalcante, Pia Bernasconi, Kandhadayar G. Srinivasan, Claudia Barzago, Silvia Bonanno, Elisa Faggiani, Lucia Mori, Francesca Andreetta, Raffaele A. Calogero, Giorgia Camera, Francesca Zolezzi, Fulvio Baggi, Carlo Antozzi, Renato Mantegazza, Barzago, C, Lum, J, Cavalcante, P, Srinivasan, K, Faggiani, E, Camera, G, Bonanno, S, Andreetta, F, Antozzi, C, Baggi, F, Calogero, R, Bernasconi, P, Mantegazza, R, Mori, L, and Zolezzi, F
- Subjects
0301 basic medicine ,Male ,RNA, Untranslated ,Myasthenia gravi ,medicine.disease_cause ,Autoimmunity ,Pathogenesis ,0302 clinical medicine ,Medicine ,Immunology and Allergy ,Cluster Analysis ,Receptors, Cholinergic ,Age of Onset ,Hematology ,microRNA ,Age Factors ,Middle Aged ,Female ,medicine.symptom ,Adult ,medicine.medical_specialty ,Immunology ,Inflammation ,Infections ,Peripheral blood mononuclear cell ,03 medical and health sciences ,Immune system ,Internal medicine ,Myasthenia Gravis ,Humans ,business.industry ,Gene Expression Profiling ,Muscle weakness ,medicine.disease ,Myasthenia gravis ,MicroRNAs ,Peripheral blood mononuclear cells ,Viral infection ,Whole-transcriptome sequencing ,030104 developmental biology ,Gene Expression Regulation ,Case-Control Studies ,Leukocytes, Mononuclear ,business ,Transcriptome ,030217 neurology & neurosurgery ,Biomarkers - 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.
- Published
- 2016