title: Transcriptome Analysis of Peripheral Blood in Chronic Inflammatory Demyelinating Polyradiculoneuropathy Patients Identifies TNFR1 and TLR Pathways in the IVIg Response.
abstract: We have studied the response to intravenous immunoglobulins (IVIg) by a transcriptomic approach in 11 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients (CIDP duration = 6 [0.83-6.5] years). RNA was extracted from cells in whole blood collected before and 3 weeks after IVIg treatment, and hybridized on Illumina chips. After RNA quality controls, gene expression was analyzed using statistical tests fitted for microarrays (R software, limma package), and a pathway analysis was performed using DAVID software. We identified 52 genes with expression that varied significantly after IVIg (fold change [FC] > 1.2, P < 0.001, false discovery rate [FDR] <0.05). Among these 52 genes, 7 were related to immunity, 3 were related to the tumor necrosis factor (TNF)-α receptor 1 (TNFR1) pathway (inhibitor of caspase-activated DNase (ICAD): FC = 1.8, P = 1.7E-7, FDR = 0.004; p21 protein-activated kinase 2 [PAK2]: FC = 1.66, P = 2.6E-5, FDR = 0.03; TNF-α-induced protein 8-like protein 1 [TNFAIP8L1]: P = 1.00E-05, FDR = 0.026), and 2 were related to Toll-like receptors (TLRs), especially TLRs 7 and 9, and were implicated in autoimmunity. These genes were UNC93B1 (FC = 1.6, P = 2E-5, FDR = 0.03), which transports TLRs 7 and 9 to the endolysosomes, and RNF216 (FC = 1.5, P = 1E-05, FDR = 0.03), which promotes TLR 9 degradation. Pathway analysis showed that the TNFR1 pathway was significantly lessened by IVIg (enrichment score = 24, Fischer exact test = 0.003). TNF-α gene expression was higher in responder patients than in nonresponders; however, it decreased after IVIg in responders (P = 0.04), but remained stable in nonresponders. Our data suggest the actions of IVIg on the TNFR1 pathway and an original mechanism involving innate immunity through TLRs in CIDP pathophysiology and the response to IVIg. We conclude that responder patients have stronger inflammatory activity that is lessened by IVIg.
authors.affiliation: From the Sorbonne Universités (AR, J-CC, KT), UPMC Univ Paris 06, INSERM UMRS_1127, CIC_1422, CNRS UMR_7225, AP-HP, and ICM, Hôpital Pitié-Salpêtrière, Département des maladies du système nerveux; Hôpital Pitié Salpêtrière (RD, PR, KV), Département de Neurophysiologie Clinique; Plateforme Post-génomique P3S (WC), UPMC, Site Pitié Salpêtrière; IHU-A-ICM Bioinformatics/Biostatistics Core Facility (JG, VG), Paris; Hôpital de Bicêtre (CL, DA), Centre de Référence des Neuropathies Amyloïdes et autres Neuropathies Périphériques Rares, Le Kremlin-Bicêtre; and AP-HP, Hôpital Pitié Salpêtrière, Service de Médecine Interne, Institut E3M, Centre National de Référence Maladies auto-immunes Systémiques Rares, et Université Paris VI Pierre et Marie Curie, Sorbonnes Université, Paris, France (FCA).
authors.forename: Alexandra
authors.initials: A
authors.lastname: Richard
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.forename: Rabab
authors.initials: R
authors.lastname: Debs
authors.forename: Pauline
authors.initials: P
authors.lastname: Reach
authors.forename: Khadija
authors.initials: K
authors.lastname: Tahiri
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.forename: Justine
authors.initials: J
authors.lastname: Gueguen
authors.forename: Vincent
authors.initials: V
authors.lastname: Guillemot
authors.forename: Céline
authors.initials: C
authors.lastname: Labeyrie
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.forename: Karine
authors.initials: K
authors.lastname: Viala
authors.forename: Fleur
authors.initials: F
authors.lastname: Cohen Aubart
mesh_terms: D000368:Aged; D000917:Antibody Formation / Q000187:drug effects / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D051193:Toll-Like Receptors / Q000097:blood / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000187:drug effects
chemical_list: D016756:Immunoglobulins, Intravenous; D047888:Receptors, Tumor Necrosis Factor, Type I; C439524:TNF protein, human; C506235:TNFRSF1A protein, human; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha