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)-a 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-a-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-a 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.