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J Immunol. 2017 Jul 15;199(2):477-488. doi: 10.4049/jimmunol.1601299. Epub 2017 Jun 19.

T Cell Transcriptomes from Paroxysmal Nocturnal Hemoglobinuria Patients Reveal Novel Signaling Pathways.

Author information

1
Cell Biology Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and kohei.hosokawa@nih.gov.
2
Cell Biology Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and.
3
Beijing Genomics Institute-Shenzhen, Shenzhen 518083, China.

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder originating from hematopoietic stem cells and is a life-threating disease characterized by intravascular hemolysis, bone marrow (BM) failure, and venous thrombosis. The etiology of PNH is a somatic mutation in the phosphatidylinositol glycan class A gene (PIG-A) on the X chromosome, which blocks synthesis of the glycolipid moiety and causes deficiency in GPI-anchored proteins. PNH is closely related to aplastic anemia, in which T cells mediate destruction of BM. To identify aberrant molecular mechanisms involved in immune targeting of hematopoietic stem cells in BM, we applied RNA-seq to examine the transcriptome of T cell subsets (CD4+ naive, CD4+ memory, CD8+ naive, and CD8+ memory) from PNH patients and healthy control subjects. Differentially expressed gene analysis in four different T cell subsets from PNH and healthy control subjects showed distinct transcriptional profiles, depending on the T cell subsets. By pathway analysis, we identified novel signaling pathways in T cell subsets from PNH, including increased gene expression involved in TNFR, IGF1, NOTCH, AP-1, and ATF2 pathways. Dysregulation of several candidate genes (JUN, TNFAIP3, TOB1, GIMAP4, GIMAP6, TRMT112, NR4A2, CD69, and TNFSF8) was validated by quantitative real-time RT-PCR and flow cytometry. We have demonstrated molecular signatures associated with positive and negative regulators in T cells, suggesting novel pathophysiologic mechanisms in PNH. These pathways may be targets for new strategies to modulate T cell immune responses in BM failure.

PMID:
28630090
PMCID:
PMC5543699
DOI:
10.4049/jimmunol.1601299
[Indexed for MEDLINE]
Free PMC Article

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