Altered editing in cyclic nucleotide phosphodiesterase 8A1 gene transcripts of systemic lupus erythematosus T lymphocytes.
The aetiopathogenesis of the abnormal immune response in systemic lupus erythematosus (SLE) remains incompletely understood. We and other investigators demonstrated altered expression of adenosine deaminase that act on RNA (ADAR) genes in SLE patients. Based on this information, we hypothesize that the altered expression and function of ADAR enzymes is a mechanism for the immunopathogenesis of SLE. ADARs edit gene transcripts through site-specific conversion of adenosine to inosine by hydrolytic deamination at C6 of the adenosine. Thirteen SLE subjects and eight healthy controls were studied. We assessed the role of ADAR enzymes in editing of PDE8A1 gene transcripts of normal and SLE T cells. These studies demonstrated the occurrence of ADAR-catalysed altered and site-selective editing profile of specific sites in the PDE8A1 gene transcripts of normal and SLE T cells. Two hot spots for A to I editing were observed in the PDE8A1 transcripts of normal and SLE T cells. A fundamental finding of this study is A to I hypo-editing followed by up-regulation of PDE8A1 transcripts in SLE T cells. These results are confirmed by analysing PDE8A1 transcripts of normal T cells activated with type I interferon-alpha. It is proposed that, the altered expression of ADAR enzymes tilt the balance of editing machinery and alter editing in SLE transcriptome. Such altered editing may contribute to the modulation of gene regulation and ultimately, immune functions in SLE and play an important role in the initiation and propagation of SLE pathogenesis.
Orlowski
Robert J
RJ
Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
O'Rourke
Kenneth S
KS
Olorenshaw
Irene
I
Hawkins
Gregory A
GA
Maas
Stefan
S
Laxminarayana
Dama
D
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics* / Q000276:immunology; D000328:Adult; D001483:Base Sequence; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D016898:Interferon-alpha / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D017393:RNA Editing; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000276:immunology
D016898:Interferon-alpha; D012333:RNA, Messenger; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C112770:PDE8A protein, human