title: Aberrantly methylated DNA regions lead to low activation of CD4+ T-cells in IgA nephropathy.
abstract: IgAN (IgA nephropathy) is the most common form of primary glomerulonephritis worldwide and has a strong genetic component. In this setting, DNA methylation could also be an important factor influencing this disease. We performed a genome-wide screening for DNA methylation in CD4(+) T-cells from IgAN patients and found three regions aberrantly methylated influencing genes involved in the response and proliferation of CD4(+) T-cells. Two hypomethylated regions codified genes involved in TCR (T-cell receptor) signalling, TRIM27 (tripartite motif-containing 27) and DUSP3 (dual-specificity phosphatase 3), and an hypermethylated region included the VTRNA2-1 (vault RNA 2-1) non-coding RNA, also known as miR-886 precursor. We showed that the aberrant methylation influences the expression of these genes in IgAN patients. Moreover, we demonstrated that the hypermethylation of the miR-886 precursor led to a decreased CD4(+) T-cell proliferation following TCR stimulation and to the overexpression of TGFβ (transforming growth factor β). Finally, we found a Th1/Th2 imbalance in IgAN patients. The IL (interleukin)-2/IL-5 ratio was notably higher in IgAN patients and clearly indicated a Th1 shift. In conclusion, we identified for the first time some specific DNA regions abnormally methylated in IgAN patients that led to the reduced TCR signal strength of the CD4(+) T-cells and to their anomalous response and activation that could explain the T-helper cell imbalance. The present study reveals new molecular mechanisms underlying the abnormal CD4(+) T-cell response in IgAN patients.
authors: University of Bari, DETO, Bari, Italy Università del Salento, DiSTeBA, Lecce, Italy C.A.R.S.O. Consortium, Valenzano, Italy.
authors: Fabio
authors: F
authors: Sallustio
authors: University of Bari, DETO, Bari, Italy IRCCS "de Bellis", Laboratory of Experimental Immunopathology, 70013 Castellana Grotte, BA, Italy.
authors: Grazia
authors: G
authors: Serino
authors: University of Bari, DETO, Bari, Italy.
authors: Sharon N
authors: SN
authors: Cox
authors: University of Verona, Department of Medicine, Verona, Italy.
authors: Alessandra
authors: A
authors: Dalla Gassa
authors: C.A.R.S.O. Consortium, Valenzano, Italy.
authors: Claudia
authors: C
authors: Curci
authors: C.A.R.S.O. Consortium, Valenzano, Italy.
authors: Giuseppe
authors: G
authors: De Palma
authors: IRCCS AOU San Martino-IST, Genova, Italy.
authors: Barbara
authors: B
authors: Banelli
authors: IRCCS "de Bellis", Laboratory of Experimental Immunopathology, 70013 Castellana Grotte, BA, Italy University of Verona, Department of Medicine, Verona, Italy.
authors: Gianluigi
authors: G
authors: Zaza
authors: IRCCS AOU San Martino-IST, Genova, Italy.
authors: Massimo
authors: M
authors: Romani
authors: University of Bari, DETO, Bari, Italy C.A.R.S.O. Consortium, Valenzano, Italy paolo.schena@uniba.it.
authors: Francesco P
authors: FP
authors: Schena
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D002460:Cell Line; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D003710:Demography; D005260:Female; D005786:Gene Expression Regulation; D015894:Genome, Human; D005922:Glomerulonephritis, IGA / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results
keywords: CD4+ T-cells; DNA methylation; DUSP3; IgA nephropathy; T-cell receptor; TRIM27; VTRNA2-1