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.
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Paraffin section of knee joint from CIA mouse model. Safranin-O/fast green staining showed significant cartilage degeneration and bone erosion in femorotibial joint. For further details see pp. 667-681. Image kindly provided by Dr. Chih-Hsin Tang.
Research Article|
March 18 2016
Aberrantly methylated DNA regions lead to low activation of CD4+ T-cells in IgA nephropathy
Fabio Sallustio;
Fabio Sallustio
1
*University of Bari, DETO, Bari, Italy
†Università del Salento, DiSTeBA, Lecce, Italy
‡C.A.R.S.O. Consortium, Valenzano, Italy
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Grazia Serino;
Grazia Serino
1
*University of Bari, DETO, Bari, Italy
§IRCCS “de Bellis”, Laboratory of Experimental Immunopathology, 70013 Castellana Grotte, BA, Italy
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Sharon N. Cox;
Sharon N. Cox
*University of Bari, DETO, Bari, Italy
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Alessandra Dalla Gassa;
Alessandra Dalla Gassa
║University of Verona, Department of Medicine, Verona, Italy
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Claudia Curci;
Claudia Curci
‡C.A.R.S.O. Consortium, Valenzano, Italy
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Giuseppe De Palma;
Giuseppe De Palma
‡C.A.R.S.O. Consortium, Valenzano, Italy
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Barbara Banelli;
Barbara Banelli
¶IRCCS AOU San Martino-IST, Genova, Italy
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Gianluigi Zaza;
Gianluigi Zaza
§IRCCS “de Bellis”, Laboratory of Experimental Immunopathology, 70013 Castellana Grotte, BA, Italy
║University of Verona, Department of Medicine, Verona, Italy
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Massimo Romani;
Massimo Romani
¶IRCCS AOU San Martino-IST, Genova, Italy
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Francesco P. Schena
*University of Bari, DETO, Bari, Italy
‡C.A.R.S.O. Consortium, Valenzano, Italy
Correspondence: Professor Francesco P. Schena (email [email protected]).
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Publisher: Portland Press Ltd
Received:
October 07 2015
Revision Received:
January 21 2016
Accepted:
February 04 2016
Accepted Manuscript online:
February 04 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 Authors; published by Portland Press Limited
2016
Clin Sci (Lond) (2016) 130 (9): 733–746.
Article history
Received:
October 07 2015
Revision Received:
January 21 2016
Accepted:
February 04 2016
Accepted Manuscript online:
February 04 2016
Citation
Fabio Sallustio, Grazia Serino, Sharon N. Cox, Alessandra Dalla Gassa, Claudia Curci, Giuseppe De Palma, Barbara Banelli, Gianluigi Zaza, Massimo Romani, Francesco P. Schena; Aberrantly methylated DNA regions lead to low activation of CD4+ T-cells in IgA nephropathy. Clin Sci (Lond) 1 May 2016; 130 (9): 733–746. doi: https://doi.org/10.1042/CS20150711
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