Aberrantly Methylated DNA Regions Lead to Low Activation of CD4+ T Cells in IgA Nephropathy

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and has a strong genetic component. In this setting, also the DNA methylation could 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 the T cell receptor (TCR) signalling, TRIM27 and DUSP3,and an hypermethylated region included the VTRNA2-1 non-coding RNA, also known as miR-886 precursor. We showed that the aberrant methylation influence the expression of these genes in IgAN patients. Moreover, we demonstrated that the hypermethylation of miR-886 precursor led to a decreased CD4+ T cell proliferation following TCR stimulation and to the over-expression of TGFβ. Finally, we found a Th1/Th2 imbalance in IgAN patients. The IL-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. This study reveals new molecular mechanisms underlying the abnormal CD4+ T cell response in IgAN patients.