Up-regulated interleukin-4 production by peripheral T-helper cells in idiopathic membranous nephropathy

Background. Helper T (Th) cells are classified into Th1 and Th2 subsets based on cytokine production and the Th1/Th2 paradigm explains differences in inflammatory effector pathways in various human diseases. Membranous nephropathy (MN) is an immune complex disease associated with Th2 nephritogenic immune response. However, overproduction of interleukin (IL)-4, a principal Th2 cytokine, has not been demonstrated. We investigated Th1/Th2 cytokine production by peripheral Th cells and its association with the degree of proteinuria in MN. Methods. We analysed production of Th1/Th2 cytokines, interferon (IFN)-γ and IL-4 by peripheral Th cells, using an intracellular cytokine detection method with flow cytometry in patients with MN (n=24). The data were compared with data from healthy subjects (n=51), subjects with minimal change nephrotic syndrome (MCNS; n=13) and subjects with focal segmental glomerulosclerosis (FSGS; n=12). We compared the percentages of IFN-γ+ and IL-4+ Th cells and the peripheral Th1/Th2 ratio (IFN-γ/IL-4 ratio) among the four groups. We also examined the association of IFN-γ and IL-4 production with clinical parameters of MN. Results. The mean percentage of IL-4+ cells in MN (3.9 ± 1.2%) was significantly higher than in the control (2.4 ± 1.0%), MCNS (2.3 ± 1.4%) and FSGS (2.3±1.2%) groups (P<0.001, respectively). The Th1/Th2 ratio was significantly lower in MN (5.3 ± 2.0) than in the control (8.2 ± 4.2, P<0.05), MCNS (10.0 ± 5.3, P<0.01) and FSGS (10.2 ± 5.3, P<0.01) groups. Moreover, the percentage of IL-4+ cells correlated significantly with the amount of proteinuria in MN (r=0.57, P<0.01). Conclusions. IL-4 production by peripheral Th cells is up-regulated in patients with MN and correlated with the severity of proteinuria. Intracellular cytokine analysis could be a useful index in idiopathic MN.