4.0 Discussion
A large body of evidence has demonstrated that the immune system may
play a crucial role in INS[3]. To date, the underlying pathogenesis
of INS remains largely unknown. Some researchers hypothesize that INS
may be caused by dysregulation of T lymphocytes or an abnormal T cell
response[3-8]. MCD is the most common cause of INS[1-2,18-19].
Th2 cells play an important role in allergic inflammatory
diseases[9-11,25, 28] . The association of pollen sensitivity and
seasonal proteinuria was first reported more than 60 years ago[12].
Minimal change nephrotic syndrome is often associated with clinical
features of allergy such as bronchial asthma, allergic rhinitis, atopic
dermatitis and urticaria. Some studies have also confirmed that patients
with INS also may show increased serum IgE levels, especially in
children with repeated recurrence[13-15,18]. However, the causal
relationship between the increase of serum IgE or atopy and the
pathogenesis of INS remains to be further explored. This study found
that the plasma IgE during the active phase was significantly increased
in the initial atopic and non-atopic groups compared with the control
group, and it also significantly decreased during the remission phase.
In remission, the IgE level of non-atopic INS children tended to be
normal, while IgE level of atopic was still high. These results
suggested that atopic and non-atopic INS have increased serum IgE
levels, but further investigation of the cytokine regulating network of
serum IgE was necessary to clarify the relationship between IgE
production and INS.
IL-13 and IL-4 secreted by Th2 cells can promote the production of IgE
in B cells[9-11]. IL-13 is known to induce a switch from IgM to IgE
in B cells and induce CD80 expression by podocytes. Concomitantly,
increased CD80 expression by podocytes is associated with
proteinuria[13-15, 18]. And, IL-13 is present in urine and serum of
patients with kidney disease and is associated with a large amount of
proteinuria[13-15, 18], which suggesting that IL-13 is related to
the pathogenesis of kidney disease, but the mechanisms resulting in
IL-13 increasing was still unclear. In recent years, studies have found
that Th2-related factors IL-13 and IL-4 are increased in active INS
[13-15, 18]. A few studies have also noted that the proportion of
Th2 cells in INS is increased[8,18, 21-22], but It is still
controversial whether the proportion is abnormally increased, so this
article further tested the expression of Th2 cells in peripheral blood
and the concentrations of IL-13 and IL-4 in the plasma. our data
demonstrate that the expression levels of Th2-related factors ( IL-13,
IL-4 ) was significantly increased in the initial atopic and non-atopic
groups, at the same time, Th2 cells were over-activation. These results
suggested that the proteinuria and increased IgE levels in the initial
atopic and non-atopic during the active phase might be related to the
high expression of IL-13 and IL-4 which were caused by Th2 drifting, but
the mechanism that lead to Th2 drifting still needed to be studied to
further explain the pathogenesis of INS immune.
MiRNAs are subtle master controllers of gene expression and therefore
play a crucial role in the pathogenesis of human diseases, especially in
chronic multifactorial diseases[23-24]. Some specific miRNAs have
been reported to be abnormally expressed in various allergic and
autoimmune diseases such as asthma, SLE, Lupus Nephritis and are
associated with disease activity [25, 29-30 ]. MiRNAs are important
for Th2 cell proliferation, differentiation and immune
function[25-27]. MiR-24 and 27 suppress allergic inflammation and
target a network of regulators of Th2 cell-associated cytokine
production[26-27]. However, it is unclear whether changes in miRNAs
expression alter Th2 expression in active INS. Therefore, In this study
we further observed the expression changes of miR-24 and miR-27 involved
in regulating Th2 cell differentiation. The results showed that miR-24
and miR-27 were lowly expressed in children with active non-atopic INS,
suggesting that Th2 cells drifting might be related to the low-
expression of miR- 24 and miR-27.
In order to verify whether this hypothesis was true, we used cell
transfection technology to transfer miRNA24 or miR-27 mimic to
non-atopic and healthy control group mononuclear cells to increase the
expression level, and transfer miR-24 or miR-27 inhibitor to reduce the
expression level. The normal control group was also set up to verify the
effect of transfection. The results showed that the proportion of Th2
cells and the expression of Th2 cell-associated cytokine IL-4 were
decreased in the miR-24 and miR-27 up-regulated groups. In contrast, the
proportion of Th2 cells and the expression of Th2 cell-associated
cytokine IL-4 were increased in miR-24 and miR-27 down-regulated groups,
indicating that miR-24, miR- 27 negatively regulated Th2 cell
expression. Combining the expression trends of miR-24, miR-27 and Th2
cells obtained from patients’ peripheral blood mononuclear cells, our
hypothesis was true, miR-24 and
miR-27 negatively regulated the change in the proportion of Th2 cells,
and they might play an important role in Th2 expression in active period
INS.
In conclusion, Th2 related-cytokine IL-13 was related to the
pathogenesis of kidney disease, but the mechanisms resulting in IL-13
increasing was still unclear. Our results suggested that there were high
IgE in children with both atopic and non-atopic INS during the active
period, which might be related to the high expression of IL-13 and IL-4
induced by Th2 cells drifting. The expressions of miR-24 and miR-27 were
down-regulated in the initial non-atopic INS, the proportion of Th2
cells and IL-4mRNA expression were remarkably increased, which leading
to IL-13 over-expression and increased IgE levels. That was, miR-24 and
miR-27 negative regulated the expressions of Th2 cells and played an
important role in the change of Th2 expression in children with active
INS. Therefore, we speculated that miRNAs would be potential therapeutic
targets for kidney disease, our research has provided a new research
direction and treatment method for the treatment of INS.