Children with juvenile idiopathic arthritis (JIA), particularly boys, have significantly lower levels of DNA methyltransferases (DNMTs) — specific enzymes that suppress gene activity without changing their sequence — than healthy children, an Iranian study shows.
A deficiency in these enzymes may contribute to the development of JIA, but further studies are required to confirm these findings, the researchers said.
The study, “The expression of DNMTs is dramatically decreased in peripheral blood mononuclear cells of male patients with juvenile idiopathic arthritis,” was published in the journal Allergologia et Immunopathologia.
JIA is the most common autoimmune rheumatic disease among children and adolescents, with symptoms usually appearing before age 16. The disorder is more common in girls than in boys, but males are more severely affected.
While the underlying mechanisms of JIA are still poorly understood, scientists believe that a combination of genetic and environmental factors contribute to its development.
Environmental factors may affect the activity of certain genes by inducing epigenetic changes. Epigenetic alterations refer to DNA modifications that determine which genes will turn “on” or “off” without altering the actual genetic sequence.
One such change is DNA methylation, which is usually associated with the silencing, or turning “off” of genes. It involves DNMTs, which add a methyl chemical group to a specific spot in DNA.
A previous study showed that, due to reduced DNA methylation, people with JIA have an abnormally high activation of the IL32 gene in specific immune cells involved in JIA. The IL32 gene contains the instructions to produce a pro-inflammatory protein.
These findings suggested that impaired DNA methylation in immune cells may contribute to JIA development.
To explore this hypothesis, researchers in Iran examined the levels of three major DNMTs — DNMT1, DNMT3a, and DNMT3b — in peripheral blood mononuclear cells (PBMCs) of children with JIA and their healthy peers. PBMCs are immune cells that comprise B-cells and T-cells, as well as monocytes and macrophages.
The team compared the levels of the three DNMTs in 28 children with JIA (19 girls and 9 boys) with those of 28 healthy children (16 girls and 12 boys). They also assessed whether there were gender differences in the levels of the enzymes.
All of children were recruited at the Mofid Children’s Hospital, in Tehran, Iran. Children in both groups had a mean age of 7.5 years.
The results showed that immune cells of children with JIA had significantly lower levels of DNMT1 (by 7-fold) and DNMT3a (by 5.5-fold), compared with those of healthy children. The lower levels of DNMT3b in the JIA group were not statistically significant.
“Given that DNMT1, DNMT3a and 3b are the only methyltransferases in mammals, these results suggest that the genome of immune cells in JIA patients is hypomethylated [less altered with DNA methylation] compared to the genome of immune cells in healthy individuals,” the researchers said.
Comparisons within the same gender showed that girls with JIA had significantly lower levels of only DNMT1 compared to healthy girls. In contrast, levels of all three DNMTs were significantly reduced in boys with JIA than in controls of the same gender.
Notably, in the JIA group, the levels of DNMTs in immune cells were substantially more reduced in boys (6 to 14.2-fold) than in girls (1.5- to 5.2-fold), compared with those of healthy children.
“In conclusion, this study shows that DNMTs are reduced in JIA patient[s] and the expression of DNMTs is severely affected in young male JIA patients,” the researchers said.
The team noted that this gender difference might be associated with still poorly understood interactions between female hormones, DNMTs and methotrexate — a JIA therapy.
However, the investigators added that future studies are required to confirm these results. More research also is needed to better understand the potential processes behind the different levels of DNMTs and their impact on the disease, they added.