New findings add to understanding of mechanisms of disease in AS
Loss of DNA modification might promote inflammatory immune cells: Study
Reductions in an epigenetic marker — a type of chemical modification to DNA — called H3K27me3 were seen in people with active ankylosing spondylitis (AS) in a new study, according to researchers, who say these findings shed light on the mechanisms of the chronic inflammatory disease.
The scientists believe the observed reductions contribute to the elevated levels of immune cell populations that are known to drive inflammation in AS.
“These findings contribute to our understanding and knowledge of the mechanisms underlying AS inflammation and may provide valuable insights for the development of novel therapeutic strategies,” the researchers wrote, noting that changes in H3K27me3 “may be one of the key regulatory factors” of the disease.
The study, “The Role of H3K27me3-Mediated Th17 Differentiation in Ankylosing Spondylitis,” was published in the journal Inflammation.
Investigating a marker called H3K27me3 in study of AS disease mechanisms
AS affects the joints of the spine, and a type of immune cells called T helper 17 (Th17) cells is considered to be a major contributor to this inflammation.
Research indicates that Th17 cell differentiation — the process by which precursor cells mature and take on their specialized functions — is altered in AS. In turn, the number of Th17 cells and the inflammatory signaling molecules, or cytokines, that they produce are elevated in AS patients relative to healthy people.
For a cell to differentiate, it involves changes in the activity of many genes. Epigenetics, or chemical modifications that influence gene activity, are thus very important for this process.
One such modification called H3K27me3 — or Histone 3 Lys 27 trimethylation — has been identified as a regulator of Th17 cell differentiation. It involves a type of epigenetic change called methylation, which works to suppress the activity of genes.
The RORyt protein is important for Th17 differentiation. Studies indicate that H3K27me3 can suppress the activation of the gene, called RORc, that encodes that protein, thereby keeping Th17 cell differentiation under control.
In their study, the researchers explored whether a change in H3K27me3 might be observed in AS, possibly contributing to the known dysregulation of Th17 cells in the inflammatory disease.
Blood samples were collected from 45 AS patients and 10 healthy people, who served as a control group. Among the AS patients, 30 had active disease and 15 were considered stable.
Levels of IL-17, an inflammatory molecule produced by Th17 cells, were elevated in both AS groups compared with the healthy controls, but were highest in those with active disease. According to the researchers, such an increase “indicates a functional deviation of Th17,” as might be expected.
Correspondingly, people with active AS also exhibited increased activity of the RORc gene relative to stable patients or healthy people. Signaling pathways that work upstream of RORc also showed certain differences between the groups.
H3K27me3 expression was significantly lower in the immune cells of people with active AS compared with stable AS patients or healthy controls.
These findings contribute to our understanding of the role of epigenetics [chemical modifications] in AS and may have implications for the development of novel therapeutic strategies for AS.
Lower expression of the epigenetic marker was significantly associated with higher levels of AS disease activity markers, namely inflammatory markers C-reactive protein and erythrocyte sedimentation rate, as well as higher RORc gene activity.
The degree of H3K27me3 in cells is determined by a balance between molecules that promote the process — namely EZH2 — and others that degrade it, such as JMJD3.
People with active disease were found to have higher levels of JMJD3 and lower levels of EZH2 relative to patients with stable AS or healthy people, consistent with the lower H3K27me3 expression in those patients.
Altogether, the findings suggest that in active AS, H3K27me3 depletion leads to an increase in RORc gene activity that in turn drives the differentiation of inflammatory Th17 cells.
“H3K27me3 may be a dynamic and important epigenetic modification in AS inflammation,” the researchers wrote.
“These findings contribute to our understanding of the role of epigenetics in AS and may have implications for the development of novel therapeutic strategies for AS,” the team added.
