Contents of cell cargo carriers may offer insights into AS biomarkers
Exosomes of patients found to be unique and to influence immune cell function
Exosomes, which are tiny carriers for cellular cargo, are found to have significantly different contents in ankylosing spondylitis (AS) patients compared with healthy people, which in turn has marked influences on immune cell function, according to a recent study.
Researchers specifically identified that the profile of molecules called microRNAs (miRNAs) is different in patient exosomes, and that these exosomes lead to a suppression of immune cells that normally work to control inflammation.
“This study suggests that exosome miRNAs have potential as informative biomarkers in AS, which can provide a prioritised set of molecular and cellular targets, for which new treatments could be developed,” scientists wrote.
The study, “Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis,” was published in Annals of the Rheumatic Diseases.
AS is an autoimmune disease in which inflammatory attacks cause rigidity and reduced mobility in the spine. In recent years, there has been a search for good disease biomarkers to aid in AS diagnosis and treatment management.
When exosomes transfer cargo to recipient cell, it influences that cell’s behavior
Exosomes are tiny vesicles released from many cell types, including immune cells, that help transport cargo to mediate various processes. When exosomes transfer their cargo to a recipient cell, it influences that cell’s behavior.
This can have significant effects on immune cell function, including the immune T-cells whose signaling is implicated in the chronic inflammation observed in AS.
Among their cargo, exosomes carry miRNAs, a family of molecules that regulate gene activity. Changes in miRNA profiles have been implicated in a number of inflammatory diseases, including AS.
By profiling the contents of exosomes, scientists believe they can learn more about how the immune system might be dysregulated in AS, and identify potential biomarkers and treatment targets, such as miRNAs of interest.
In their study, researchers in Canada examined the protein and miRNA content in exosomes obtained from the blood of 22 AS patients and 18 healthy adults, who served as controls.
Two immune signaling proteins — interleukin-8 and interleukin-10 (IL-10) — were at significantly lower levels in AS exosomes compared to healthy ones.
IL-10 is known to suppress inflammatory responses. Thus, its reduction could “set the stage for chronic inflammation,” the team wrote.
When healthy immune T-cells were incubated with exosomes from AS patients, the cells had altered production of certain cytokines that was not observed with exosomes from healthy people.
AS exosomes exhibit unique miRNA signature
The AS exosomes also exhibited a unique miRNA signature compared with healthy people, with 22 miRNAs found at higher levels and two found at lower levels in patients compared with controls.
One miRNA, called miR-30c-5p, was of interest because it targets interferon regulatory factor 4 (IRF4), a protein important for the development of regulatory T-cells (Tregs).
Tregs are a type of immune cell that work to regulate the activity of other T-cells, thereby helping to keep inflammation under control. Their dysregulation has been implicated in a range of autoimmune diseases.
The activity of miR-30c-5p was generally found to be higher in AS patients than in healthy people. It’s possible that excessive miR-30c-5p activity could lead to too much IRF inhibition, and thus there would not be enough Treg activity to keep inflammation under control, the scientists wrote.
Indeed, when cultured with AS exosomes, the growth, or proliferation, of Tregs was inhibited, as was the proliferation of CD4-positive T-cells, the family of T-cells from which Tregs are derived.
T-cells incubated with the patient exosomes also showed increases in miR-30c-5p, confirming that exosomes “could transfer their cargo to the recipient cells,” the team noted.
Fewer IRF4-expressing Tregs were found when incubated with the AS exosomes. These cells also reduced their expression of CTLA-4, a molecule that helps Tregs with their suppressive activity.
“In subsequent studies, we will focus on providing validation to confirm the hypothesis that miR-30c-5p can transfer via exosomes to [CD4-positive] T cells and affect their function,” the scientists wrote.
They noted that while the role miR-30c-5p in AS is interesting, a range of other miRNAs could also be involved. Moreover, miR-30c-5p may influence immune cells other than T-cells to exert its effects.
“Future cohort studies will be required for the further elucidation of the molecular network orchestrating the suppressive capacity of Tregs and for the identification of specific factors that are perpetuating T-cell activation in AS,” the team concluded.
