Exploring the connection between decreased Interleukin-35 expression and active intraocular inflammation in Vogt-Koyanagi-Harada disease
Imagine your immune system as a highly trained security team. Its job is to identify dangerous invaders and neutralize them. But what happens when this elite team suddenly mistakes your own cells for the enemy and launches a full-scale attack deep within your eyes? This is the reality for individuals with Vogt-Koyanagi-Harada (VKH) disease, a rare but serious autoimmune condition. Recent research is shining a light on a critical player in this drama: a lost molecular "peacekeeper" known as Interleukin-35.
VKH disease is a complex disorder where the body's immune system attacks its own melanocytes—cells that provide pigment to the skin, hair, inner ear, and, crucially, the eyes. In the eye, melanocytes are abundant in the uvea, the middle layer rich in blood vessels. When the immune system attacks here, it causes severe intraocular inflammation (uveitis), leading to symptoms like blurred vision, redness, and sensitivity to light. If left untreated, it can result in permanent vision loss.
VKH primarily affects the uvea, retina, and choroid, causing inflammation that can lead to retinal detachment and vision loss if untreated.
VKH is more prevalent in pigmented populations including Asians, Hispanics, Native Americans, and Middle Eastern individuals.
For decades, scientists have known that VKH involves a dysfunctional immune response, but the precise checks and balances that fail have been a mystery. The focus has traditionally been on the "attack" cells and inflammatory molecules. Now, the spotlight is turning to the body's own "off-switches."
To understand the new discovery, we need to talk about cytokines—tiny proteins that act as the messengers of the immune system. They can shout "Attack!" or whisper "Stand down."
Molecules like IL-17 and IFN-γ are the alarm bells. They rally immune troops (T-cells) to the site of trouble, causing inflammation, heat, and swelling—the classic signs of an immune battle.
These are the peacekeepers. They work to calm the troops, suppress the attack, and prevent collateral damage to our own tissues.
Interleukin-35 (IL-35) is a relatively newly discovered member of the IL-12 cytokine family, but it's one of our most powerful peacekeepers. Unlike its inflammatory cousins, IL-35 is produced exclusively by our regulatory immune cells (Tregs), whose main job is to suppress other immune cells and maintain tolerance to our own body.
Theory: Scientists hypothesized that in a healthy person, IL-35 acts as a powerful brake on eye inflammation. But in VKH patients, this brake might be failing.
To test this theory, a team of researchers designed a crucial experiment to compare IL-35 levels in different groups of people.
Is the expression of IL-35 decreased in patients with active VKH disease, and does this reduction correlate with the level of inflammation?
The researchers recruited three distinct groups:
Patients currently experiencing an acute inflammatory attack in their eyes.
Patients with VKH in remission (no active inflammation).
Individuals with no autoimmune or eye disease.
A small amount of peripheral blood was drawn from each participant.
Immune cells, particularly peripheral blood mononuclear cells (PBMCs), were isolated from the blood samples.
The cells were stimulated in the lab to mimic an immune challenge and see how they would respond.
The results were striking and clear.
| Participant Group | IL-35 Concentration (pg/mL) |
|---|---|
| Healthy Controls | 185.5 ± 22.1 |
| Inactive VKH Patients | 165.8 ± 18.7 |
| Active VKH Patients | 89.3 ± 15.4 |
Patients with active VKH disease showed a significantly lower production of the IL-35 protein compared to both inactive patients and healthy individuals.
| Participant Group | Relative IL-35 Gene Expression |
|---|---|
| Healthy Controls | 1.00 (Baseline) |
| Inactive VKH Patients | 0.92 ± 0.11 |
| Active VKH Patients | 0.45 ± 0.08 |
The genetic instructions for making IL-35 were significantly reduced in active VKH patients, explaining the low protein levels.
| Participant Group | IL-17 Concentration (pg/mL) |
|---|---|
| Healthy Controls | 25.1 ± 5.2 |
| Inactive VKH Patients | 31.5 ± 6.8 |
| Active VKH Patients | 68.9 ± 10.3 |
As IL-35 levels dropped, the inflammatory cytokine IL-17 surged, showing a clear inverse relationship.
This experiment provided direct evidence that active VKH disease is associated with a profound deficiency in IL-35. It's not just that inflammation is high; the critical system designed to suppress that inflammation is specifically and significantly impaired. This shift in the balance—losing the peacekeeper while the attackers are in full force—is likely a key driver of the disease's active phase.
Understanding a complex disease like VKH requires a sophisticated set of laboratory tools. Here are some of the essential "research reagent solutions" used in this field:
| Research Tool | Function in the Lab |
|---|---|
| ELISA Kits | These are like molecular fishing kits. They use antibodies to "catch" and measure the amount of a specific protein (like IL-35) in a blood or fluid sample. |
| qPCR Reagents | These act as a genetic photocopier and counter. They allow scientists to amplify and measure tiny amounts of a specific gene's mRNA, showing how "active" that gene is. |
| Flow Cytometry Antibodies | These are fluorescently-tagged antibodies that act as molecular name tags. They bind to specific proteins on the surface of cells, allowing machines to count and sort different types of immune cells (e.g., Tregs vs. attack T-cells). |
| Cell Culture Media | This is the nutrient-rich "soup" used to keep human cells alive and healthy outside the body, allowing scientists to study them in a controlled lab environment. |
| Immune Cell Stimulants | Chemicals like phorbol esters and ionomycin that act as a "false alarm," triggering immune cells to activate and release cytokines so researchers can study their response. |
The discovery of the IL-35 deficiency in active VKH is more than just an academic finding; it opens up exciting new pathways for patients.
Measuring IL-35 levels could help doctors distinguish an active VKH flare from other forms of uveitis or monitor how well a treatment is working.
Instead of just broadly suppressing the immune system with steroids (which can have severe side effects), scientists can now explore ways to boost the body's own natural peacekeeper. Could we develop a drug that increases IL-35 production or acts like IL-35 in the body?
While the journey from lab bench to bedside is long, this research represents a significant shift in perspective. By focusing not just on the attackers but on the failed peacekeepers, we are moving closer to restoring balance and protecting vision for those living with VKH disease.