Sarcoidosis immune biomarkers, potential targeted treatment ID’d
Current medications that inhibit CXCR4 pathway may be able to treat disease
An immune cell called a type 1 innate lymphoid cell is found at much higher levels in skin granulomas, that is, clumps of immune cells, of people with sarcoidosis relative to those with non-sarcoid skin granulomas, according to research that shows high levels of the cells were also found in blood and lung samples of sarcoidosis patients, meaning they may be a useful diagnostic biomarker of the disease.
In a mouse model of the disease, University of Pennsylvania researchers found that blocking an immune pathway called CXCR4 in the cells can prevent granulomas from forming. The study, “Recruitment of CXCR4+ type 1 lymphoid cells distinguishes sarcoidosis from other skin granulomatous disease,” was published in The Journal of Clinical Investigation. The findings suggest measuring type 1 innate lymphoid cell levels may aid a sarcoidosis diagnosis and that current medications that inhibit the CXCR4 pathway may be able to treat the disease.
“By identifying a cause of the disease, we may have found a better way to diagnose the disease as well as a potential treatment that avoids major side effects,” Thomas Leung, MD, PhD, an assistant professor of dermatology at Penn, said in a press release.
In sarcoidosis, granulomas form in different tissues and organs, and can cause scarring and interfere with an organ’s function. About 25% of all sarcoidosis patients have cutaneous sarcoidosis where granulomas form on the skin, but patients also often have granuloma formation in other organs, commonly the lungs.
Diagnosing sarcoidosis is challenging because its symptoms vary greatly between people. Early symptoms are also shared with other disorders and there are no diagnostic tests to distinguish between sarcoidosis and other diseases.
“Knowing that type 1 innate lymphoid cells are a biomarker for sarcoidosis should lead to timelier diagnoses for patients,” said Misha Rosenbach, MD, the director of Penn’s Cutaneous Sarcoidosis and Granulomatous Disease Clinic.
Comparing immune cell types
Here, researchers compared unaffected and affected skin samples from 18 sarcoidosis patients against samples from 10 people with skin granulomas caused by diseases other than sarcoidosis. Most of the sarcoidosis patients exhibited the disease in multiple organs.
Samples showed affected skin from sarcoidosis patients contained on average five times more innate lymphoid cells than affected skin from granulomas of patients without sarcoidosis. Innate lymphoid cells are essential for managing immune reactions to disease-causing agents, controlling inflammation, healing tissues, and sustaining the balance of the immune system.
The researchers also compared immune cell types in the blood of 13 patients with sarcoidosis, five with non-sarcoidosis granulomas, and 17 healthy people.
While blood from those with granulomas not caused by sarcoidosis didn’t exhibit higher levels of innate lymphoid cells, people with sarcoidosis had substantially higher levels of type 1 innate lymphoid cells. The researchers found 12 times greater levels of sarcoidosis type 1 innate lymphoid cells in those with active sarcoidosis who weren’t treated relative to the healthy controls. When patients received treatment, these levels decreased by four times.
Elevated levels of innate lymphoid cells were also present in lung granulomas.
A genetic analysis of granulomas from sarcoidosis patients showed high levels of CXCR4, an immune-related gene, but its expression was minimal in people with psoriasis or healthy, unaffected skin. CXCR4, the protein produced by this gene, is critical for the movement of immune cells, including innate lymphoid cells, throughout the body.
Using a mouse model of sarcoidosis, the researchers found that type 1 innate lymphoid cells were required for granulomas to form. When mice were treated with plerixafor, an established clinically available CXCR4 inhibitor, they had fewer lung granulomas.
Similarly, after treatment with plerixafor, blood cells isolated from sarcoidosis patients, which naturally exhibited an increased capacity for cellular migration, no longer had increased migration in a laboratory setting. This confirmed that CXCR4-based signaling in immune cells is occurring in sarcoidosis patients and is necessary for tissue granulomas to form.
“CXCR4 inhibitors are already available in the clinic as an injection and used to safely mobilize stem cells before stem cell transplants,” Leung said. “I’m eager to work with Misha Rosenbach and the sarcoidosis clinic at Penn to run a clinical test to study whether repurposing these medications may be the first targeted treatment for sarcoidosis. Repurposing medications is more efficient than developing a new drug because the safety and nuances of the drug are already well known.”
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