Interferon dysregulation associated with neutrophil, PBMC signaling in SLE

Interferon activity in patients with systemic lupus erythematosus and low Systemic Lupus Erythematosus Disease Activity Index scores correlated with biologic differences in signaling in neutrophils vs. peripheral blood mononuclear cell fractions, according to study findings presented at the American College of Rheumatology Annual Meeting.

Researchers collected RNA from isolated peripheral blood mononuclear cell (PBMC) and neutrophil fractions from a cohort of 46 patients with systemic lupus erythematosus (SLE) and 23 healthy participants. Patients with SLE fulfilled both American College of Rheumatology and Systemic Lupus International Collaborating Clinics criteria for SLE and had a range of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores between 0 and 12. Sixty-three percent of the patients were being treated with prednisone, a cytotoxic immunosuppressant or both.

The researchers grouped patients by positive or negative interferon activity based on an assessment of 21 interferon-inducible genes, and RNA sequencing was used to determine changes in gene expression.

Differences in gene expression were further analyzed to determine the most likely potential upstream mechanisms of change based on two metrics, and differential mechanisms between positive- and negative-interferon groups were compared with blood samples from healthy participants.

The researchers found positive-interferon neutrophils showed active biologic signaling in interferon-gamma, mechanistic target of rapamycin and chemokine ligand 5. Mechanisms associated with interferon-positive neutrophils, including toll-like receptor pathway signaling, interferon-alpha and other mechanisms, were also active, according to the researchers.

Transforming growth factor beta 1 and mitogen-activated protein kinase 1 activation were shown in negative interferon neutrophils. Similar mechanisms were exhibited in PBMCs between interferon groups.

“Our analysis supports that in a patient population with low SLEDAI scores, the interferon activity signature in blood correlates with biological differences that predominate in neutrophils,” the researchers wrote in the abstract. “The work permits better understanding of the impact of interferon signaling in SLE, by demonstrating different effects in neutrophil vs. PBMC fractions in an academic cohort.”

Reference:

Drubin D. Paper #1619. Presented at: American College of Rheumatology Annual Meeting. Nov. 14-19, 2014; Boston.

Disclosure: See the study for a full list of all authors’ relevant financial disclosures.