Award
NIH Reporter #1R01AI201499-01
IFN-dependent and IFN-independent pathways in SLE
Recipient
Johns Hopkins University, Baltimore, MD
Award Amount
$748,333.00
Ceiling
$748,333.00
Awarded
August 14, 2026
Identifier
1R01AI201499-01
This award funds research at Johns Hopkins University to investigate the mechanisms behind the interferon (IFN) signature in systemic lupus erythematosus (SLE) patients. The study aims to classify SLE patients into subsets based on IFN levels and signatures to explain variable clinical trial responses and to develop targeted therapies.
Description
Systemic lupus erythematosus (SLE) is characterized by increased expression of interferon (IFN)-induced genes, known as the IFN signature, pointing to IFNs as promising therapeutic targets in SLE. Disappointingly, only a subset of SLE patients who express the IFN signature have shown benefit in clinical trials targeting the type I IFN (IFN-I) pathway, and inhibiting IFN-II has completely failed to treat SLE. To date, there is no explanation for this puzzle. Our studies indicate that dysregulated IFN expression is not a unifying feature among patients with SLE, and that the IFN signature is not always analogous to increased levels of IFNs. Instead, based on IFN levels and the IFN signature, patients with SLE can be classified into at least three disease subsets of mechanistic relevance. One subset is distinguished by increased levels of IFN-I alone and is associated with cutaneous lupus. The second subset is linked to systemic disease and is associated with elevated levels of IFN-I in combination with IFN-II and IFN-III, indicating a synergistic effect of IFN types on disease severity. The third subset includes SLE patients whose IFN signature is not explained by IFNs, but rather by stimuli that mimic IFN signaling. Together, the proposed subsets provide novel insights into mechanisms of disease heterogeneity in SLE, as well as a rational explanation for the variable response in clinical trials targeting the IFN-I pathway, even among patients expressing the IFN signature. Our long-term goal is to develop precise mechanism-guided preventive and therapeutic interventions for SLE.