Dr. Tsokos says the biggest challenge will be to identify patients with CNS lupus in whom the interferon pathway is the driving force behind the symptoms and treat only those patients.
A Closer Look
Previous research by Dr. Carroll and colleagues identified a role of type 1 interferon in regulating autoreactive B cell frequencies.2 The current study builds on that research by showing that activation of type I interferon in mouse models of lupus was associated with significant neurological deficits and that blocking the type I interferon receptor (IFNAR) prevented these symptoms.1
“Our work in mouse models suggests there may be some shared disease mechanisms in early stages of neurodegenerative diseases and in lupus,” says lead author of the earlier study Allison R. Bialas, PhD, research fellow in the Program in Cellular and Molecular Medicine, Boston Children’s Hospital. “Also, behavioral results indicate that some circuitry involved in cognitive performance, sociability and mood, may be most vulnerable to damage.”
In a commentary on the study, Sarah McGlasson and David Hunt describe well the trajectory of this research and how it led to the current study to determine which cells were responsible for this process and the discovery that microglia were a “prime suspect.”2
“In a series of elegant experiments, the authors demonstrated an association between the observed microglial activation and an increased engulfment of neuronal material, particularly of material from synapses, which form the junctions between two neurons,” McGlasson and Hunt state.2
Along with these findings in mice models of lupus, Dr. Carroll and colleagues observed a similar activation of an interferon response in the microglia in post-mortem examinations of sections of the hippocampus in brains of lupus patients. They say these findings—in both mice models of lupus and post-mortem examinations of lupus patients—support their model, in which the neuropsychiatric manifestations of lupus are the result, in part at least, of the activation of microglia by type I interferon that results in the loss of neuronal synapses.
“While CNS [central nervous system] lupus remains a heterogenous disease with many symptoms and probably many causes, our findings suggest that some CNS lupus patients may benefit from anti-IFNAR treatment,” state the authors in the study conclusion.
Broader Implications
In their commentary, McGlasson and Hunt point to the broader implications of the study that extend to looking at how microglial-mediated synaptic pruning may be involved in brain health and disease. Saying the study’s findings “add to the growing scientific rationale for classifying lupus brain disease according to the molecular mechanisms involved,” McGlasson and Hunt highlight the need for clinical trials of targeted therapies for neurological disease associated with lupus.3
