Interferon Alpha as a Primary Pathogenic Factor in Human Lupus

Interferon alpha (IFN-alpha) is a critical mediator of human systemic lupus erythematosus (SLE). This review will summarize evidence supporting the role for IFN-alpha in the initiation of human SLE. IFN-alpha functions in viral immunity at the interface of innate and adaptive immunity, a position well suited to setting thresholds for autoimmunity. Some individuals treated with IFN-alpha for chronic viral infections develop de novo SLE, which frequently resolves when IFN-alpha is withdrawn, supporting the idea that IFN-alpha was causal. Abnormally high IFN-alpha levels are clustered within SLE families, suggesting that high serum IFN-alpha is a heritable risk factor for SLE. Additionally, SLE-risk genetic variants in the IFN-alpha pathway are gain of function in nature, resulting in either higher circulating IFN-alpha levels or greater sensitivity to IFN-alpha signaling in SLE patients. A recent genome-wide association study has identified additional novel genetic loci associated with high serum IFN-alpha in SLE patients. These data support the idea that genetically determined endogenous elevations in IFN-alpha predispose to human SLE. It is possible that some of these gain-of-function polymorphisms in the IFN-alpha pathway are useful in viral defense, and that risk of SLE is a burden we have taken on in the fight to defend ourselves against viral infection.