The regulation of IFN-alpha production in systemic and neuropsychiatric lupus erythematosus

Systemic lupus erythematosus (SLE) patients develop a variety of potentially life-threatening symptoms affecting multiple organs including the brain, kidneys and skin. A key cytokine implicated in SLE pathogenesis is IFN-alpha (IFN-alpha) as most SLE patients have a blood 'type I IFN-signature' that correlates with disease severity. Furthermore, IFN-alpha therapy can induce SLE symptoms in some patients with cancer or hepatitis C virus infection.;Of all the clinical manifestations of lupus, neuropsychiatrie lupus (NPSLE) is one of the least well understood. Considering the primacy of IFN-alpha in SLE pathogenesis as well as it's detection in another neurologic disease that overlaps with SLE, we hypothesized that IFN-alpha was involved in the pathogenesis of NPSLE. We showed, for the first time, that autoantibodies present in cerebrospinal fluid (CSF) stimulate high concentrations of IFN-alpha as well as other cytokines and chemokines previously shown to be elevated in NPSLE patients. The most striking finding was that, in an IFN-a bioassay, immune complexes (ICs) from CSF were >800-fold more potent than paired serum. This led us to identify and study serum inhibitory factors that naturally control the magnitude of IFN-alpha induction.;We identified two potent inhibitors of IFN-alpha induced by SLE ICs: IgG and C1q. C1q is of special relevance as greater than 90% of C1q deficient (C1qD) patients develop SLE. Since we observed that C1q is a natural suppressor of IC-induced IFN-alpha, we hypothesized that low levels of ICs would lead to an exaggerated IFN-alpha response in C1qD patients. Indeed, we detected high serum concentrations of IFN-alpha in patients with C1qD. To explore mechanisms for C1q suppression of IFN-alpha, we observed that C1q strikingly increases the binding of SLE ICs to monocytes and away from plasmacytoid dendritic cells. In addition, the presence of C1q in immune complexes leads to altered intracellular trafficking of ICs with retention in early endosomes.;In summary, our findings strongly support a pathogenic role of type I IFN in NPSLE. In addition, they identify C1q as a suppressor of IFN-alpha, thus helping to explain the remarkable susceptibility of C1qD individuals to develop SLE.