Regulation of IFN-α produced by plasmacytoid dendritic cells (pDC) is critically important in Systemic Lupus Erythematosus (SLE) as patients have an 'IFN-signature' which correlates with disease severity. We observed that, normalized for IgG, SLE patient cerebrospinal fluid (CSF) induced 800-fold more IFN-α by pDCs compared to paired serum due to potent inhibitory factors in serum.
Depletion of IgG from normal serum and addition of purified IgG to SLE immune complex (IC) stimulation assays revealed that normal IgG was one inhibitor in serum. Although the inhibitory capacity of IVIG has recently been attributed to a small subfraction of sialylated IgG in mouse models, sialylation of IgG did not significantly affect IVIG inhibition of IC stimulation of IFN-α. This result indicates either species differences or differences in pDC inflammatory pathways.
Deficiencies of early complement components predispose to SLE. Heat inactivation of normal serum and utilization of sera selectively deficient in early complement components revealed that a second serum inhibitor of IC mediated IFN-α stimulation was complement. Suppression of IFN-α produced by pDC was restored by adding back the missing complement component.
In summary, we have identified two serum factors that potently attenuate IFN-α induced by SLE ICs. Modulation of these components in vivo could be used therapeutically.