Network analysis identifies proinflammatory plasma cell polarization for secretion of ISG15 in human autoimmunity

Plasma cells (PCs) as effectors of humoral immunity produce immunoglobulins to match pathogenic insult. Emerging data suggests more diverse roles exist for PCs as regulators of immune and inflammatory responses via secretion of factors other than immunoglobulins. The extent to which such responses are pre-programmed in Blineage cells or can be induced in PCs by the microenvironment is unknown. Here we dissect the impact of IFNs on the regulatory networks of human plasma cells. We show that core PC programs are unaffected, while PCs respond to IFNs with distinctive transcriptional responses. The ISG15-system emerges as a major transcriptional output induced in a sustained fashion by IFN-α in PCs and linked both to intracellular conjugation and ISG15 secretion. This leads to the identification of ISG15-secreting plasmablasts/PCs in patients with active SLE. Thus ISG15-secreting PCs represent a distinct pro-inflammatory PC subset providing an immunoglobulinindependent mechanism of PC action in human autoimmunity.