Dysregulated Fc Gamma Receptor Iia-Induced Cytokine Production In Dendritic Cells Of Lupus Nephritis Patients

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. One of the key factors associated with SLE pathogenesis is excessive production of type I interferons (IFNs). This could result from increased activation of type I IFN-stimulating pathways, but also from decreased activation of type I IFN-inhibitory pathways. Recently, we have identified that immunoglobulin (Ig)G immune complexes strongly inhibit type I IFN production in healthy individuals by inhibitory signaling through Fc gamma receptor IIa (Fc gamma RIIa) on dendritic cells (DCs). Because, in SLE patients, immune complexes are characteristically present, we assessed whether Fc gamma R-induced suppression of type I IFN is functional in DCs of SLE patients. We divided the SLE patients into one group without, and one group with, previous major organ involvement, for which we chose nephritis as a prototypical example. We show that DCs of lupus nephritis patients displayed impaired Fc gamma R-mediated type I IFN inhibition compared to SLE patients without major organ involvement or healthy controls. We verified that this impaired type I IFN inhibition was not related to differences in disease activity, medication, Fc gamma RIIa expression or expression of IFN regulatory transcription factors (IRF)1 and IRF5. In addition, we identified that DCs of lupus nephritis patients show increased Fc gamma R-induced interleukin (IL)-1 beta production, which is another important cytokine that promotes kidney inflammation. Taken together, these data indicate that DCs of lupus nephritis patients display altered Fc gamma R-mediated regulation of cytokine production, resulting in elevated levels of type I IFN and IL-1 beta. This dysregulation may contribute to the development of nephritis in SLE patients.