Dysregulated Fcγ receptor IIa-induced cytokine production in dendritic cells of lupus nephritis patients

Summary 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 Fcγ receptor IIa (FcγRIIa) on dendritic cells (DCs). Because, in SLE patients, immune complexes are characteristically present, we assessed whether FcγR‐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 FcγR‐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, FcγRIIa expression or expression of IFN regulatory transcription factors (IRF)1 and IRF5. In addition, we identified that DCs of lupus nephritis patients show increased FcγR‐induced interleukin (IL)‐1β production, which is another important cytokine that promotes kidney inflammation. Taken together, these data indicate that DCs of lupus nephritis patients display altered FcγR‐mediated regulation of cytokine production, resulting in elevated levels of type I IFN and IL‐1β. This dysregulation may contribute to the development of nephritis in SLE patients.
In healthy individuals, immune complexes stimulate FcγRIIa, which signals through two parallel pathways: an inhibitory pathway that suppresses type I IFN and is Syk‐independent, and an activating pathway which amplifies the production of proinflammatory cytokines such as IL‐1β and is Syk‐dependent. In lupus nephritis patients these pathways are dysregulated, leading to (over)activation of the Syk‐dependent pathway (resulting in more IL‐1β), while the Syk‐independent pathway is dysfunctional (resulting in higher type I IFN levels).