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

Clin Exp Immunol. 2020 Jan;199(1):39-49. doi: 10.1111/cei.13371. Epub 2019 Oct 7.

Abstract

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.

Keywords: Fcγ receptor; dendritic cells; lupus nephritis; systemic lupus erythematosus.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Female
  • Humans
  • Interferon Type I / immunology*
  • Interleukin-1beta / immunology*
  • Lupus Nephritis / immunology*
  • Lupus Nephritis / pathology
  • Male
  • Middle Aged
  • Receptors, IgG / immunology*

Substances

  • FCGR2A protein, human
  • IL1B protein, human
  • Interferon Type I
  • Interleukin-1beta
  • Receptors, IgG