Induction of interferon-alpha by immune complexes or liposomes containing systemic lupus erythematosus autoantigen- and Sjögren's syndrome autoantigen-associated RNA.
OBJECTIVE
To investigate the ability of systemic lupus erythematosus (SLE) autoantigen- and Sjögren's syndrome (SS) autoantigen-associated U1 small nuclear RNA (U1 snRNA) and hY1RNA to induce interferon-alpha (IFNalpha) production.


METHODS
In vitro-transcribed U1 snRNA or hY1RNA and lipofectin were added to peripheral blood mononuclear cell (PBMC) cultures. Purified U1 snRNP particles and IgG from SLE patients (SLE-IgG) were added to cultures of PBMCs, enriched monocytes, or natural interferon-producing cells (NIPCs); the latter are also known as plasmacytoid dendritic cells (pDC). Cells were double-stained for IFNalpha and either blood dendritic cell antigen 2 (NIPCs/pDC) or CD14 (monocytes) and then analyzed by flow cytometry. In some experiments, RNase or inhibitors of Fc gamma receptor IIa (Fc gammaRIIa) (specific antibodies), endocytosis (chloroquine, bafilomycin A), or Toll-like receptors (TLRs; oligodeoxynucleotide 2088) were used. The produced IFNalpha was measured by immunoassay.


RESULTS
Lipofected U1 snRNA and hY1RNA both induced IFNalpha production in monocytes, but not in NIPC/pDC. In contrast, U1 snRNP combined with SLE-IgG induced IFNalpha production only in NIPCs/pDC, and this response was decreased by RNase treatment or inhibition of the Fc gammaRIIa, the endocytosis pathways, or the TLRs.


CONCLUSIONS
Our finding that U1 snRNA and hY1RNA have IFNalpha-inducing capacity indicates that immune complexes containing such RNA, for example U1 snRNP particles, can be at least partly responsible for the ongoing IFNalpha production seen in SLE and SS. These results may help to explain the molecular mechanisms behind the pathogenesis of these and other autoimmune diseases in which autoantibodies to RNA-binding proteins occur.
Lövgren
Tanja
T
Uppsala University, Uppsala, Sweden. Tanja.Lovgren@medsci.uu.se
Eloranta
Maija-Leena
ML
Kastner
Berthold
B
Wahren-Herlenius
Marie
M
Alm
Gunnar V
GV
Rönnblom
Lars
L
D000936:Antigen-Antibody Complex / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D010714:Phosphatidylethanolamines; D012342:RNA, Small Nuclear / Q000276:immunology*; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000276:immunology; D012859:Sjogren's Syndrome / Q000276:immunology*
D000936:Antigen-Antibody Complex; D015703:Antigens, CD; D001324:Autoantigens; C080568:Fc gamma receptor IIA; D007074:Immunoglobulin G; D016898:Interferon-alpha; D010714:Phosphatidylethanolamines; D012342:RNA, Small Nuclear; D017452:Receptors, IgG; C405483:U1 small nuclear RNA; C020888:1,2-dielaidoylphosphatidylethanolamine