Dysfunctional interferon-α production by peripheral plasmacytoid dendritic cells upon Toll-like receptor-9 stimulation in patients with systemic lupus erythematosus
- Seung-Ki Kwok†1,
- June-Yong Lee†1, 2,
- Se-Ho Park2,
- Mi-La Cho1,
- So-Youn Min1,
- Sung-Hwan Park1,
- Ho-Youn Kim1Email author and
- Young-Gyu Cho1Email author
© Kwok et al.; licensee BioMed Central Ltd. 2008
Received: 9 October 2007
Accepted: 6 March 2008
Published: 06 March 2008
It is well known that interferon (IFN)-α is important to the pathogenesis of systemic lupus erythematosus (SLE). However, several reports have indicated that the number of IFN-α producing cells are decreased or that their function is defective in patients with SLE. We studied the function of plasmacytoid dendritic cells (pDCs) under persistent stimulation of Toll-like receptor (TLR)9 via a TLR9 ligand (CpG ODN2216) or SLE serum.
The concentrations of IFN-α were determined in serum and culture supernatant of peripheral blood mononuclear cells (PBMCs) from SLE patients and healthy controls after stimulation with CpG ODN2216 or SLE serum. The numbers of circulating pDCs were analyzed by fluoresence-activated cell sorting analysis. pDCs were treated with CpG ODN2216 and SLE serum repeatedly, and levels of produced IFN-α were measured. The expression of IFN-α signature genes and inhibitory molecules of TLR signaling were examined in PBMCs from SLE patients and healthy control individuals.
Although there was no significant difference in serum concentration of IFN-α and number of circulating pDCs between SLE patients and healthy control individuals, the IFN-α producing capacity of PBMCs was significantly reduced in SLE patients. Interestingly, the degree which TLR9 ligand-induced IFN-α production in SLE PBMCs was inversely correlated with the SLE serum-induced production of IFN-α in healthy PMBCs. Because repeated stimulation pDCs with TLR9 ligands showed decreased level of IFN-α production, continuous TLR9 stimulation may lead to decreased production of IFN-α in SLE PBMCs. In addition, PBMCs isolated from SLE patients exhibited higher expression of IFN-α signature genes and inhibitory molecules of TLR signaling, indicating that these cells had already undergone IFN-α stimulation and had become desensitized to TLR signaling.
We suggest that the persistent presence of endogenous IFN-α inducing factors induces TLR tolerance in pDCs of SLE patients, leading to impaired production of IFN-α.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is characterized by generation of autoantibodies against nuclear DNA and/or nuclear proteins . The precise pathogenesis of SLE remains unknown, but both genetic and environmental factors are involved . Over the past two decades numerous studies have suggested that interferon (IFN)-α may play a pathogenic role in SLE. This view is derived from the observation that IFN-α treatment in patients with nonautoimmune diseases, such as malignant tumors, induced anti-double-stranded DNA antibodies and occasionally resulted in the development of an SLE-like syndrome [3–7]. SLE patients exhibit ongoing IFN-α production, and IFN-α serum levels are correlated with both disease activity and severity [8, 9]. IFN-α levels also correlate with anti-double-stranded DNA antibody production, complement activation, and IL-10 production, all of which are important indicators in SLE disease progression .
IFN-α plays a role in the activation, differentiation, and survival of B cells, T cells, and dendritic cells. IFN-α is mainly produced in plasmacytoid dendritic cells (pDCs); they were originally termed natural IFN-α producing cells [10–12]. pDCs are key effector cells in the innate immune system because of their ability to produce large amounts of IFN-α in response to microbial and viral infections. Human pDCs selectively express Toll-like receptor (TLR)7 and TLR9 within the endosomal compartment. These receptors are activated in response to viral RNA and DNA, leading to production of IFN-α [12, 13]. Recent studies have shown that DNA-containing immune complexes within SLE serum stimulate pDCs to produce IFN-α [14, 15], which is mediated cooperatively by TLR9 and FcγRIIa (CD32) .
Patients with SLE have reduced numbers of circulating natural IFN-α producing cells. The levels of IFN-α produced by SLE peripheral blood mononuclear cells (PBMCs) induced by SLE serum that contained an endogenous IFN-α-inducing factor, herpes simplex virus type 1, or the D type of CpG motif were lower than those produced by healthy control PBMCs, and the IFN-α producing capability of circulating pDCs in SLE patients may be impaired [16–18]. These results do not fit well with the role of IFN-α in SLE pathogenesis described above, although they suggest that the local concentration of IFN-α in an affected region is important. Furthermore, there have been reports that the pDCs from SLE patients and healthy control individuals produce similar amounts of IFN-α on a per cell basis in response to viral infection [17, 19]. We wished to establish definitively the IFN-α production capability of PBMCs from SLE patients, and we show that IFN-α production is dysfunctional in pDCs from such patients.
We hypothesized that the persistent presence of DNA-containing immune complexes, which stimulate TLR9, affects the function of pDCs resulting in their malfunction. We analyzed serum levels of IFN-α in SLE patients and in vitro production of IFN-α in isolated PBMCs subjected to artificial stimulation by CpG ODN2216, which specifically activates human TLR9 in pDCs but not in B cells . We also examined the number of circulating pDCs in SLE patients, as compared with those in healthy control individuals, using specific pDC surface markers and flow cytometry. The expression of IFN-α signature genes (IFN-α responsive genes) and inhibitory molecules of the TLR signaling cascade were examined. Our findings suggest that pDCs are dysfunctional in patients with chronic SLE, which is probably due to desensitization of TLR9 as a result of over-stimulation by DNA-containing immune complexes that are present in the sera of SLE patients.
Materials and methods
Patients and control individuals
Demographic and clinical characteristics of SLE patients
SLE patients (n = 43)
Age (years; mean [range])
35.0 (21 to 56)
Sex (n; males/females)
Disease duration (years; mean [range])
8.5 (0.1 to 18)
SLEDAI (mean ± SD)
3.72 ± 3.84
Active (n = 9)a
9.55 ± 4.50
Inactive (n = 34)
2.17 ± 1.42
Cutaneous manifestation (n [%])
Arthritis (n [%])
Renal manifestation (n [%])
Cytopenia (n [%])
Serositis (n [%])
Prednisolone (n [%]; mean dosage [mg/day])
41 (95.3); 13.0
Hydroxychloroquine (n [%])
Azathioprine (n [%])
Cyclosporin (n [%])
Mizoribine (n [%])
Mycophenolate mofetil (n [%])
Preparation of PBMCs and pDCs
Blood samples obtained from patients and healthy control individuals were collected in heparinized tubes (BD Biosciences, San Jose, CA, USA), and PBMCs were prepared using Ficoll-Hypaque (Amersham Bioscience, Pascataway, NJ, USA) density gradient centrifugation. Cells were washed and suspended in RPMI 1640 medium (GibcoBRL, Carlsbad, CA, USA) containing penicillin (100 U/ml), streptomycin (100 μg/ml), and 10% fetal bovine serum (GibcoBRL) that had been inactivated by heating to 56°C for 1 hour. Healthy pDCs were isolated from PBMCs using a Diamond Plasmacytoid Dendritic Cell Isolation Kit (Miltenyi Biotec, Bergisch Gladbach, Germany); pDC purity was greater than 95%. The purified pDCs were cultured in RPMI 1640 medium containing 10% fetal bovine serum, granulocyte-macrophage colony stimulating factor (10 ng/ml), and IL-3 (10 ng/ml).
PBMCs were incubated with human IgG to block the Fc receptor and then incubated with anti-CD123-PE-Cy5 monoclonal antibody (Mouse IgG1; BD Pharmingen™, San Jose, CA, USA), anti-BDCA-2-fluorescein isothiocyanate, and monoclonal antibody (Mouse IgG1; Miltenyi Biotec) for 30 minutes at 4°C; isotype control experiments were conducted in parallel. After two washes, the cells were re-suspended in phosphate-buffered saline and analyzed by flow cytometry. pDCs were identified by dual staining for both CD123 and blood dendritic cell antigen (BDCA)-2.
PBMCs (1 × 106 cells) were stimulated using 1 μmol/l CpG ODN2216 (InvivoGen, San Diego, CA, USA) or 30% serum from SLE patients. Duplicate cultures were performed in 48-well plates (NUNK, Roskilde Denmark) at a final volume of 500 μl/well. After 24 hours IFN-α was measured from the supernatant.
Measurement of IFN-α
Supernatants collected from sera and cell cultures were stored at -70°C until further use. The amounts of IFN-α in the sera and supernatants were then measured using a sensitive sandwich ELISA kit (Bender MedSystems, Vienna, Austria). A representative standard curve for the IFN-α ELISA is shown in Additional file 1 (Supplementary Figure 1). All measurements were performed in duplicate and averaged values were used in the data analysis.
pDC stimulation with TLR9 ligand and SLE serum
Purified pDCs (2 × 104 cells) were incubated with or without the TLR9 ligand CpG ODN2216 (1 μmol/l; InvivoGen) or 30% serum from SLE patients in 96-well plates (NUNK) at a final volume of 200 μl/well. After 24 hours the pDCs were carefully washed with serum-free RPMI and re-treated with or without CpG ODN2216 (1 μmol/l) or 30% serum from SLE patients. The supernatants were harvested after an additional 24 hours and IFN-α production was measured using ELISA. In the recovery assay, pDCs were treated with 1 μmol/l CpG ODN2216 for 24 hours, washed with serum-free medium, cultured with serum-containing medium for 0, 24, or 48 hours, and then treated again with CpG ODN2216 (1 μmol/l). After 24 hours IFN-α production was measured from the supernatant.
Cell viability assay
Relative cell viability was measured by Quick Cell Proliferation Assay kit (BioVision, Mountain View, CA, USA). Briefly, 1/10 volume of WST-1/electrocoupling solution were added into the culture media, incubated 4 hours in 5% carbon dioxide incubator, and measured the absorbance of the treated and untreated samples with water-soluble tetrazolium salt (WST)-1/electrocoupling solution using a microtiter plate reader at 450 nm. Each sample was duplicated and averages of the absorbance were used in comparisons. The differences in absorbance between treated and untreated samples was shown as relative cell viability.
Reverse transcription PCR
Sequences of primer pairs
Forward: 5'-CGA TGC TGG GCG TGA GTA C-3'
Reverse: 5'-CGT TCA GCT CAG GGA TGA CC-3'
Forward: 5'-GGA CTT CGA GCA AGA GAT GG-3'
Reverse: 5'-TGT GTT GGC GTA CAG GTC TTT G-3'
Forward: 5'-GTG CCC CAC TTC TCC ATG-3'
Reverse: 5'-GGC ACA GTC ATG ATG TTG TTG-3'
Forward: 5'-CTC GGT GGT TAG CAA TTA TTC CTC-3'
Reverse: 5'-AGC CCA TAG CAT TCG TCT CAG-3'
Forward: 5'-CTC CTT GGG TTC GTC TAC AAA TTG-3'
Reverse: 5'-AGT CAG CAG CCA GTC TCA G-3'
Forward: 5'-CTT CCA TCT GAC TCA GGT TT-3'
Reverse: 5'-TGC TTC TGA C G GTA TGT ATT A-3'
Forward: 5'-CGG CAA CTG GAG ACA CAA G-3'
Reverse: 5'-TCT GGA AGT CAC ATT CCT TGC-3'
Forward: 5'-TTT GAA TGC AGC CAG TCT GA-3'
Reverse: 5'-GCA TTG CTT ATG GAG CCA AT-3'
Measuring immune complex levels in SLE patients' sera
To measure the serum levels of immune complexes in SLE patients, we used the CIC-C1Q Circulating Immune Complexes ELISA kit (Bühlmann Laboratories AG, Schonenbuch, Switzerland). Circulating immune complexes from sera from patients with chronic SLE and control individuals were incubated with human C1q, which was adsorbed onto microtiter wells. After a washing step, we added alkaline phosphatase-conjugated protein A, which binds to the Fc region of human IgG. After an additional washing step, the enzyme substrate (paranitrophenyl-phosphate) was added, followed by a stop solution. The absorption at 405 nm of each sample was measured. We used 14 SLE sera, two of which were from patients with SLEDAI values of 12 and 16, and the remainder were from patients with SLEDAI values of less than 4. The two active SLE sera exhibited 1.8 U and 6.3 U of immune complexes.
Differences between groups were analyzed using the Mann-Whitney U-test or Student's t-test. Correlation analyses were performed using Spearman's rank correlation test. All analyses were performed using SPSS (version 10.0; SPSS Inc., Chicago, IL, USA). Data are expressed as the mean ± standard deviation.
In vitroIFN-α production is reduced in PBMCs from SLE patients
Because the number of circulating pDCs is very low among total PMBCs, making it difficult to isolate this cell type from a blood sample, IFN-α production was measured in total PBMCs using a pDC-specific TLR9 ligand . PBMCs from patients with SLE and healthy controls werestimulated in vitro for 24 hours using the TLR9 ligand CpG ODN2216. IFN-α production was then measured using ELISA. CpG DNA induced IFN-α production was markedly reduced in PBMCs from SLE patients as compared with PBMCs from healthy control individuals (342.46 ± 636.82 pg/ml in SLE patients versus 1610.35 ± 759.56 pg/ml in healthy control individuals; P < 0.001; Figure 1b). In addition, IFN-α production was slightly higher in patients with active SLE than in those with inactive SLE, but the difference was not significant (P = 0133). No correlation was observed between serum levels of IFN-α and CpG-induced IFN-α production in vitro in patients with active SLE. Interestingly, IFN-α production was completely abolished in PBMCs from one-third of SLE patients. These data are almost identical to those reported previously . Although CpG ODN2216 was not used in that previous work, CPG oligonucleotides, herpesviruses, and DNA-containing immune complexes are all TLR9 ligands. Our findings are in accordance with thosse of previous studies showing that PBMCs from SLE patients have reduced capacity to produce IFN-α in response to TLR9 stimulation [16, 17].
Decreased IFN-α production in SLE patients cannot be fully explained in terms of decreased numbers of circulating pDCs
Downregulation of TLR9 may also contribute to decreases in IFN-α production in SLE patients. We used semiquantitative reverse transcription PCR to determine the expression of TLR9 in PBMCs. Interestingly, TLR9 expression was higher in SLE PBMCs than in cells from healthy control individuals (Figure 2d). These data demonstrate that the decrease in IFN-α production was not caused by downregulation of TLR9 expression.
CpG-induced IFN-α production in SLE PBMCs is inversely correlated with SLE serum induced IFN-α production in healthy PMBCs
Repeated stimulation induces TLR9 tolerance in pDCs
TLR9 tolerance may be the result of negative feedback in the TLR signaling pathway . Therefore, we examined whether TLR9 tolerance is reversible. pDC PBMCs from healthy individuals were incubated with CpG ODN2216 or 30% SLE serum for 1 day, washed, and then re-stimulated with CpG ODN2216 or 30% SLE serum after a given interval (0, 24, or 48 hours), as indicated in Figure 4b. IFN-α production was measured 24 hours after re-stimulation. IFN-α production decreased upon repeated stimulation at the 0 hours interval and recovered within 48 hours of the first stimulation in repeatedly stimulated pDCs (Figure 4c,d). The cell viability did not differ significantly between stimulation and re-stimulation groups (lower panels of Figure 4c,d). Although we could not test the recovery of IFN-α production capability by pDCs purified from SLE patients, the PBMCs from SLE patients recovered IFN-α production capability over time in vitro, without further stimulation, as shown in Additional file 1 (Supplementary Figure 2). These data indicate that TLR9 tolerance is reversible over time and that continuous TLR9 stimulation is required to induce persistent nonresponsiveness in pDCs.
SLE PBMCs are exposed to IFN-α to a greater degree
We demonstrated that TLR9-induced IFN-α production is reduced in PBMCsPMBCs from SLE patients (Figure 1 and Table 1). SLE patients exhibit ongoing IFN-α production, and IFN-α serum levels are closely correlated with SLE disease activity [8, 9]. Although active SLE serum contains slightly increased levels of IFN-α as compared with inactive SLE and healthy control sera, there were no significant differences in serum levels between total or inactive SLE patients and healthy control individuals. Because some chronic SLE patients had lymphophenia (data not shown), the number of pDCs per blood unit was reduced in SLE patients, which would affect the serum levels of IFN-α. The proportion of circulating pDCs was slightly reduced in SLE patients, and IFN-α production was markedly impaired after in vitro stimulation with TLR9, regardless of disease activity (Figures 1b and 2b). Although SLE patients exhibited a slight, nonsignificant decrease in the proportion of pDCs to total PBMCs, we cannot exclude the possibility that this decrease contributes to the decrease in TLR-induced IFN-α production in SLE patients, because the composition of pDC subtypes may differ between SLE patients and healthy control individuals. There is evidence that the Ly6C/Ly49Q pDC subtypes are effective producers of IFN-α , and so further investigation is required to determine the composition of pDC subtypes in SLE patients. Other studies have reported that SLE patients exhibit a reduced number of BDCA-2 expressing pDCs, and that herpes virus induced IFN-α production is decreased in SLE PBMCs ; furthermore, CpG-induced IFN-α secretion was significantly reduced in monocytes and dendritic cells from SLE patients . However, CpG-induced IFN-α production was completely abolished in one-third of SLE patients, and the decrease in IFN-α production was more marked than the decrease in pDCs, indicating that a different mechanism is at play.
SLE patients exhibited decreased numbers of circulating pDCs (Figure 2b), which is consistent with the findings of a number of other studies [16, 23, 34], but they also showed increased numbers of pDCs in cutaneous lesions [35, 36]. It has been suggested that circulating pDCs are low in SLE patients because this cell type is recruited from the blood to peripheral tissues. However, the fate of circulating pDCs after activation by DNA-containing immune complexes, which present in the blood of SLE patients, is not yet clear. Our results showed that significant numbers of pDCs are still present in the PBMC fraction isolated from SLE patients. Furthermore, we demonstrated that TLR-tolerant pDCs can recover over time and restore IFN-α production (Figure 4c,d), suggesting that pDCs in SLE patients are still present but inactive as a result of TLR tolerance or exhaustion.
The marked decrease or abrogation of IFN-α production may be explained by factors other than cell count. We noted that CpG-induced IFN-α production in SLE PBMCs was inversely correlated with SLE serum-stimulated cytokine production in healthy PBMCs (Figure 3b). We also found that repeated or chronic stimulation of TLR9 by appropriate ligands, such as CpG ODN 2216 or DNA-containing immune complexes, leads to TLR tolerance in pDCs. Although the mechanism of TLR tolerance has not been fully explained, it is a well known occurrence for cells that have been persistently stimulated with TLR ligands to fail to respond to re-stimulation [31, 37]. One possible mechanism is inhibition of TLR signaling via dysregulation of lipopolysaccharide-induced TLR4-MyD88 complex formation and IL-1 receptor-associated kinase (IRAK)-1 activation in endotoxin-tolerant cells . Another possibility is induction of genes that negatively regulate TLR signaling, such as IRAK-M and suppressor of cytokine signaling (SOCS)-1 [31, 37, 39].
We found an increase in the expression of IFN-α signature genes, indicating that SLE PBMCs have already been exposed to IFN-α, which is mainly produced by pDCs (Figure 5). Although we did not check the expression levels of molecules that inhibit the TLR signaling cascade in pDCs from SLE patients, the SLE PBMCs showed elevated levels of IRAK-M and MyD88s compared with the healthy PBMCs (Additional file 1 [Supplementary Figure 3a,b]). Because inflammation may also increase the expression of TLR signaling molecules, we examined the expression of MyD88, which is a positive regulator of the TLR signaling pathway. MyD88 expression was also slightly elevated in SLE PBMCs (Additional file 1 [Supplementary Figure 3c]), although the ratio of MyD88s to MyD88 indicated that the negative regulator, MyD88s, was dominantly expressed in the SLE PBMCs (Additional file 1 [Supplementary Figure 3d]). Although these data do not reveal the functional status of the pDCs in SLE patients, they suggest that the expression of negative regulators of TLR signaling may be responsible for the development of TLR tolerance in the PBMCs of SLE patients. In addition, dysfunctional IFN-α production by SLE pDCs can be induced by other TLR ligands that are found frequently in SLE sera, such as RNA-containing immune complexes and heat shock proteins. However, our investigation was hampered by the limited number of pDCs that could be isolated from the available blood sample, and thus the exact mechanism of TLR-9 tolerance remains to be elucidated. Further investigation is required to clarify this issue.
Another possible mechanism for TLR tolerance is that SLE medications may affect the function of pDCs. Although no correlations were observed among serum IFN-α levels, CpG-induced IFN-α production in vitro, and the type and dosage of medicines taken by SLE patients (data not shown), the immuno-suppressors, such as cyclosporine and hydroxychloroquine, can affect the function of pDCs. Hydroxychloroquine, in particular, is a known inhibitor of TLR9 signaling; this drug blocks the acidification of endosomes (phagosomes), which is essential for TLR9 signaling . To rule out the effect of hydroxychloroquine, pDCs from healthy individuals were pretreated with 1 mmol/l hydroxychloroquine for 24 hours, washed twice in serum-free medium, and then treated with CpG ODN2216. After 24 hours of incubation, IFN-α production decreased by up to 60% compared with non-pretreated pDCs (data not shown). These findings indicate that the residual amounts of hydroxychloroquine in pDCs from SLE patients may contribute to TLR tolerance. Moreover, we cannot exclude the potential influences of other medications on pDC numbers and functions. However, not all SLE patients were taking hydroxychloroquine, and the inhibition of TLR9 by residual hydroxychloroquine cannot fully explain the abrogation of IFN-α observed in one-third of SLE patients (Figure 1).
In the present study we demonstrated that circulating pDCs are desensitized to TLR9 stimulation in patients with chronic SLE. This desensitization is probably the result of persistent stimulation by DNA-containing immune complexes, which are a hallmark of SLE. In SLE patients, pDCs become tolerant to TLR9 stimulation or exhausted in terms of IFN-α production. These findings provide important insight into the pathogenesis of SLE and the markedly increased incidence of certain viral infections in SLE patients. In addition, our data indicate that the role of IFN-α is different in developing SLE and in chronic SLE.
blood dendritic cell antigen
enzyme-linked immunosorbent assay
IL-1 receptor-associated kinase
peripheral blood mononuclear cell
polymerase chain reaction
plasmacytoid dendritic cell
systemic lupus erythematosus
SLE Disease Activity Index
This work was supported by the SRC/ERC program of MOST/KOSEF (grant R11-2002-098-08002-0).
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