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The type I interferon system in systemic lupus erythematosus.

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Vol. 54, No. 2, February 2006, pp 408–420
DOI 10.1002/art.21571
© 2006, American College of Rheumatology
The Type I Interferon System in Systemic Lupus Erythematosus
Lars Rönnblom,1 Maija-Leena Eloranta,2 and Gunnar V. Alm3
the type I IFN system and summarize the present
knowledge of its involvement in SLE and some other
autoimmune diseases. Therapeutic consequences of this
information and some unanswered questions will be
The type I IFN system. The type I IFN system can
be defined as the type I IFN genes and proteins, the
inducers of type I IFN production, the cells producing
type I IFNs, as well as the target cells affected by the
type I IFNs.
The IFN proteins and genes. The human type I
IFNs constitute a family of related proteins acting on the
same receptor, the type I IFN receptor (IFNAR). The
IFN␣ subtypes are quantitatively most important in this
family and have a high degree of homology but unique
activity profiles. They are products of 13 different genes
clustered on chromosome 9, while single genes exist for
IFN␤, IFN␻, IFN␬, and IFN␧/␶ (7). Recently, a new
class of type I IFN–like molecules with 3 members, IFN␭
1–3, was identified (8,9). These novel IFNs do not use
the IFNAR and are therefore sometimes classified as
type III IFNs. Type II IFN has only a single member,
IFN␥, which is unrelated to either type I or type III IFNs
and signals through a separate receptor.
IFN inducers and their recognition. Enveloped
viruses are the classic type I IFN inducers, but some
bacteria and protozoa can also trigger IFN production.
The critical activators of IFN gene transcription are
DNA or RNA that is recognized by either cell membrane–
associated or intracellular receptors (Figure 1).
The Toll-like receptors (TLRs) are a family of
pattern recognition molecules that are activated by a
wide spectrum of microbial components (10,11). TLR-3
mediates IFN␣ production induced by double-stranded
RNA (dsRNA), whereas TLR-7 and TLR-8 are involved
in recognition of single-stranded RNA (ssRNA) IFN
inducers. In contrast, unmethylated CpG-rich DNA
triggers IFN production via TLR-9. TLR-4, a receptor
for lipopolysaccharide, can also mediate induction of
IFN␤ expression by certain viral proteins. Most TLRs
signal via the myeloid differentiation factor 88 (MyD88)
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease characterized by a large
number of aberrations in the immune system, typically
resulting in the formation of autoantibodies against
nucleic acid and associated proteins. In order to better
understand the disease mechanisms and develop efficient therapies for SLE, new technologies such as microarray analysis have been applied to cells and tissues
from patients with SLE. Studies of the gene expression
profile in SLE have revealed that the majority of patients have the dominant pattern of type I interferon
(IFN)–inducible gene expression, commonly referred to
as an IFN signature (1,2). These discoveries are consistent with earlier observations that patients with SLE
have increased serum levels of IFN␣ and cellular expression of the IFN␣-inducible protein MxA (3). The observation that an SLE syndrome can develop during longterm IFN␣ treatment of patients with chronic infections
and malignant diseases (4) further supports a critical
role for the type I IFN system in the etiopathogenesis of
SLE (5,6).
Several investigations also suggest that type I
IFNs may be important in autoimmune diseases other
than SLE and point to the possibility that the type I IFN
system is a key actor when tolerance is lost and autoreactivity appears. Here, we present a short overview of
Supported in part by the Swedish Research Council, the
Swedish Rheumatism Foundation, the King Gustaf V 80-Year Foundation, and the Uppsala University Hospital Research and Development Fund.
Lars Rönnblom, PhD, MD: Uppsala University, Uppsala,
Sweden; 2Maija-Leena Eloranta, PhD: Uppsala University and Swedish University of Agricultural Sciences, Uppsala, Sweden; 3Gunnar V.
Alm, PhD, MD: Swedish University of Agricultural Sciences, Uppsala,
Drs. Rönnblom and Alm have received consulting fees (less
than $10,000 per year) from Miltenyi Biotec.
Address correspondence and reprint requests to Lars Rönnblom, PhD, MD, Department of Medical Sciences, Section of Rheumatology, Uppsala University Hospital, SE-75185 Uppsala, Sweden.
Submitted for publication June 30, 2005; accepted in revised
form October 25, 2005.
Figure 1. Overview of the activation of natural interferon (IFN)–
producing cells (also termed plasmacytoid dendritic cells) by interferogenic immune complexes and virus. Viral DNA or RNA are recognized by either intracellular molecules (e.g., RNA is recognized by the
helicase retinoic acid inducible gene I [RIG-I]) or endosomal Toll-like
receptor 7 (TLR-7), TLR-8, and TLR-9. Immune complexes containing CpG-rich DNA or single-stranded RNA (and associated proteins)
derived from dying cells can, after Fc␥ receptor IIa (Fc␥RIIa)–
mediated endocytosis, activate endosomal TLRs 7–9. Via these receptors, nucleic acids activate the kinases tumor necrosis factor (TNF)
receptor–associated factor (TRAF) family member–associated NF-␬B
activator (TANK)–binding kinase 1 (TBK1) and IKK␧, which in turn
phosphorylate (P) transcription factors, especially IFN regulatory
factor 3 (IRF-3), IRF-5, and IRF-7. The IRFs, together with additional
transcription factors (not shown), initiate expression from both type I
IFN and IRF genes. Signaling via the type I IFN receptor (IFNAR)
involves activation of the receptor-associated kinases Tyk-2 and Jak-1,
which phosphorylate the transcription factors Stat-1 and Stat-2. The
latter associate with IRF-9 and form a complex (ISGF3) that interacts
with IFN-stimulated response elements (ISRE) in the promoters of
hundreds of IFN-stimulated genes (ISG). Several other pathways used
by IFNAR are not shown. CARD ⫽ caspase activation and recruitment domain; MyD88 ⫽ myeloid differentiation factor 88; IRAK-1 ⫽
interleukin-1 receptor–associated kinase 1.
adaptor protein, but MyD88-independent pathways also
exist. Thus, TLR-3 exclusively uses Toll/interleukin-1
(IL-1) receptor domain–containing adaptor-inducing
IFN␤ (TRIF) and not MyD88 as the adaptor. Furthermore, TLR-4 acts on IFN␤ genes via a TRIF and
TRIF-related adaptor molecule pathway (12). The adaptor molecules recruit protein kinases, notably IKK␧ and
tumor necrosis factor (TNF) receptor–associated factor
family member–associated NF-␬B activator (TANK)–
binding kinase 1 (TBK1). The latter protein kinases
phosphorylate IFN regulatory factor 3 (IRF-3), IRF-5,
and IRF-7, which form enhanceosomes together with
other transcription factors, such as CREB protein/p300,
activating transcription factor 2/c-Jun, and NF-␬B (13).
Here, mostly IFN␤ and IFN␣ gene expression has been
studied, and the activation of type III IFNs and the other
members of the type I IFN family remains to be
There are also TLR-independent intracellular
pathways mediating type I IFN production induced by
RNA that enters the cytosol. One pathway involves
protein kinase R, which is activated by dsRNA (14). In
addition, caspase activation and recruitment domain–
containing helicase retinoic acid inducible gene I
(RIG-I) has been implicated in the intracellular recognition of viral RNA, involving TANK, TBK1, and IKK␧
in the activation of IRFs (15).
Producers. Most cells can produce small amounts
of IFN␣/␤ in response to certain RNA viruses. In
contrast, natural IFN␣-producing cells (NIPCs), also
termed immature plasmacytoid dendritic cells (PDCs),
produce extremely large amounts of IFN␣ (⬃1 ⫻ 109
molecules in 12 hours) in response to many different
microorganisms (16). NIPCs/PDCs are infrequent in the
circulation (⬍1% of peripheral blood mononuclear cells
[PBMCs]) and can be recruited to sites of inflammation.
The cells express, for instance, class II major histocompatibility complex (MHC), CD4, CD40, CD83, high
levels of the IL-3 receptor (CD123), and 2 specific
markers termed blood dendritic cell antigen 2
(BDCA-2) and BDCA-4, but lack the costimulatory
molecules CD80 and CD86 (17,18). The BDCA-2 molecule represents an endocytic type II C-type lectin,
which might function as an antigen-capturing molecule
(19). NIPCs/PDCs also express Fc␥ receptor IIa
(Fc␥RIIa) (20) and TLR-1, TLR-6, TLR-7, TLR-9, and
TLR-10 (21), which explains their capacity to sense a
wide variety of different molecules in the external milieu
and respond to potential danger signals.
Monocyte/macrophages and myeloid/monocytederived dendritic cells produce type I IFN in response to
certain RNA viruses, such as influenza and Sendai
viruses, and the dsRNA poly(I-C) (22,23). These cells
express TLRs 3, 4, 7, and 8 but produce IL-12 instead of
type I IFN upon exposure to TLR-7/8 agonists (22,23).
IFNAR-mediated effects. The IFNAR consists of
2 polypeptide chains, IFNAR-1 and IFNAR-2. Interaction of type I IFN with the IFNAR results in activation
of the receptor-associated kinases Tyk-2 and Jak-1,
Table 1.
Immunomodulatory effects of type I interferon*
Target cell
Dendritic cell
Th cell
Tc cell
B cell
NK cell
Survival, maturation, and activation, with increased cross-presentation
to Tc cells and stimulation of Th and B cells via, e.g., enhanced
expression of costimulatory molecules and class I/II major
histocompatibility complex.
Prolonged survival, increased type I IFN production.
Up-regulation of TLR-1, TLR-2, TLR-3, and TLR-7. Modulates
antimicrobial activity, stimulates iNOS expression.
Differentiation to myeloid dendritic cells and inhibition of their IL-12
Promotes the Th1 pathway by, e.g., increased expression of IL-12
receptor, IFN␥, and T-Bet. Enhances activation and survival of
naive and memory T cells.
Increased cytotoxic activity, prolonged survival.
Enhanced activation and differentiation of plasmablasts to plasma
cells, immunoglobulin class switch, and antibody production.
Enhanced cytotoxicity and IFN␥ production.
* Tc ⫽ cytotoxic T; NIPC/PDC ⫽ natural interferon-␣ (IFN␣)–producing cell/plasmacytoid dendritic cell;
TLR-1 ⫽ Toll-like receptor 1; iNOS ⫽ inducible nitric oxide synthase; IL-12 ⫽ interleukin-12; NK ⫽
natural killer.
which phosphorylate the transcription factors Stat-1 and
Stat-2 (Figure 1). Stat-1 and Stat-2 associate with IRF-9
and form a complex (ISGF3) that interacts with IFNstimulated response elements in the promoters of hundreds of IFN-stimulated genes (24–26). Several other
pathways are, however, also involved in the action of the
IFNAR (24). The proteins corresponding to the IFNstimulated genes have a wide spectrum of effects on
many different cell types, including inhibition of viral
replication and induction of apoptosis in cells infected
by at least some viruses. The IFN-stimulated genes also
include genes that encode proteins such as RIG-I and
IRF-5/7 that are involved in expression of type I IFN
genes. By such mechanisms, type I IFNs constitute a
major defense system in the innate immune response
against viruses.
The prominent immunomodulatory actions of
IFN␣/␤ have attracted a great deal of interest in recent
years (Table 1). Thus, IFN␣/␤ causes dendritic cell
maturation and activation, with increased expression of
class I and class II MHC molecules, chemokine and
chemokine receptors, as well as costimulatory molecules
such as CD80, CD86, the B lymphocyte stimulator
(BLyS; trademark of Human Genome Sciences, Rockville, MD), and a proliferation-inducing ligand (APRIL)
(27). This facilitates antigen presentation, homing to
lymphoid organs, and activation of immune cells. Helper
T cells are in this way stimulated and develop along the
Th1 pathway, at least in part because type I IFN
stimulates expression of the IL-12 receptor and transcription factor T-bet, which counteract the GATA-
dependent Th2 default pathway (28,29). Type I IFNs
also markedly stimulate development of cytotoxic T
cells, in part because of an increased cross-presenting
function of dendritic cells (30) and prevention of apoptosis of activated T cells (31,32). Furthermore, the type
I IFNs decrease the threshold for activation of B cells via
the B cell receptor (BCR) and enhance differentiation,
antibody production, and immunoglobulin isotype class
switching (33–35). Therefore, the type I IFNs serve as a
bridge between innate and adaptive immunity and can
be viewed as stress hormones in the immune system,
signaling danger and contributing to its activation. However, as discussed below, this also entails an increased
risk of immunization by autoantigens.
The type I IFN system in SLE
Serum IFN␣. It has been known for more than 25
years that patients with SLE have elevated serum IFN␣
levels (36), and that these levels correlate to both disease
activity and severity (36–38). There is also a correlation
between serum IFN␣ levels and several markers of
immune activation typical for SLE, e.g., anti-dsDNA
titers, IL-10 levels, and degree of complement activation. From a clinical point of view, there is an association
between serum levels of IFN␣ and certain disease
manifestations, such as fever, skin rash, and leukopenia.
In addition, increased IFN␣ levels are more common
early in the disease course compared with later stages of
disease, suggesting a role for IFN␣ in the initial events of
the disease process. However, some patients with SLE
do not have detectable levels of serum IFN␣ at the time
of any investigation—not even during disease flares.
Blood leukocytes from such patients nevertheless often
display increased levels of the IFN␣-inducible protein
MxA, indicating in vivo IFN␣ production (39). It is
therefore possible that all patients with SLE have increased type I IFN production at some time point during
the disease course. In order to clarify this issue, sensitive
IFN␣ assays need to be developed and applied to large
patient cohorts that are followed up longitudinally.
NIPCs/PDCs. The number of circulating NIPCs/
PDCs in patients with SLE is reduced ⬎70-fold compared with that in normal individuals (40); this observation has been confirmed in several studies (41–43). The
remaining cells have an intact IFN␣-producing capacity
and express the cell surface antigens BDCA-2 and
BDCA-4 (42). Furthermore, a marked increase in the
number of functionally active NIPCs/PDCs was noted
when PBMCs from SLE patients were cultured with
granulocyte–macrophage colony-stimulating factor
(GM-CSF) and IFN␣/␥ in vitro, suggesting that there is
no intrinsic defect in NIPCs/PDCs from patients with
SLE. Consequently, the reduced number of NIPCs/
PDCs in the circulation is probably attributable to
recruitment to tissues, and such cells can in fact be
demonstrated in both skin biopsy specimens and lymph
nodes obtained from patients with SLE (44–47). Chemokines, such as CXCL10/CXCL12 and their corresponding receptors CXCR3/CXCR4, are important in
this recruitment of NIPCs/PDCs to tissues (16). Interestingly, IFN␣ messenger RNA (mRNA) and proteinexpressing cells could be detected in biopsy specimens
obtained from both lesional and apparently normal skin,
indicating a general activation of NIPCs/PDCs in the
setting of SLE (44). However, the lymphoid tissues may
be the most important compartment for the NIPCs/
PDCs in SLE, where locally produced IFN␣ can directly
act on cells in the immune system and promote the
ongoing immune response.
Gene signature. Several investigators have used
the microarray technique to study the gene expression
profile in cells from patients with SLE (1,2,48). A
consistent finding in these studies has been a clear
up-regulation of IFN-stimulated genes in the majority of
patients, which is known as the IFN signature. It has
been established that type I IFN, not IFN␥, is responsible for this IFN signature (49). However, it remains to
be elucidated to what extent type III IFNs (IL-28/29)
also contribute, because these cytokines activate Stat-1
and Stat-2 like the type I IFNs, despite acting on a
receptor other than the IFNAR (50). The IFN signature
was observed in PBMCs from almost all pediatric SLE
patients with relatively active disease of recent onset
(48). This is in contrast to studies in adults with more
long-lasting and less active disease, in which approximately half of the patients displayed the IFN signature
(1,2). In adult patients, the IFN signature is associated
with severe disease manifestations, such as central nervous system involvement or nephritis (1). The IFN
signature was also seen in the majority of laser-captured
glomeruli in patients with lupus nephritis, although
some patients demonstrated other gene expression profiles (51).
These findings support previous observations
(36–38,52,53) that activation of the type I IFN system is
most prominent in early and active disease. An important observation in the gene expression studies is the
finding that several lupus autoantigens, such as Ro 52
and laminin-1b, are up-regulated by IFN␣ (48). An
increased expression of these autoantigens may influence the autoantibody repertoire (see below).
At the moment, it is not known how the IFN
signature is expressed and varies in SLE patients during
long-term followup, but longitudinal studies are under
way (1). Such investigations will provide important information on the value of analyzing the gene signature in
SLE patients in order to predict and monitor flares and
organ manifestations, as well as treatment response and
Polymorphisms of IFN-related genes. Several
genes are associated with increased susceptibility for the
development of SLE (54), but genes with major functions in the type I IFN system (type I IFN–related genes)
have not until recently been investigated in humans. We
analyzed single-nucleotide polymorphisms (SNPs) in 11
type I IFN–related genes in SLE patients, 4 of which
were linked to the production and 7 of which were linked
to the action of type I IFN (55). This investigation
revealed SNPs in 2 of the studied genes, Tyk-2 and
IRF-5, with strong signals in joint analysis of linkage
and association with SLE. Tyk-2 binds to the IFNAR-1
and is responsible both for maintaining the expression of
the complete IFNAR on the cell surface and for signaling via the receptor after IFN␣/␤ ligation. Interestingly,
Tyk-2 is also involved in the function of several other
cytokines that have been reported to be elevated in SLE
patients, such as IL-6 and IL-10 (56). The importance of
Tyk-2 in autoimmunity is further supported by the
observation that Tyk-2–deficient mice are resistant to
experimental arthritis (57). IRF-5, in contrast, is important for induction of IFN␣ production by viral infections
and TLR-7/8 agonists and is constitutively expressed in
NIPCs/PDCs (58,59). In addition, IRF-5 increases the
expression of several other genes involved in cell signaling, apoptosis, cell cycle regulation, and immune activation (60). Therefore, polymorphisms altering the function of IRF-5 may, in many ways, facilitate the
development of an autoimmune disease such as SLE.
The association of TYK-2 and IRF-5 genes to
SLE further strengthens the proposed important role of
the type I IFN system in the etiopathogenesis of this
disease. Because many hundreds of genes are involved in
the activation, regulation, and action of the type I IFN
system, more type I IFN–related genes should be analyzed for a possible connection to SLE. Several genes
already reported to be associated to SLE may actually
have their most important effect on the disease by
affecting the type I IFN system (e.g., the genes encoding
Fc␥RIIa, which are important in the activation of
NIPCs/PDCs by interferogenic immune complexes (see
below), and the genes for complement factors C1q and
C-reactive protein, which contribute to clearance of
apoptotic cells) (54).
Murine models. A role for type I IFN in the
development of experimental SLE was suggested early
on by the finding that administration of exogenous
IFN␣/␤ to NZB and NZB/W mice accelerates the
progression and severity of the disease (61,62). In addition, when agents that induce type I IFN production
were injected into lupus-prone mice, a more severe
disease was observed (63–65). The importance of IFN␣
in the disease process is also supported by the observation that in vivo expression of IFN␣ by an adenovirus
vector induced early lethal lupus in susceptible animals
(66). The potential role of the type I IFN system as a
therapeutic target in SLE is suggested by the finding that
crosses between lupus-prone NZB or C57BL/6-lpr/lpr
mice and type I IFNAR–knock-out mice have a dramatically reduced SLE disease (67,68). In contrast, the
absence of a functional IFNAR in lupus-prone MRL/lpr
mice causes enhanced production of autoantibodies,
increased lymphadenopathy, and a more severe renal
disease (69). The reason for the contradicting results is
unclear, but the results indicate important differences
between experimental murine lupus models.
Activation and regulation of NIPCs/PDCs in SLE
Activation. The ongoing production of IFN␣ in
many patients with SLE suggests the presence of inducers that trigger expression of IFN␣ genes. Therefore, an
important finding was that DNA-containing immune
complexes in patients with SLE can induce IFN␣ pro-
duction by NIPCs/PDCs, and that the occurrence of such
interferogenic immune complexes is associated with
active disease (5,6,70). When formed, these immune
complexes are internalized via Fc␥RIIa and reach the
endosomes of NIPCs/PDCs, with subsequent activation
of the relevant TLR and induction of IFN␣/␤ production (20,70).
The nature of the cellular nucleic acids that
trigger IFN production by these immune complexes is
unknown, but in vitro studies show that apoptotic cells
generate DNA-containing material that can form interferogenic immune complexes (71,72). Cells dying by
apoptosis or necrosis also release RNA-containing material with interferogenic properties (72), and it was
recently shown that ssRNA with guanosine- and uridinerich sequences can activate IFN␣ production via interaction with TLR-7 (73,74). Such RNA sequences are
commonly observed in normal RNA, and obvious candidate IFN␣ inducers include the U-series small nuclear
RNA that are associated with several RNPs and are part
of the spliceosomes. Autoantibodies to the small nuclear
RNPs are common in SLE and may be responsible for
the formation of interferogenic immune complexes.
Accordingly, the same molecules that are released at the
time of cell death and constitute major autoantigens in
SLE and several other systemic autoimmune diseases
are also potent IFN␣ inducers and can act as endogenous adjuvants in the autoimmune process (see below).
Because patients with SLE have reduced clearance and
increased numbers of apoptotic cells (75), apoptotic cell
material should be readily available in vivo to generate
interferogenic immune complexes.
Regulation. The in vitro production of IFN␣
triggered by interferogenic immune complexes in
NIPCs/PDCs is markedly increased in the presence of
IFN␣/␤ and, in some instances, also GM-CSF (6,76).
One possible reason for this phenomenon, which is
termed priming, is that type I IFNs increase the levels of
transcription factors IRF-5 and IRF-7 necessary for
induction of major IFN␣ genes (13). During viral infection, this positive feedback mechanism for enhancement
of IFN␣ production is essential and gives rise to an early
and strong antiviral response. In contrast, the disease
flares that are frequently seen during infection in patients with SLE (77) may be attributable to priming
effects of type I IFN induced by virus or bacteria.
Most immune complexes do not induce IFN
production in NIPCs/PDCs. In fact, immune complexes
that lack interferogenic DNA or RNA cause a general
inhibition of the response of NIPCs/PDCs to a wide
variety of IFN inducers, even those that are independent
of Fc␥RIIa (20). One possible explanation for such
inhibition is that immune complex delivers negative
signals to NIPCs/PDCs via crosslinking of the Fc␥RIIa.
This Fc receptor is regarded as an activating receptor
because of its content of immunoreceptor tyrosinebased activation motifs, but it can also be inhibitory by
activating SH2-containing inositol phosphatase 1 and
the protein tyrosine phosphatase src homology phosphatase 1 in a manner similar to that of the inhibitory
Fc␥RIIb (78,79).
Several other receptors on NIPCs/PDCs can also
modulate IFN␣ production. Thus, ligation of not only
BDCA-2, but also BDCA-4, inhibits the IFN␣ response
(19,42). In addition, certain cytokines have a negative
impact on NIPCs/PDCs. In particular, IL-10 is a potent
inhibitor of the IFN␣ production triggered by both
viruses and immune complexes, but TNF␣ also reduces
IFN␣ production by NIPCs/PDCs (76,80).
Induction of autoimmunity by type I IFN
The possible role of IFN␣ as an inducer of
autoimmunity was originally suggested by the observation that in patients with malignant disease treated with
IFN␣, autoantibodies and sometimes also overt autoimmune disease frequently developed (4). For instance,
as many as 19% of patients with malignant carcinoid
tumors who were receiving long-term treatment with
IFN␣ eventually manifested an autoimmune disease,
including SLE (81). Preexisting autoantibodies are not
necessary for the development of autoimmunity, although the presence of autoantibodies before IFN␣
therapy considerably increases the risk of autoimmune
disease developing. The conclusions from these observations are that type I IFN can both break tolerance and
promote ongoing autoimmune reactions in humans.
What are the mechanisms behind this propensity
of type I IFNs to cause autoimmune reactions? As
outlined above, type I IFNs have several effects on key
immune cells that are likely to promote the activation of
potential autoimmune cells (Table 1). Furthermore,
type I IFN promotes the production of IFN␥ and other
cytokines such as IL-6, IL-10, and IL-15 that are important for sustained activation of the immune system (27).
Type I IFN also potentiates the effects of IFN␥ and IL-6
(82,83) and shifts the actions of IL-10 from an antiinflammatory to a more proinflammatory profile (84). The
increased expression of all of these molecules decreases
the threshold for cellular activation and increases the
likelihood for the initiation of an autoimmune reaction.
Type I IFN can also have direct effects on target tissues
in autoimmune disease by causing expression of autoantigens to which autoantibodies are directed, a phenomenon commonly seen in SLE (48,85). This action of type
I IFNs may be as important as their direct effects on the
immune system in the initial phase of the development
of autoimmunity. In addition, it has been proposed that
class I MHC up-regulation caused by IFN␣ in tissues
makes them a target for autoimmune attack by cytotoxic
T cells (86).
A special case is the human endogenous retrovirus (HERV)-K18 superantigen, which is induced by
IFN␣ and may have a pathogenic role in type I diabetes
(87). A role for HERV in SLE has also been postulated,
because sex hormones, especially estrogens, appear to
increase the expression of autoantigens such as HERV
(88). This could contribute to the fact that the prevalence of SLE is higher in females than in males.
Taken together, results of many clinical and
experimental studies have established that type I IFN
can push the immune system toward an autoimmune
state. Several of the alterations seen in the immune
system after type I IFN exposure have also been observed in SLE and may be highly relevant for the
understanding of the pathogenesis of this disease.
The type I IFN system in the etiopathogenesis of SLE
We have integrated the many findings concerning
the type I IFN system in SLE in an etiopathogenic
model of SLE, which also includes other observations in
this disease (Figure 2). This model was first described in
1999 (6) and has subsequently been updated (89,90). It is
envisioned that infections by viruses or bacteria can
provoke an initial autoimmune response by activating
dendritic cells (in particular NIPCs/PDCs). The production and action of type I IFN are important in this
context. Indeed, autoantibodies are common during
viral infections (91), either due to loss of tolerance to
ubiquitous cellular autoantigens or due to molecular
mimicry. The latter possibility is supported by data that
link Epstein-Barr virus to SLE, because the major
autoantigens SmB⬘ and SmD1 cross-react with sequences from Epstein-Barr nuclear antigen 1 (EBNA-1),
and immunization of mice with cross-reactive EBNA-1
sequences precipitates lupus-like autoimmunity (92).
Furthermore, a peptide from the EBNA-1 antigen induces production of antibodies against 60-kd Ro in mice,
and autoantibodies to this EBNA-1–related Ro 60
epitope were detected in patients an average of 3.9 years
before the development of SLE. In fact, low levels of
different autoantibodies directed to nucleic acid–
Figure 2. The role of interferogenic DNA/RNA-containing immune complexes and
type I IFN produced by immature plasmacytoid dendritic cells (PDCs; also termed
natural IFN␣-producing cells [NIPCs]) in the induction and maintenance of autoimmune disease. Production of autoantibodies occurs during viral or bacterial
infection, in part because of adjuvant effects of microbial components and molecular
mimicries. Cells dying by apoptosis or necrosis release DNA- or RNA-containing
autoantigens that form interferogenic immune complexes with autoantibodies. Such
immune complexes act as endogenous inducers of type I IFN production in
NIPCs/PDCs (see Figure 1) and can directly activate autoantibody-producing B cells
via the B cell receptor (BCR) and TLRs 7–9. Type I IFN, especially IFN␣, has
multiple immunostimulatory actions that include induced maturation of monocytederived dendritic cells (moDC), development of Th1 cells and cytotoxic T (Tc) cells,
as well as facilitation of B cell activation. All of this results in further autoantibody
production, formation of more IFN-inducing immune complexes, IFN␣ production,
and IFN-mediated immunostimulation. The autoimmune process is consequently
sustained by a mechanism with the features of a vicious circle. IL-12R ⫽
interleukin-12 receptor (see Figure 1 for other definitions).
associated proteins or nucleic acids can be detected for
long periods of time in apparently healthy individuals in
whom SLE eventually develops (93).
Once autoantibodies are available, they can form
immune complexes by combining with apoptotic or
necrotic cell material that contains interferogenic DNA
or RNA. Such interferogenic immune complexes stimulate long-term IFN␣ production by NIPCs/PDCs in the
absence of exogenous inducers such as virus or bacteria,
thereby explaining the IFN signature that is present in
patients with SLE. The produced IFN␣ will increase
autoantibody production by promoting dendritic cell
maturation, T cell activation, and stimulation of B cells,
as outlined above. DNA-containing immune complexes
can, in addition, directly activate autoreactive B cells
(94), which will further increase the production of
autoantibodies necessary for formation of interferogenic
immune complexes. The increased apoptosis and decreased clearance of apoptotic cell material seen in SLE
will provide autoantigens that will be both immunogenic
and IFN␣ inducing. Exposure to ultraviolet light or
infections will generate more apoptotic or necrotic material, and the resulting inflammatory process will promote the extracellular release of nucleic acid (95). In
addition, IFN␣ can increase both apoptosis (96) and
expression of autoantigens (85), thereby adding fuel to
the autoimmune process.
A process that has the features of a vicious circle
is thus established and maintains autoimmunity by continuously exposing the immune system to endogenous
IFN␣ inducers and to the IFN␣ produced by NIPCs/
PDCs. The activity of this vicious circle is increased by
recruitment of new NIPCs/PDCs to tissues by chemokines and priming of these cells by, for example, IFN␣.
The induction of production of such cytokines by microorganisms may reactivate the vicious circle, explaining
the disease flares sometimes observed in SLE patients
during infection. Finally, cytokines that limit the activity
of NIPCs/PDCs, especially IL-10 and TNF␣, may constitute a beneficial negative feedback mechanism in SLE (76).
The described disease process is obviously dependent on several environmental and genetic factors.
Genes that influence the function of the type I IFN
system, including the capacity of the immune system to
be activated by type I IFN and establish a vicious circle,
are expected to confer increased or decreased risk for
SLE. It is, however, important to recognize the many
different hormonal, inflammatory, and vascular factors
that determine the final clinical phenotype of SLE
disease in individual patients.
The type I IFN system in other autoimmune diseases
Given the fact that the type I IFN system acts as
a sensor of environmental danger and has potent and
pleiotropic effects on the immune system, one could
anticipate that type I IFN is involved in other autoimmune diseases besides SLE. In fact, a large number of
different autoimmune conditions develop in patients
during IFN␣ treatment (4). Furthermore, studies of the
type I IFN system in several autoimmune diseases
indicate that NIPC/PDC activation and IFN␣ production may be common events in autoimmunity. Increased
serum levels of IFN␣ and expression of IFN␣ mRNA in
the pancreatic islets have been observed in patients with
insulin-dependent diabetes mellitus (97). In addition,
expression of IFN␣ genes in islets precedes the lymphocyte infiltration and islet cell destruction observed in
experimental diabetes, which moreover can be prevented by neutralizing anti-IFN␣ antibodies. Recently,
increased IFN␣ mRNA expression was also noted in
liver biopsy specimens obtained from patients with primary biliary cirrhosis (98).
Among patients seen in rheumatology clinics,
those with rheumatoid arthritis, dermatomyositis, primary Sjögren’s syndrome (pSS), and psoriasis all have
signs of type I IFN production. Thus, infiltration of
NIPCs/PDCs and expression of IFN␤ and the type I
IFN–inducible protein MxA can be detected in the
synovia of patients with rheumatoid arthritis (99–101).
Patients with dermatomyositis have a typical IFN gene
signature and IFN␣–containing BDCA-2–positive cells
in muscle tissue (102,103). In a recent study, we found
IFN␣-producing cells in the salivary glands of patients
with pSS (104). In addition, necrotic or apoptotic cell
material in combination with autoantibodies to RNAbinding proteins from pSS patients specifically triggered
IFN␣ production by NIPCs/PDCs. This IFN␣-inducing
capacity of pSS sera was associated with both lymphocytic foci in the labial salivary glands and several extraglandular disease manifestations (e.g., dermatologic, hematologic, and pulmonary involvement). Gene
expression profiles of minor salivary gland biopsy specimens also show an up-regulation of type I IFN–
regulated genes (105). Skin biopsy specimens obtained
from patients with psoriasis display increased expression
of mRNA for both IFN␣ and IFN-induced proteins as
well as an infiltration of NIPCs/PDCs (46,106). Furthermore, an essential role for NIPCs/PDCs and IFN␣ in the
development of psoriatic lesions was recently demonstrated in a xenograft model of human psoriasis (107).
Taken together, emerging data suggest that the
type I IFN system could be an important etiopathogenic
factor in several systemic and organ-specific autoimmune diseases. The genetic background of the individual, the nature of the initial trigger of the IFN␣
production, as well as the target organ affected by
NIPCs/PDCs and IFN␣, could all be factors determining
the type of disease that eventually develops.
Therapeutic consequences
Although the precise role of the type I IFN
system in the various autoimmune disorders remains to
be established, the observed connection between IFN␣
and autoimmune disease suggests that down-regulation
of this system should have beneficial effects in patients.
In fact, 2 of the best-documented therapeutic agents in
SLE, chloroquine and glucocorticoids, inhibit IFN␣
production by NIPCs/PDCs (108) and down-regulate the
IFN signature (48), respectively. These drugs, however,
have multiple cellular effects, and more specific therapies directed to the type I IFN system should be
explored (Table 2). The most obvious therapeutic target
in SLE is IFN␣, and a humanized monoclonal anti-IFN␣
antibody that neutralizes all IFN␣ subtypes has been
developed (109). Soluble IFNAR is another therapeutic
option, although such a molecule might also act as a
ligand-dependent agonist (110). Furthermore, the
NIPCs/PDCs could be directly targeted by human monoclonal antibodies to BDCA-2, because ligation of this
molecule turns off the IFN␣ production by NIPCs/PDCs
Several approaches can be used to reduce the
amount of endogenous IFN␣ inducers or the expression
of type I IFN genes in response to these inducers. DNase
Table 2. Therapeutic targets of potential importance for reducing the action of type I interferon in
systemic lupus erythematosus*
Type of drug
Interferogenic DNA
and RNA
Fc␥ receptor IIa
Toll-like receptors
Type I IFN
Type I IFN receptor
Type I IFN signaling
IFN-inducible genes
Inhibitory ODN or ORN
Antibody/soluble IFN receptor
Kinase inhibitors, etc
Tolerogen/B cell depletion
Histone deacetylase inhibitors
Anti–BDCA-2 antibodies
Reduce amount of IFN inducer in immune
Reduce amount of interferogenic immune
Prevent uptake by NIPC/PDC of
interferogenic immune complexes
Block induction of IFN production
Neutralize biologically active IFN
Prevent binding of IFN to the receptor
Reduce the IFN signal downstream of the
Inhibit IFN-stimulated gene transcription
Inhibit IFN production
* ODN ⫽ oligodeoxynucleotide; ORN ⫽ oligoribonucleotide; BDCA-2 ⫽ blood dendritic cell antigen 2
(see Table 1 for other definitions).
treatment has been tried in SLE patients, with the
rationale to eliminate pathogenic dsDNA/anti-dsDNA
antibody complexes (111). No clear therapeutic effect
was noted, but this could theoretically be due to the
importance of RNA-containing immune complexes in
the induction of IFN␣ in SLE in vivo. The tolerogen
LPJ-394 that reduces the level of anti-dsDNA antibodies
in SLE has only a moderate effect on disease activity
(112), perhaps because antibodies with other specificities are important in the generation of interferogenic
immune complexes. There are several possible ways to
prevent the action of interferogenic immune complexes
on NIPCs/PDCs. Besides blocking Fc␥RIIa by specific
antibodies (20), the TLRs involved in IFN␣ gene activation by such immune complexes could be inhibited by
TLR antagonists in the form of oligodeoxynucleotides
(ODNs) or oligoribonucleotides. In fact, treatment of
lupus-prone mice with suppressive ODNs prolonged
their survival (113), but the effects on the type I IFN
system was not extensively investigated. Several of the
signaling molecules downstream of the TLRs, such as
MyD88, IL-1 receptor–associated kinase 1, IRF-5, and
IRF-7, remain to be investigated as therapeutic targets
in SLE (55,114,115).
Drugs that interfere with the post-IFNAR events
could be used to reduce the effects of IFN␣. Several
possible target molecules exist, with inhibitors of Tyk-2
being one example. In addition, the transcription of
IFN-stimulated genes could be blocked by histone
deacetylase inhibitors (116,117). In fact, such drugs can
reduce glomerulonephritis in the MLR-lpr/lpr mouse
In conclusion, a large number of molecules within
the type I IFN system have the potential to serve as
therapeutic targets in SLE. Several of these molecules
have pleiotropic effects in the immune system, and
inhibition of their function can have additional beneficial effects besides those on the type I IFN system.
Unresolved questions
There are several questions that should be addressed before embarking on clinical trials with the
objective to inhibit the type I IFN system in patients with
SLE. The first question is, will the therapy work as well
in humans as in some experimental lupus models? One
word of caution is warranted, because MLR/lpr mice
lacking the IFNAR developed a more severe disease
compared with wild-type animals (69). This is in contrast
to the NZB and C57BL/6-lpr/lpr strains (67,68). Which
of these 2 experimental SLE disease models is most
relevant to human SLE? This issue can be resolved only
by clinical studies in human patients. Second, why do not
all patients with SLE have an activated type I IFN
system? As discussed above, there may be several reasons for this observation, but patients without an activated type I IFN system cannot be expected to benefit
from type I IFN inhibitors. Alternatively, some patients
with SLE may display an activation of the type I IFN
system due to ongoing viral infection, and not because of
increased SLE disease activity. In this situation, interference with the type I IFN system may be dangerous
and even cause mortality in treated patients.
How is it possible to discriminate between active
lupus disease and an infection, since these 2 conditions
often resemble each other and may even exist together
in the same individual? The answer to this question is
complex and illustrates the fact that clinical skill and
judgment, as well as advanced laboratory techniques, are
necessary in order to optimize therapy for each patient.
In addition, even if therapy that targets type I IFN is
administrated based on the correct indication, this treatment may increase susceptibility to viral infections.
Therefore, the challenge is to selectively inhibit the
SLE-related overproduction of IFN␣ and at the same
time spare the capacity of the type I IFN system to
execute its normal function in the innate and adaptive
immune response.
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