TYPE INTERFERONS IN SYSTEMIC LUPUS ERYTHEMATOSUS

In: Type I Interferon in Autoimmune Diseases … ISBN: 978-1-62417-379-0

Editor: Yihong Yao © 2013 Nova Science Publishers, Inc.

Chapter 3

TYPE I INTERFERONS IN SYSTEMIC LUPUS

ERYTHEMATOSUS

Gary P. Sims , Daniel C. Rowe, Bo Chen and Ronald Herbst*

Respiratory, Inflammation and Autoimmunity,

MedImmune LLC, Gaithersburg, Maryland, US

ABSTRACT

Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown

etiology. The disease is relapsing and remitting in nature and can virtually affect any

organ system, leading to significant organ damage and morbidity. Often observed clinical

manifestations include skin lesions, arthritis, renal involvement, neuropsychiatric events

and hematologic disorders. A hallmark of SLE is the presence of autoantibodies, in

particular against nuclear autoantigens (ANA) and double stranded DNA, and deposition

of antibodies and immune complexes in target organs such as the kidney. In recent years

significant progress has been made in understanding the alterations in innate and adaptive

immunity observed in SLE patients and how these may relate to pathogenic mechanisms,

causing loss of tolerance, autoantibody production, inflammation, and tissue damage.

These studies have revealed a central role for type I interferons (IFN) in the pathogenesis

of SLE. IFN and transcripts of type I IFN responsive genes are elevated in SLE and

associated with disease activity. In addition, polymorphisms in several components of the

type I IFN pathway are associated with susceptibility to SLE. Type I IFNs have

pleiotropic effects on the innate and adaptive immune system and influence the function

of a broad spectrum of cells, including dendritic cells, macrophages, and T cells.

Importantly, type I IFNs have also been implicated in the loss of B cell tolerance. This

chapter provides an overview on the regulation and function of type I IFNs in SLE. The

prominent role of IFNs in this debilitating disease makes this pathway an attractive target

for therapeutic intervention and several novel therapeutics are already undergoing testing

in the clinic.

Correspondence: Gary P. Sims and Ronald Herbst MedImmune, LLC, One MedImmune Way, Gaithersburg, MD

20878, USA, E-mail: [email protected], [email protected]

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Gary P. Sims, Daniel C. Rowe, Bo Chen et al. 60

1. SYSTEM LUPUS ERYTHEMATOSUS

The term lupus erythematosus (LE) was first introduced by Cazenave in 1853, and

replaced the previous designation as seborrheah congestiva by Hebra. These early

descriptions of the typical skin lesions clearly distinguished the disease from cutaneous

tuberculosis (lupus vulgaris), with which LE was often confused [Thin, 1875; Grosse, 1903].

During the second half of the 19th

century Kaposi characterized the skin lesions in greater

detail and also recognized the systemic nature of the disease and involvement of other organ

systems. Today, systemic lupus erythematosus (SLE) is often referred to as the most diverse

and complex of the autoimmune diseases, with an annual incidence ranging from 2.2 to 7.8

per 100,000, depending on the geography, ethnic background and other factors [O'Neill et al,

2010]. While we still know very little about the underlying causes, which may well be

multifactorial, the disease is characterized by autoantibodies to DNA and nuclear antigens.

These autoantibodies can lead to immune cell activation, immune complex deposition, and

organ damage. Organ system involvement can be cumulative over time and lead to increased

morbidity with increased duration of the disease [Lam et al, 2005]. Due to the variable course

of the disease and multiple organ systems involved accurate diagnosis of SLE can be

challenging. To improve diagnosis the American College of Rheumatology (ACR) has

developed 11 criteria to identify and classify SLE patients (Table I). The most common

clinical manifestations include skin involvement (malar and discoid rash), photosensitivity,

oral ulcers, arthritis, kidney function, neurological disorders, and hematologic abnormalities

[Tan et al, 1982; Hochberg, 1997].

A patient can be classified as having SLE if any combination of 4 or more of these

criteria can be observed serially or simultaneously [O'Neill et al, 2010]. In addition, the

European League Against Rheumatism (EULAR) has developed a set of recommendations

for monitoring SLE patients in clinical practice, to provide a more standardized assessment of

disease progression, organ involvement, and comorbidities such as cardiovascular risk,

osteoporosis, and infection risk [Mosca et al, 2010]. Further, SLE is associated with a variety

of symptoms, including fatigue, fibromyalgia (and associated pain), and depression. Although

not strongly linked to disease severity, these symptoms have a significant effect on the quality

of life of SLE patients [Kiani et al, 2010]. Importantly, the mortality associated with SLE has

greatly decreased over the past 50 years, likely as a result of better diagnosis and improved

management of the disease. A multi-center prospective study with 1,000 patients in the Euro-

Lupus cohort demonstrated a 95% survival over five years and 93% survival over 10 years,

but the overall mortality in SLE is still four- to five-fold greater as compared to healthy

individuals [Cervera et al, 1999; Cervera et al, 2003]. These studies also revealed that

cardiovascular complications (thrombosis) are now the leading cause of death among SLE

patients.

An important feature of SLE is the relapsing and remitting nature of the disease. The

measurement of flares and quantifying their severity has been a challenge in clinical trials,

where reductions in flare severity or frequency are often incorporated as endpoints. The

general approach was a combination of scores from disease activity indices, such as the

Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), together with serologic

measures over time. In a prospective cohort study a three point increase in the SLEDAI score

was considered to be indicative of a flare [Petri et al, 1991].

Type I Interferons in Systemic Lupus Erythematosus 61

Table I. Updated (1997)

American College of Rheumatology classification criteria for SLE

1. Malar rash

Fixed erythema, flat or raised, over the malar eminences,

tending to spare the nasolabial folds

2. Discoid rash Erythematous raised patches with adherent keratotic scaling

and follicular plugging; atrophic scarring may occur in older

lesions

3. Photosensitivity Skin rash as a result of unusual reaction to sun light, by

patient history or physician observation

4. Oral ulcer Oral or nasopharyngeal ulceration, usually painless,

observed by a physician

5. Arthritis Non-erosive arthritis involving two or more peripheral

joints, characterized by tenderness, swelling or effusion

6. Serositis

a) Pleurisy Convincing history of pleuritic pain or rub heard by a

physician or evidence of pleural effusion

b) Pericarditis Documented by ECG or rub or evidence of pericardial

effusion

7. Renal disorder

a) Persistent proteinuria Proteinuria > 0.5 g/day or greater or greater than 3+ if

quantification not performed, or

b) Cellular casts May be red cell, hemoglobin, granular, tubular, or mixed

8. Neurologic disorder ACR definitions of 19 separate syndromes (including

psychosis seizures)

9. Hematologic disorders

a) Hemolytic anemia With reticulocytes

b) Leukopenia < 4000/mm3 total on two or more occasions

c) Lymphopenia < 1500/mm3 total on two or more occasions

d) Thrombocytopenia < 100000/mm3 in the absence of offending drugs

10. Immunologic disorder (autoantibodies)

a) anti-DNA Antibody to native DNA in abnormal titer

b) anti-Sm Presence of antibody to Sm nuclear antigen

c) antiphospholipid A positive test result for lupus coagulant using a standard

method, or a false positive serological test for syphilis

known to be positive for at least 6 months and confirmed by

Treponema pallidum immobilization or fluorescent

treponema antibody absorption test

11. Antinuclear antibodies Abnormal tire of antinuclear antibody by

immunofluorescence or an equivalent assay at any point in

time, and in the absence of drugs known to be associated

with “drug-induced Lupus” syndrome

In a more recent prospective study Nikpour et al used a flare definition of a >4 point

increase in the updated SLEDAI-2K disease activity index from the last assessment to

monitor flare frequency over a two year period. In this study about one third of the patients

experienced at least one flare in a given year, while 25 % had persistently active disease

without achieving the definition of flare [Nikpour et al, 2009]. The rate and severity of flares

during the course of the disease are important factors determining outcome. Early detection


and treatment of flares could be critical in preventing progressive kidney damage and

ultimately renal failure. At the moment, however, no validated biomarkers are available that

could predict flares with reasonable accuracy in order to improve disease management and

treatment.

Genetic factors likely contribute to the risk of developing SLE. For example, the age-

adjusted incidence of SLE is significantly higher in Afro-Caribbean population as compared

to Caucasian subjects (25.8 versus 4.3 per 100000, respectively) [Johnson et al, 1995]. A

genetic component to SLE development is further supported by the familial aggregation of

the disease and a higher concordance in monozygotic versus dizygotic twins [Deapen et al,

1992; Alarcón-Segovia et al, 2005]. In addition to ethnicity, gender is another important

factor influencing susceptibility to developing SLE. Interestingly, SLE is most common in

women of child bearing age, with an average female to male ratio of about 9:1 [Lockshin,

2006]. This gender difference is also observed in animal models, such as lupus prone mouse

strains. The sex bias in SLE has led to the hypothesis that hormones, in particular estrogens,

may be involved in the development of SLE [Rubtsov et al, 2010]. Further, genome-wide

association studies conducted over the past few years have identified more than 30 loci

associated with SLE risk [Deng et al, 2010]. A recent study investigated the association of 16

susceptibility loci with SLE phenotypes in a large 8329 patient cohort [Sanchez et al, 2011].

The results from this study demonstrate that single nucleotide polymorphisms (SNPs) in

select genes are indeed associated with specific clinical manifestations of SLE. For example,

SNPs in ITGAM (encoding integrin M, a subunit of Mac-1/complement receptor 3) were

associated with renal disorder and discoid rash, confirming previous studies [Yang et al,

2009; Kim-Howard et al, 2010]. In contrast, FcγRIIA, which was previously identified as a

lupus susceptibility gene, appears to be associated with the typical malar rash. Interestingly,

several important genetic risk loci are within genes encoding for components of the IFN

signaling pathway (see section 3), suggesting a close link between type I IFN and SLE [Deng

et al, 2010].

As mentioned above, SLE is characterized by the presence of various autoantibodies,

which has been incorporated into the ACR criteria (Table I). Prominent are anti-double-

stranded-DNA (dsDNA), anti-nuclear antigen (ANA), anti-Smith (Sm), anti-Ro/La,

phospholipid autoantibodies, and antibodies against ribonuclear protein complexes (RNP).

The available data suggest that these autoantibodies can be pathogenic and directly contribute

to tissue damage [Elkon et al, 2008]. Interestingly, autoantibodies can be detected years

before diagnosis of the disease. In a study of 130 SLE patients, for whom pre-diagnosis serum

samples were available, plus 130 matched controls, Arbuckle et al (2003) detected the

presence of autoantibodies years before the onset of disease. Anti-dsDNA, ANA, anti-Ro,

anti-Sm, and anti-RNP were detectable in pre-diagnosis samples of 55%, 78%, 47%, 32%,

and 26% of patients, respectively, while control subjects were mostly negative for these

autoantibodies (3% for anti-dsDNA, 3% for Ro, 2% for anti-RNP, and 0% for anti-La and

anti-Sm). Anti-cardiolipin antibodies were present in 18.5% of the SLE patients and could be

detected up to 7.6 years before diagnosis [McClain et al, 2004]. Certain autoantibodies have

also been associated with distinct clinical manifestations of SLE. For example, autoantibodies

against C1q are present in patients with SLE as well as other autoimmune diseases. In SLE,

anti-C1q levels correlate with disease activity scores and show a strong association with

nephritis [Marto et al, 2005; Grootscholten et al, 2007]. Here it should be noted that

deficiency in C1q is also a strong risk factor for developing SLE. Further, anti-neuronal


antibodies have been implicated in the development of neuropsychiatric SLE (NPSLE) [Dale

et al, 2011]. Similarly, anti-phospholipid and anti-ribosomal P protein autoantibodies seem to

be associated with NPSLE [Arnett et al, 1996; Karassa et al, 2006; Hanly et al, 2011].

Autoantibodies can also form immune complexes with their respective antigens, activate a

variety of inflammatory cells and stimulate cytokine production. Importantly, nucleic acid

containing immune complexes trigger the induction of type I IFNs by plasmacytoid dendritic

cells (pDC) [Vallin et al, 1999; Båve et al, 2003]. Following capture by Fc RIIA, DNA and

RNA containing immune complexes can be internalized and trigger the production of type-I

interferons (IFN) through activation of the endosomal Toll-like receptors (TLRs) TLR7 and

TLR9 [Means et al, 2005; Pascual et al, 2006] (see section 5). Indeed, elevated type-I IFN

levels are prominent in lupus patients, have been implicated in various aspects of the disease,

and are associated with disease severity [Baechler et al, 2003; Feng et al, 2006; Hall et al,

2010]. In a recent study of 1,089 SLE patients with African, European, or Hipanic ancestry,

Weckerle et al (2011) interrogated the association between serum IFN activity,

autoantibodies, and ACR clinical criteria. While autoantibodies and IFN were not associated

with any specific clinical feature of SLE, there was a strong association of serum IFN

activity with autoantibodies, in particular anti-Ro, anti-dsDNA, and anti-RNP [Weckerle et al,

2011].

2. ASSOCIATION OF TYPE I IFNS WITH SLE

Type I IFNs are a family of pleiotropic cytokines that may modulate nearly all phases of

immune and inflammatory responses by altering the differentiation or function of a broad

range of different cell types [Pestka et al, 1987; Pestka et al, 2004]. Type I IFNs include 13

functional IFN-α genes, and single IFN-β, IFN-ε, IFN-κ, and IFN-ω genes [Pestka et al,

2004]. Binding of type I IFNs to a common receptor (IFNAR) composed of a unique IFNAR1

subunit and a functionally active IFNAR2c subunit, results in the activation of JAK1 and

TYK2 kinases that subsequently activate the signal transducer and activator of transcription

(STAT) proteins 1, 2, 3, 4, and 5, and regulate the expression of hundreds of IFN-stimulated

genes (ISGs) [Darnell, Jr. et al, 1994; Stark et al, 1998; Platanias, 2005]. The association

between type I IFNs (particularly IFN-α) and SLE is compelling [Pascual et al, 2006]. In

1979, increased serum levels of IFN α and β were shown for the first time in SLE, and about

71% of patients with active SLE had raised serum IFN levels. The elevated IFNα correlated

positively with disease activity and anti-dsDNA titers, and inversely with C3 levels [Hooks et

al, 1979]. Subsequent studies from other groups have also indicated that elevated levels of

IFNα in SLE patients correlate with both disease activity and severity, and was particularly

associated with African-American patients [Bengtsson et al, 2000; Baechler et al, 2003; Kirou

et al, 2005; Dall'era et al, 2005]. Patients with non-autoimmune disorders, such as melanoma

or hepatitis C infection, who are treated with recombinant IFN-α may transiently generate

anti-dsDNA and antinuclear autoantibodies and autoimmune manifestations, and occasionally

SLE [Rönnblom et al, 2003]. The involvement of type I IFN in SLE development was further

supported by the finding that IFNα regulated genes are significantly overexpressed in

peripheral blood of pediatric and adult SLE patients upon gene expression profiling [Baechler

et al, 2003; Bennett et al, 2003; Kirou et al, 2005] (Figure 1). Active SLE patients had a


remarkably similar whole blood IFN-inducible gene expression pattern which included ISG

15, Cig45, HepC microtubular Agg, TRIP14, MX1, PLSCR1, XIAPAF1 and RIGE/TSA1.

The expression of the IFN inducible genes Cig45 and PLSCR1 were shown to correlate with

SLEDAI score [Bennett et al, 2003].

Furthermore, the expression of IFN-inducible genes has also been observed in various

tissue samples from SLE patients. A type I gene signature was found in skin lesions

[Blomberg et al, 2001], IFN-inducible protein 10 (CXCL10) is increased in the cerebrospinal

fluid of patients with central nervous involvement [Okamoto et al, 2004], and IFN inducible

proteins IFI27 and STAT1 are overexpressed in the synovium of SLE patients with arthritis

[Nzeusseu et al, 2007]. Finally, the type I IFN-inducible genes, ISG 15 and IFIT 1, were also

found to be upregulated in kidney biopsies from patients diagnosed with lupus

glomerulonephritis [Peterson et al, 2004].

AB

C

Figure 1: Association of type I IFN gene signature

and SLE disease activity

Figure 1. Association of type I IFN gene signature and SLE disease activity. (A) Active SLE patients

leukocytes (left panel) display 36 IFN-up-regulated and 13 down-regulated transcript sequences. The

same genes are altered in healthy PBMCs cultured in vitro with IFN-α (right panel). Median expression

and the number of patients who display more than two-fold increase in gene expression. ** Significant

after Bonferroni correction, * significant after Benjamini and Hochberg correction. (B) A numerical

score was calculated by using the normalized expression levels of the 14 IFN-regulated genes that

comprise the IFN signature. The differences between patients and controls were significant, P = 2.8 ×

10−7

. (C) Linear regression analysis demonstrates a significant correlation between IFN score and the

number of SLE disease criteria (r = 0.51, P = 0.0002). [Figure 1A ©2003 Rockefeller University Press.

Originally published in J Exp Med 197:711-723 [Bennett et al, 2003]; Figure1B,C from Baechler et al.,

2003 PNAS 100:2610-2615. ©2003 Proceedings of the National Academy of Sciences, U.S.A

[Baechler et al, 2003]].


3. GENETIC EVIDENCE LINKING TYPE I IFN SIGNALING AND SLE

For an individual to be diagnosed with SLE they must satisfy only 4 of 11 specific

criteria, and consequently the clinical and serological manifestations vary substantially.

Despite this heterogeneity the heritability of the disease is indicative of a strong genetic

component. The concordance rate for SLE in monozygotic twins is 25-56% versus only 2-5%

for dizygotic twins, and the risk ratio of siblings developing SLE is much greater than in

general population [Deapen et al, 1992; Alarcón-Segovia et al, 2005]. Epidemiological

studies have been conducted to understand the genetic basis for disease. Candidate gene case

control studies typically test variants of a single gene suspected to underlie the disease

pathogenesis, whereas a more powerful approach uses unbiased genome-wide association

studies with commercial genotyping arrays that can assess hundreds of thousands of single

nucleotide polymorphisms. These studies have yielded in excess of 30 SLE-associated risk

loci that highlight the roles of both the innate and adaptive immune system [Deng et al, 2010].

The majority of SLE susceptibility genes are associated with just a handful of classes of

immune mediators, all of which can be envisioned to modulate cellular functions that may be

involved in SLE; i) complement and their receptors (e.g., C2 C4, C1q, and ITGAM), ii) FcγR

(e.g. FcγRIIA, FcγRIIB, FcγRIIIA, and FcγRIIIB) may influence immune-complex clearance

or activation of antibody-mediated effector functions, iii) MHC Class II (eg. several HLA-

DR2 and HLA-DR3 genes) are likely important in the presentation of autoantigens to T cells,

iv) regulators of lymphocyte function (eg. BLK, BANK1, LYN, FcγRIIB, ETS1, IKZF1, IL-

21R) will influence B and T cell signaling and differentiation, v) NFκB regulation (e.g.

TNFAIP3 and TNIP1) which is fundamental to immune cell activation, and finally vi) genes

associated with type I IFN signaling (e.g. IRF5, STAT4, TYK2, IRAK1, IRF7, and SPI1). IRF5

is a key transcription factor in the type I IFN pathway that is constitutively expressed in pDC.

IRF5 was the first gene involved with the type I IFN pathway to be associated with a risk for

SLE [Sigurdsson et al, 2005]. It is one of the most strongly and consistently SLE-associated

genes outside the MHC region [Hom et al, 2008; Harley et al, 2008; Gateva et al, 2009; Han

et al, 2009]. Multiple independent functional variants were associated with SLE. Haplotypes

associated with increased expression and IRF5-mediated signaling and IFN-inducible

cytokines [Niewold et al, 2008; Rullo et al, 2010]. Moreover, IRF5 is necessary for the

development of lupus-like disease in mice [Richez et al, 2010].

Multiple genetic studies have identified STAT4 as a SLE disease susceptibility locus

[Remmers et al, 2007; Sigurdsson et al, 2008; Harley et al, 2008; Graham et al, 2008; Taylor

et al, 2008; Gateva et al, 2009; Han et al, 2009; Yang et al, 2010]. Signal transducer and

activator of transcription 4 protein (STAT4) interacts with the cytoplasmic domain of IFNAR

[Tyler et al, 2007]. STAT4 variants associated with SLE have an increased sensitivity to

IFNα, presence of dsDNA autoantibodies, and a more severe phenotype that includes

nephritis and increased likelihood of strokes [Tyler et al, 2007; Sigurdsson et al, 2008; Taylor

et al, 2008; Kariuki et al, 2009; Gateva et al, 2009]. Tyrosine kinase 2 (TYK2) which also

binds to the IFNAR and is necessary for type I IFN signaling, and polymorphisms in the gene

encoding TYK2 are also associated with SLE [Sigurdsson et al, 2005; Graham et al, 2007].

IRAK1 has been identified as a risk gene associated with the pathogenesis of SLE [Jacob et al,

2007; Jacob et al, 2009]. IL-1 receptor-associated kinase 1 (IRAK-1) is a serine-threonine

protein kinase that regulates multiple pathways in both innate and adaptive responses by


linking several immune-receptor complexes to TNF receptor-associated factor 6 (TRAF6),

including an essential role in TLR7 and TLR9 mediated type I IFN production [Uematsu et al,

2005; Jacob et al, 2007; Jacob et al, 2009]. Studies examining the genetic basis for the

induction of lupus-like disease in the NZB/NZW mice identified two critical loci. Sle1 was

responsible for a breakdown in B cell tolerance, and Sle3 altered dendritic cell activation, and

when combined on a C57Bl/6 (B6) background develop full-blown SLE and lupus nephritis

[Mohan et al, 1998; Mohan et al, 1999; Zhu et al, 2005]. Remarkably, IRAK1 deficiency was

shown to inhibit the induction of autoimmunity in congenic B6.Sle1z mice, and the dendritic

cell hyperactivity in B6.Sle3z mice [Jacob et al, 2009]. Together these studies indicate IRAK1

plays a critical role in the development of SLE.

A SLE-associated SNP in PHRF1 (KIAA1542) was recently reported in European

populations [Hom et al, 2008]. This gene encodes an elongation factor, however, the genetic

association may be attributable to IRF7 which is found in close proximity and is known to

play a key role in type I IFN signaling. The PHRF1-IRF7 risk allele was associated with

SLE-associated autoantibodies and elevated IFNα activity in serum samples from SLE

patients which would implicate IRF7 rather than PHRF1 in the pathogenesis of SLE [Salloum

et al, 2010]. Finally, SPI1 encodes an Ets family transcription factor (also known as PU.1)

that is important in hematopoietic differentiation by regulating the expression of genes such

as MCSFR and IL-7R. It also upregulates the MHCII transcription activator and regulates

expression of various genes in coordination with the IFN response factors IRF2, IRF4, and

IRF8 [Yee et al, 1998; Huang et al, 2007]. The rs1057233 polymorphism in the 3'-UTR of

SPI1 is associated with elevated SPI1 mRNA level and with susceptibility to SLE (in a

Japanese population) with a stronger association with nephropathy [Hikami et al, 2011]. The

polymorphism alters the target sequence of mir-569 suggesting that loss of microRNA-

mediated regulation may be the mechanism by which SPI1 is over-expressed and may

contribute to the occurrence of SLE. Interestingly, SPI1 was also identified as one of the 49

hypomethylated genes in genome-wide DNA methylation analysis of monozygotic twins

discordant for SLE [Javierre et al, 2010], indicating both genetic and epigenetic elements may

be involved with this SLE susceptibility locus.

4. MURINE MODELS OF SLE

There are numerous murine models of SLE that have been employed to assist with our

understanding of the genetics and the cellular processes that give rise to the disease, and to

provide tools to test therapeutic interventions. The classical spontaneous models of lupus-like

disease include the MRL/lpr mice, the F1 hybrid of the New Zealand Black (NZB) and New

Zealand White (NZW) strains (NZB/W F1) and their derivatives, and the BXSB/Yaa strains.

Various linkage analyses have been employed to determine the genetic loci which are

responsible for the disease susceptibility [Morel, 2010]. Moreover, the pristane induced

model has also provided valuable insight to the mechanisms that drive the disease. Each

model has its own subset of lupus-associated characteristics, but common to all these models

are the generation of autoantibodies, lymphoid activation and hyperplasia and lupus nephritis

[Perry et al, 2011]. These models will be briefly described below and intersections with the

type I IFN pathway are highlighted.


4.1. MRL/lpr Model

Characterization of MRL sub-strains revealed that one strain, termed MRL/lpr, developed an

SLE-like phenotype with lymphadenopathy caused by the accumulation of B220+ CD4-

/CD8- double negative T cells. These mice had high levels of circulating immunoglobulins

with ANA, anti-ssDNA, anti-dsDNA, anti-Sm and rheumatoid factor autoantibody

specificities and circulating immune complexes, which was associated with nephritis and

accelerated mortality rate [Andrews et al, 1978]. The lymphoproliferative (lpr) SLE

phenotype was attributed to a recessive autosomal mutation that caused a defect in the Fas

receptor expression. Engagement of the surface bound Fas receptor with Fas ligand is

necessary for the induction of apoptosis and the homeostatic control of T cells [Reap et al,

1995]. A mutation on the FasL gene, termed generalized lymphoproliferative disease (gld)

induced a similar autoimmune disorder [Takahashi et al, 1994; Lynch et al, 1994]. The role of

TLRs and type I IFNs in the development of lupus-like disease in mice with defective Fas

signaling is rather interesting. In vitro, TLR9 is required for the activation of rheumatoid

factor B cells by chromatin immune complexes [Leadbetter et al, 2002], and in vivo TLR9

was shown to be required for the generation of anti-dsDNA and anti-chromatin antibodies

[Christensen et al, 2005]. Remarkably, TLR9-deficiency in MLR or MLR/lpr mice develop

an accelerated, more severe lupus phenotype with increased type I IFN [Christensen et al,

2006; Wu et al, 2006], whereas TLR7-deifciency ameliorated disease [Christensen et al,

2006]. Wu et al attributed this phenotype to defective Treg function in TLR9-deficient mice

[Wu et al, 2006], whereas Christensen et al suggested that TLR9-driven responses may

regulate more pathogenic TLR7-driven autoantibody responses, or anti-DNA/chromatin Abs

may be important in the clearance of cellular debris and thereby limit availability of

endogenous inflammatory mediators [Christensen et al, 2006]. Intriguingly, the absence of the

type I IFN receptor also worsens the disease in MRL/lpr mice [Hron et al, 2004].

Interestingly, IFNγ is required for the development of the lymphoproliferation and the lupus-

like pathology in the MRL/lpr model [Balomenos et al, 1998], so type I IFNs are not the

primary drivers and indeed may be important in suppressing a dominant Th1 response in

these mice. However, care should be taken in extrapolating these data to humans when it is

considered that defects in Fas signaling lead to a lymphoproliferative syndrome (ALPS) in

humans which can be relatively easily distinguished from SLE [Balomenos et al, 1998; Worth

et al, 2006]. Lymphadenopathy, splenamegaly or hepatomegaly is very common feature in

ALPS patients, and they often present with autoimmune mediated destruction of blood cells,

whereas development of skin, kidney, joint and neurological manifestations which are

associated with SLE patients, are rather less common [Teachey et al, 2010].

4.2. NZB/W F1 Models

Both NZB and NZW develop a limited autoimmune phenotype, but NZB/W F1 hybrids

develop a severe lupus-like phenotype. Similar to human SLE, the NZB/W F1 mice also

exhibit a strong female bias and may develop lymphadenopathy, splenamegaly, elevated

levels of serum ANA and immune complex mediated kidney failure. However, unlike SLE

patients and the MRL/lpr and BXSB/Yaa models, the NZB/W F1 mice do not generate anti-

RNA associated autoantibodies. The NZB/NZW F1 mice typically develop glomer-


ulonephritis after 5-6 months which leads to kidney failure and death at 10-12 months of age

[Theofilopoulos et al, 1985]. The female sex bias appears at least in part to be regulated by

estrogen since ovariectomy of NZB/W F1 mice delayed the onset of disease and decreased

autoantibody titers which can be circumvented by the addition of estradiol [Roubinian et al,

1978]. Type I IFNs are not necessarily associated with the NZB/W mice or their congenic

derivatives, but manipulation of this axis impacts disease development. Type I IFN receptor

deficiency reduces lupus-like disease in NZB mice [Santiago-Raber et al, 2003], and

conversely, in vivo delivery of IFNα to preimmune NZB/W F1 mice rapidly results in severe

SLE [Mathian et al, 2005]. These mice generate anti-dsDNA autoantibodies as early as 10

days after IFNα treatment and proteinuria and glomerulonephritis induced cell death occurs in

all treated mice at 9 and 18 weeks, respectively, well before symptoms are apparent in

untreated mice [Mathian et al, 2005]. The congenic strains NZM2328 and NZM2410 were

derived from inter-crossing progeny from the NZB x NZB matings and breeding to

homozygosity. Linkage analyses of NZM2410 have identified three SLE susceptibility loci

(Sle1,2,3) that significantly correlated with the development of glomerulonephritis [Morel et

al, 1994]. Adenoviral delivery of murine IFNα5 also accelerated immune-complex mediated

kidney damage in congenic B6.Sle1,2,3 mice but not B6 controls [Fairhurst et al, 2008].

Studies to ascertain which genes within the Sle1,2,3 loci are responsible for the type I IFN

mediated sensitivity to kidney damage are on-going.

4.3. BXSB/Yaa Model

Males generated from matings between C57Bl/6J and SB/Le mice were observed to

exhibit lymphoproliferation. The F1 mice were backcrossed to an SB/Le background to

generate the inbred BXSB strain that develops a lupus-like disease with near 100%

dissemination with a more severe and early onset in males [Andrews et al, 1978]. The mice

develop lymphoid hyperplasia, hypergammaglobulinemia with ANAs and anti-rbc autoanti-

bodies and monocytosis. Immune-complex mediated proliferative glomerulonephritis which

is primarily responsible for premature death that usually occurs at 14 months for females, and

just 5 months for males [Andrews et al, 1978; Murphy et al, 1979]. Consomic studies

demonstrated that the BXSB Y chromosome exacerbated disease when combined with the

NZW or MRL genetic backgrounds [Hudgins et al, 1985; Merino et al, 1989]. The Y-linked

autoimmune accelerator (Yaa) element responsible for the exacerbated disease is a

consequence of a translocation of telomeric end of X chromosome to the Y chromosome

resulting in a duplication of at least 16 genes which includes TLR7 [Pisitkun et al, 2006;

Subramanian et al, 2006]. TLR7 is expressed in B cells and antigen-presenting cells.

Activation of TLR7 by viral or endogenous ligands promotes B cell activation and

differentiation, and MyD88-dependent expression of type I IFNs and other proinflammatory

cytokines [Lau et al, 2005; von Landenberg P. et al, 2007]. Disease activity is extremely

sensitive to TLR7 expression with a 2-fold increase sufficient to induce overt disease in the

presence of other susceptible genes, whereas greater increases in expression result in disease

in the absence of other lupus susceptibility loci [Deane et al, 2007]. The importance of TLR7

as the major contributor to the Yaa phenotype was confirmed when the endogenous copy of

TLR7 was deleted from the X-chromosome and the Yaa-induced monocytosis, splenamegaly,

glomerulonephritis and mortality were abrogated [Deane et al, 2007; Fairhurst et al, 2008;


Santiago-Raber et al, 2008]. The duplication of X-linked genes (without actual duplication of

the X chromosome) may also explain the male bias for developing lupus-like disease in this

mouse strain. Interestingly, a similar phenomenon is observed in humans. The prevalence of

Kleinefelter’s syndrome, caused by duplication of the X chromosome in males, is much

higher in SLE patients than in patients without lupus [Scofield et al, 2008]. Indeed, the risk of

males with Kleinefelter’s syndrome to developing SLE is slightly higher than the average risk

among women, further emphasizing the relevance of X-linked genes for the development of

SLE.

4.4. Pristane-Induced Model

Intraperitoneal injections of pristane (2,6,10, and 14-tetramethylpentadecane, TMPD), an

isoprenoid alkane found in mineral oil, in Balb/c mice induces a repertoire of SLE-associated

autoantibodies which include anti-Sm, anti-U1RNP, anti-DNA, and anti-histone antibodies at

levels comparable to those induced in the MRL/lpr model. Immune-complex deposition leads

to a severe proteinuria and kidney damage [Satoh et al, 1995], and the mice also develop

other phenotypes associated with SLE such as hemorrhagic pulmonary capillaritis and

arthritis [Chowdhary et al, 2007]. Almost all strains are susceptible to pristane-induced

autoimmunity and lupus-like manifestations to varying extents [Satoh et al, 2000], which has

permitted the use of knock-out mice to investigate the mechanisms driving the lupus

phenotypes. Interestingly, the induction of anti-ssDNA, anti-dsDNA and anti-chromatin

antibodies were IL-6 dependent [Yoshida et al, 2002], IL-12 deficiency blocked the induction

of anti-RNP/Sm, anti-Su and anti-RNP antibodies and nephritis [Calvani et al, 2003]. IFNγ

deficiency also prevented the development of pristane-induced kidney damage whereas IL-4

deficiency had no effect [Richards et al, 2001], which indicates that the lupus phenotype in

TMPD-treated mice may be driven by a Th1 response. Intriguingly, pristane-induced lupus is

the only model with a significant type I IFN gene signature. IFNAR-deficiency completely

blocked the type I IFN signature, eliminated anti-RNP, anti-Sm and anti-dsDNA antibodies,

prevented the induction of IL-12, and significantly improved glomerulonephritis [Nacionales

et al, 2007; Thibault et al, 2009]. The induction of type I IFN in this model appears to be

exclusively driven through the TLR7/MyD88 pathway since TLR7-deficiency blocks type I

IFN induction, autoantibody production and renal disease [Lee et al, 2008; Savarese et al,

2008]. Arguably, the predominant role of type I IFN, the similar autoantibody profiles, and

the broad range of affected organs could make pristane-induced lupus the model of choice for

studying human lupus, although there are a few caveats. The precise mechanism by which

TLR7 is activated remains unclear since type I IFN induction appears to be independent of

FcγR-mediated immune-complex activation [Lee et al, 2008]. Moreover, rather than pDC

which appear to be most important for the generation of type I IFNs in human SLE, it appears

that an immature population of Ly6Chi

expressing monocytes are the primary producers of

type I IFN in this model, since their depletion abolishes the IFN signature and autoantibody

production [Lee et al, 2008]. Finally, the mechanisms that drive hemorrhagic pulmonary

capillaritis and arthritis warrant further attention since they may not be necessarily dependent

on type I IFN, as the arthritis symptoms at least can be ameliorated by TNFα neutralizing

antibodies [Beech et al, 1997].


5. INDUCTION OF TYPE I IFNS IN SLE

There are several mechanisms by which type I IFN may be induced in SLE (Figure 2).

Viruses, bacteria, and endogenous ligands, either soluble or associated with neutrophil

extracellular traps, may all participate in the induction of type I IFN through the engagement

of pattern recognition receptors. However, the consensus opinion is that FcγRIIA mediated

uptake of DNA and RNA-containing immune-complexes and subsequent activation of

endosomal TLR by pDC is the primary mechanism by which type I IFNs are induced in SLE.

5.1. Type I IFN are Induced Following Engagement of DNA

and RNA Sensors

Type I IFNs play a critical role in the host defense against viral infections [Baron et al,

1991; Liu et al, 2011]. The rapid and prominent induction of type I IFNs following viral

infection serves to limit the spread of the virus by “interfering” with viral replication and

inducing apoptosis of the infected cell [Sen, 2001]. Host cells detect infectious agents through

several classes of pattern recognition receptors (PRRs) located in different cellular

compartments which permits a thorough immune surveillance. Cell surface expressed TLR2

and TLR4 primarily recognize bacterial products but they may also be triggered by viruses or

endogenous danger signals, and may induce type I IFNs in some circumstances [Barbalat et

al, 2009; Richez et al, 2009]. There are some reports that indicate that TLR2 or TLR4 may

play a role in SLE [Urbonaviciute et al, 2008; Lartigue et al, 2009; Lee et al, 2010; Lood et al,

2011], but further validation studies are required to assess their contribution to disease.

Interestingly, it is the recognition of the viral nucleic acid genomes with endosomal TLRs or

cytosolic receptors that is predominately required for triggering the induction of type I IFN.

TLR3 recognizes dsRNA, TLR7 and TLR8 recognize ssRNA, and TLR9 detects

unmethylated CpG motifs in DNA that are common in DNA viruses and some bacteria.

Engagement of the ligand with TLR3, 7, 8 or 9 leads to a cascade of events involving the

recruitment of adaptor proteins such as Myd88, TRAF6 or TRAF3, interactions with kinases

TBK1, IKK-ε, IRAK1, or IRAK4, phosphorylation of the IFN regulatory factors (IRF)3, 5

and 7 and the transcription of the type I IFN genes [Rönnblom et al, 2011]. Cytosolic

receptors are broadly expressed and facilitate the detection of infectious agents that evade or

escape endosomes. The list of cytosolic receptors has rapidly increased over the last few years

and is likely to increase further. To date the RNA sensors include protein kinase R (PKR),

and the RNA helicases, retinoic acid inducible gene I (RIG-I), melanoma differentiation

antigen (MDA5) and laboratory of genetic and physiology 2 (LPG2), each of which triggers

type I IFN, is important in the host response to particular viruses [Diebold et al, 2003;

Yoneyama et al, 2004; Sumpter, Jr. et al, 2005; Gitlin et al, 2006; Kato et al, 2006; Baum et

al, 2010]. The cytosolic DNA sensors include the DNA-dependent activator of IFN-

regulatory factors (DAI) [Takaoka et al, 2007], RNA polymerase III, IFI16 [Unterholzner et

al, 2010], the leucine-rich repeat containing protein, LRRFIP1 [Yang et al, 2010], Ku70

[Zhang et al, 2011], and the DEAD/H-box helicases DHX9 and DHX36 [Kim et al, 2010;

Keating et al, 2011].


Figure 2: Induction of type I IFN

IFN

viruses

Immune-complexes

NETs

TLR7 endosome

CD32A

TLR9

LL37

endocytosis

anti-DNA

autoantibody

Figure 2. Induction of type I IFNs. Nucleic acids and nucleic acid containing protein complexes,

through activation of endosomal TLRs, are strong inducers of type I IFN from pDC. In the context of

viral infection, induction of type I IFN is a central mechanism in the innate host response, but may also

exacerbate type I IFN production in SLE. The type I IFN response, however, can also be triggered by

self-DNA or self-RNA containing immune complexes, which are captured by the Fc receptor CD32A,

internalized and presented to TLR7 and TLR9. In addition, type I IFN is induced by chromatin

complexed with amphipathic proteins, such as LL37 and HMGB1, in the form of neutrophil

extracellular traps (NETs).

The signaling pathways by which these receptors drive the IFN machinery are becoming

delineated [Balachandran et al, 2004; Kawai et al, 2005; Meylan et al, 2005; Seth et al, 2005],

and Stimulator of Interferon Genes (STING) is emerging as a key player [Ishikawa et al,

2008; Ishikawa et al, 2009; Kerur et al, 2011]. The induction of type I IFNs by viruses may

suggest that viral infections could be responsible for the IFN signature found in SLE patients.

Ebstein-Barr Virus (EBV) has had a long-standing association with SLE, and has been

hypothesized to be involved in the etiology of the disease through molecular mimicry. EBV

persists in a latent form in memory B cells in the majority of the world’s population and

exhibits increased titers in SLE patients [McClain et al, 2005; Toussirot et al, 2008].

However, prospective monitoring of viral titers in SLE patients indicated that flares in disease

activity proceeded EBV reactivation so the virus may be an aggravating factor rather than a

driver of disease [Larsen et al, 2011]. Individual case reports have also indicated that

cytomegalovirus infections can precipitate SLE flares [Vasquez et al, 1992; Sakamoto et al,

2002; Cunha et al, 2009]. It is likely that viral infections, which can be promoted by

immunosuppressive treatments, may contribute to the induction of type I IFNs in lupus

patients, but the overall contribution of latent viruses and opportunistic viral infections to the

chronic expression of type I IFN and disease pathology remains unknown.


5.2. RNA/DNA Immune Complexes Activate pDC to Induce Type I IFN

Production Via TLR7 and TLR9 in SLE Patients

As described previously (section 1), SLE is associated with a spectrum of autoantibodies

targeting nucleic acids and self DNA/RNA-associated nuclear proteins. Their nuclear location

ensures that these antigens are not usually exposed to the immune system, however, they may

become assessable during apoptosis, necrotic cell death or NETosis, particularly if clearance

mechanisms to remove them are compromised. Autoantibodies targeting these autoantigens

can form immune-complexes which can trigger a variety of inflammatory responses including

the induction of type I IFNs (Figure 2). Initially it was demonstrated that sera of SLE patients

with active disease could induce high levels of type I IFNs from the PBMCs of healthy

volunteers and the IFN inducing component appeared to be complexes of DNA and

immunoglobulin [Vallin et al, 1999]. It was subsequently shown that combining apoptotic

cells or plasmid DNA with seropositive SLE sera could also induce production of type I IFN

from normal peripheral blood PBMCs, and the key cell type responsible for this induction

was the plasmacytoid dendritic cell (pDC)[Vallin et al, 1999; Båve et al, 2001]. Blockade of

the FcγRIIa revealed that this receptor was responsible for the uptake of the immune complex

[Båve et al, 2003], and further studies revealed that endosomal TLR9 was responsible for the

recognition of the DNA immune complex [Means et al, 2005]. Besides DNA immune

complexes, it was also shown that RNA-containing immune complexes were potentially more

interferogenic than the DNA complexes [Lövgren et al, 2004], and they also require FcγRIIa-

mediated uptake but signal through TLR7 and TLR8, rather than TLR9 [Vollmer et al, 2005;

Barrat et al, 2005]. The main source of type I IFNs induced in response to immune complexes

appears to be the pDCs. They are the only cell type that constitutively express both TLR7 and

TLR9, and although infrequent in the blood (~0.1% of the mononuclear cells), they have the

capacity to produce extremely large amounts of IFNα (up to 109 IFNα molecules per cell

within 24h) in response to a wide-range of exogenous and endogenous inducers [Rönnblom et

al, 2011]. Depletion of pDC demonstrates that ~95% of the type I IFN induced by immune

complexes or viruses by PBMCs from healthy volunteers is derived from pDCs indicating

that these cells are the primary producers of type I IFN [Blanco et al, 2001; Blomberg et al,

2003]. Interestingly, despite the increased levels of type I IFNs found in SLE patients, the

frequency of pDCs is much lower in the blood of SLE patients than healthy controls [Blanco

et al, 2001]. This apparent contradiction appears to be a consequence of increased migration

of pDCs to inflammatory sites such as the skin, lymph nodes and kidney where pDC numbers

are increased in SLE patients [Farkas et al, 2001; Vermi et al, 2009]. It has been noted that an

immature Ly6Chigh

monocyte population has been identified as a major source of type I IFN

in 2,6,10,14-tetramethypentadecane-induced lupus model [Lee et al, 2008], but an equivalent

population in SLE patients has not been documented. There is also evidence that neutrophils

may play a role in the induction of type I IFN responses in SLE patients (see section 5.3), and

a recent study also indicated that type I IFN can be produced by resident renal cells and this

local production may promote glomerulonephritis development [Fairhurst et al, 2009].


5.3. Neutrophils and the Generation of Type I IFNs

Besides the striking type I IFN signature, microarray analysis has also revealed that SLE

patients have a prominent signature of neutrophil-specific transcripts whose expression also

correlates with disease activity, and the occurrence of lupus nephritis [Bennett et al,

2003](Figure 3A). The neutrophil signature in SLE patients is associated with the presence of

an expanded population of low density granulocytes.

Figure 3: Role of SLE Neutrophils in the

generation of type I IFNs

A B

C

D E

F

Figure 3. Role of SLE neutrophils in the generation of type I IFN. (A) SLE Granulopoiesis signature.

Genes have been divided into three categories: enzymes and their inhibitors, bactericidal proteins, and

others. Median expression and the number of patients who display more than two-fold increase (red) in

gene expression. ** Significant after Bonferroni correction, * significant after Benjamini and Hochberg

correction. (B) Presence of granular cells in leukocytes that display granulopoiesis-related RNA. Flow

cytometry analysis (forward scatter vs. side scatter) of Ficoll-separated mononuclear cells. The gated

cells are low-density neutrophils. (C) Correlation between the defensin α (DEF3) levels and the

numbers of cells gated as shown in B. (D) Confocal microscopy of NETting neutrophils activated for 3

hours with phorbol 12-myristate 13-acetate (PMA) stained for DNA (green), LL37 (red), or HNPs (red)

as indicated. Representative images are shown. Bars, 10 µm. Arrows indicate DNA–antimicrobial

peptide complexes contained in NETs. (E) Percentages of SLE patients with or without significant anti-

LL37 antibody titers (cutoff value OD index, 1.611; sensitivity, 41%; specificity, 100%; left panel) or

SLE patients with or without anti-HNP antibody titers (cutoff value OD index, 1.15; sensitivity, 59%;

specificity, 91%; right panel) among patients with detectable IFN-a (n = 9) and patients without IFN-a

in the serum (n =29). *P = 0.001; **P = 0.05, Fisher’s exact test. (F) IFNα produced by pDCs


stimulated with supernatants of NETting neutrophils alone or in the presence of anti-LL37, anti-HNP,

anti-DNA, or control antibodies. In some experiments, the pDCs were pretreated with the TLR9

inhibitor ODN-TTAGGG. Each symbol represents an independent experiment, and horizontal bars

represent the mean. *P = 0.023; **P <0.04, ANOVA (Bonferroni adjustment). [Figure 3A, B and C

©2003 Rockefeller University Press. Originally published in J Exp Med 197:711-723 [Bennett et al,

2003]; Figure3D,E and F from Lande et al., 2011 Sci Transl Med 3:73ra19. Reprinted with permission

from The American Society for the Advancement of Science [Lande et al, 2011]].

Characterization of these low density granulocytes indicates that they may have

pathogenic potential, since they have impaired phagocytic properties, an activated phenotype,

direct contact with endothelial cells induces cytotoxicity, and importantly, an increased

capacity to induce proinflammatory cytokines including type I IFNs, IFNγ and TNFα [Denny

et al, 2010]. The induction of these cytokines may be realized by GMCSF and GCSF which

are induced upon cross-linking of FcγRIII [Shirafuji et al, 1990; Durand et al, 2001; Denny et

al, 2010]. The morphology of these low density granulocytes indicates that they are a

heterogeneous population reflecting early, immature and mature stages of differentiation.

Importantly, type I IFNs can prime neutrophils to undergo immune-complexes mediated

NETosis, a form of cell death that results in the release of neutrophil extracellular traps

(NETs) [Garcia-Romo et al, 2011], a network of extracellular fibers primarily containing self-

DNA and antimicrobial peptides such as LL37 and Hmgb1. These NETs may serve as a

source of autoantigen to trigger B cell activation. Autoantibody responses targeting self DNA,

LL37, Hmgb1 or other DNA-associated human neutrophil peptides (HNPs) generated by the

NETs can trigger TLR9-dependent activation and type I IFN production by pDCs, and this

may represent an important source of type I IFNs in SLE patients [Garcia-Romo et al, 2011;

Lande et al, 2011](Figures 2 and 3). Moreover, it is evident that neutrophils isolated from

SLE patients have a greater propensity to form NETs than neutrophils from healthy donors

[Lande et al, 2011], and SLE patients also have a deficiency in the ability to clear these

immunogenic traps [Leffler et al, 2012]. Taken together these data indicate neutrophils may

produce and respond to type I IFNs, promote the generation of immunogenic autoantigens,

trigger autoreactive B cell responses, and stimulate dendritic cells to produce type I IFNs

which may act in a positive feedback loop in SLE patients.

6. REGULATION OF TYPE I IFNS IN SLE

As previously described, the activation of pDCs by RNA- or DNA-containing immune

complex or amphipathic peptide-DNA complexes triggers the TLR7 and TLR9-dependent

induction of type I IFNs in SLE patients. Type I IFNs may promote their own production in a

positive feedback since IFN and IFN 4 induce the expression of the transcription factors

IRF7 and IRF8 which, once phosphorylated, drive the expression of the type I IFN family

[Marie et al, 1998; Tailor et al, 2007]. However, considering the pleiotropic effects of type I

IFN on the immune system, one would expect that type I IFN producing cells are tightly

regulated. Upon viral infections pDCs from healthy donors transiently secrete type I IFNs for

a few hours, and then secrete other cytokines such as TNFα. So how is type I IFN production

controlled in pDCs and is this homeostasis dysregulated in SLE patients?


6.1. Persistence of IFN-Inducing Ligands

In SLE patients it remains unclear why the production of type I IFNs or at least the

response to type I IFNs is protracted, but it is likely that the response is driven by persistent or

repeated exposure to TLR-triggering autoantigens and autoantibodies. The source of

autoantigens is likely to be material from apoptotic cells and cellular debris [Andrade et al,

2000]. Increased rates of apoptosis, deficiencies in the clearance of apoptotic material and

NETs are associated with SLE and murine models of the disease [Botto et al, 1998; Denny et

al, 2006; Gaipl et al, 2006; Ogden et al, 2006; Hakkim et al, 2010; Leffler et al, 2012].

Similarly, deficiencies in these processes likely contribute to the release of amphipathic

proteins like LL37 and Hmgb1 that increase the stimulatory capacity of DNA by enhancing

uptake and TLR ligation (Figure 3D-F) [Lande et al, 2007; Tian et al, 2007; Ganguly et al,

2009]. Importantly, short or long-lived plasma cells generating autoantibodies targeting DNA,

RNA and associated proteins enable the formation of immune-complexes that efficiently

drive type I IFN production predominately by pDCs (Figure 2).

6.2. Cell Surface Receptors on pDC

Immune complexes are endocytosed by a broad range of cell types expressing low

affinity IgG receptors, FcγRII and FcγRIII. Human pDCs express modest levels of FcγRIIA,

yet it has been clearly shown that this receptor is solely responsible for uptake of immune-

complexes and triggering TLR-dependent type I IFN production [Båve et al, 2003; Means et

al, 2005]. Activation of FcγRIIA on monocytes and mDCs is regulated by the co-engagement

of the closely related low affinity inhibitory receptor FcγRIIB, and the balance of activating

and inhibitory receptors, which can be influenced by the inflammatory milieu, sets the

threshold of immune activation [Nimmerjahn et al, 2007]. The expression of the inhibitory

FcγRIIB on pDCs is low to undetectable (GS, BC unpublished observations), so this

regulatory mechanism may not directly influence immune complex induced activation of

pDCs, although the receptor expression profile of both FcRγIIA and FcRγIIB may also be

influenced by the cytokine milieu [Liu et al, 2005]. It is likely that immune-complex mediated

uptake and degradation of FcγRIIA serves to self-regulate the expression of the receptor and

the capacity to induce type I IFNs [Zhang et al, 2010]. Several other cell surface receptors

expressed on pDCs may modulate type I IFN responses. Crosslinking ILT7, BDCA-2, NK44p

and LAIR-1 inhibit type I IFNs production by pDC, whereas crosslinking of CD300a/c has

been shown to enhance type IFN production [Fuchs et al, 2005; Cao et al, 2006; Cao et al,

2007; Ju et al, 2008; Bonaccorsi et al, 2010; Javierre et al, 2010].

The natural ligand for CD300a/c and the signaling pathway by which CD300a/c

engagement promotes type I IFN induction requires clarification. ILT7 and the C-type lectin

BDCA-2 both pair with the FcєRI gamma chain and signal through its immunoreceptor-based

tyrosine activation motif [Cao et al, 2006; Cao et al, 2007]. NK44p and LAIR-1, which are

differentially regulated by IL-3, signal via the DNAX associated protein 12 (DAP12) and also

inhibit type I IFNs [Fuchs et al, 2005; Bonaccorsi et al, 2010]. LAIR-1 recognizes a common

collagen motif and functions as an inhibitory receptor on multiple cell types besides pDCs.

The reduced expression following IFN stimulation or TLR ligation likely reflects the

activation state seen in SLE patients. ILT7 directly interacts with bone marrow stromal cell


antigen 2 (BST2) [Cao et al, 2009]. BST2 is well known to be robustly induced on the surface

of various types of cells after exposure to IFN and other proinflammatory cytokines via STAT

activation [Ohtomo et al, 1999; Blasius et al, 2006; Van et al, 2008]. The BST2–ILT7 inter-

action, therefore, likely serves as an important negative feedback mechanism for preventing

prolonged IFN production after viral infection. Identification of the cognate receptors for

BDCA-2, NK44p and CD300a/c, and will provide a better understanding of the spatial and

temporal regulation and their relative importance in SLE.

6.3. Differential Effects of Monocytes, NK Cells and Platelets

Besides factors intrinsically associated with pDCs, complex interactions between other

cell types may also be at work to set the threshold of pDC activation. Immune complex

activation of monocytes induced the production of TNFα, PGE2 and ROS which in turn

inhibit type I IFN production by pDCs, but it is interesting to note that this inhibitory capacity

appears to be diminished in SLE [Eloranta et al, 2009]. This may reflect alterations in

monocyte differentiation and function promoted by type I IFNs. Nevertheless, TNFα

produced by monocytes and other cell types may be particularly important in regulating type I

IFN responses, since it inhibits the generation of pDCs from CD34+ hematopoietic

progenitors, and it also inhibits IFNα release from pDCs exposed to influenza virus [Palucka

et al, 2005]. This is likely to be clinically relevant as neutralization of endogenous TNFα in

systemic juvenile arthritis patients with TNF antagonists resulted in a sustained over

expression of IFNα regulated genes, and provides a mechanistic explanation for the

development of anti-DNA antibodies and a lupus-like syndrome in patients undergoing anti-

TNF therapy [Palucka et al, 2005]. In contrast to the inhibitory effects of monocytes on pDC

responses, NK cells can strongly promote production of type I IFNs by pDCs. The

mechanism appears to involve the FcγRIII-mediated immune-complex activation of

CD56dim NK cells that drives production of Mip1α, Mip1β, RANTES, IFNγ and TNFα.

LFA-1 mediated cell-to-cell interactions with pDCs and secretion of Mip1β appear to be

important in driving the type I IFN production [Eloranta et al, 2009; Hagberg et al, 2011].

Platelets may also play an important role in potentiating the type I IFN production from pDCs

in SLE patients. Activated platelets can modulate immune responses by upregulating CD40L

and inducing dendritic cell maturation, B cell isotype switching and augmenting T cell

responses in vitro and in vivo [Elzey et al, 2003]. Immune complexes stimulate platelets via

FcγRIIA causing the release of their CD40L and RANTES reservoirs [Antczak et al, 2011].

Levels of immune complexes, frequency of activated platelets and levels of CD40L all track

with disease activity in SLE patients, and in vitro activated platelets directly interact with

pDCs through CD40L/CD40 interactions and enhance IFNα secretion [Duffau et al, 2010].

Moreover, in lupus prone NZB/W F1 and MRL.lpr mice, treatment with the P2Y12 receptor

antagonist (clopidogrel) which inhibits platelet activation improved measures of disease and

overall survival, whereas transfusion with activated platelets worsened the disease course

[Duffau et al, 2010].


6.4. Estrogen

Female sex hormones have also been implicated to play a role in the development of

lupus and this would provide some explanation for the high female prevalence in the disease

[Cohen-Solal et al, 2008]. The sustained increased levels of estrogen during pregnancy, and

the commencement of oral contraceptives have both been associated with disease flares

[Beaumont et al, 1989; Petri et al, 1991; Urowitz et al, 1993], and elevated serum levels of

16-hydroxyesterone, a metabolite of 17β-estradiol (E2), have also been reported in SLE

patients [Lahita et al, 1982]. E2 may directly promote B cell survival and impair negative

selection [Grimaldi et al, 2002; Grimaldi et al, 2006], but it has also been shown to enhance

the viability and activation of stimulated pDCs by increasing type I IFN production and B cell

costimulation [Li et al, 2009].

6.5. Vitamin D3

Several studies have demonstrated that serum levels of the active form of vitamin D3 (1-

25-dihydroxyvitamin D3) in SLE patients inversely correlated with disease activity [Chen et

al, 2007; Ben-Zvi et al, 2010; Amital et al, 2010; Mok et al, 2012]. Moreover, SLE patients

with vitamin D deficiency also have increased levels of serum IFNα activity than patients

without vitamin D deficiency [Ritterhouse et al, 2011]. Several factors associated with SLE,

such as dark skin pigmentation, photosensitivity, fatigue and disability, may certainly impact

normal levels of sunlight exposure necessary for the conversion to the active form. Moreover,

polymorphisms in the Vitamin D receptor have also been associated with SLE [Lee et al,

2011]. Importantly, vitamin D3 has been shown to have direct immunosuppressive effects on

a broad range of immune cell types including monocytes, dendritic cells, B cells and T cells

that can contribute towards the disease [Boonstra et al, 2001; Hewison et al, 2003; Sadeghi et

al, 2006; Chen et al, 2007]. Vitamin D3 has also been shown to suppress type I IFN-mediated

monocyte differentiation [Gauzzi et al, 2005], and the type I IFN gene signature induced by

SLE serum [Ben-Zvi et al, 2010]. Further studies are warranted to determine if vitamin D3

can suppress the effects of type I IFNs on other relevant cell types. Nevertheless, the broad

immunosuppressive roles of Vitamin D3 have promoted clinical investigations to determine if

correcting Vitamin D3 levels with supplementation will alter type I IFNs in SLE patients and

provide clinical benefit (e.g. www.clinicaltrials.gov NCT01413230, NCT00710021).

6.6. Micro RNA

It has long been known that microRNA (miRNA) species provide important protection

from viral infections in plants. Processed single-stranded miRNA sequences bind their

complimentary mRNA target and thereby promote mRNA degradation or interfere with

translation. A growing body of evidence demonstrates that miRNA species play a crucial role

in regulating gene expression in both plants and animals [Bartel, 2004]. Indeed it has been

estimated that ~30% of the mammalian transcriptome are regulated by miRNAs [Lewis et al,

2005]. Considering the importance of type I IFNs in regulating anti-viral responses in

mammals, it was perhaps not surprising that IFNβ was found to rapidly upregulate numerous


cellular miRNAs associated with anti-viral and innate immune responses [Pedersen et al,

2007]. Subsequently, miRNA array chip and northern blot analyses identified 16 miRNAs

differentially expressed in SLE patients indicating their potential involvement in disease

pathogenesis and utility as diagnostic biomarkers [Dai et al, 2007]. Interestingly, miR-146a is

downregulated in SLE patients and the levels negatively correlated with disease activity. It

was also shown that miR-146a has a direct effect on the type I IFN signaling pathway by

repressing the expression of IRAK-1, TRAF6, IRF5 and STAT-1 [Tang et al, 2009].

The effects of miR-146a are not limited to the type I IFN pathway, since its expression

upregulates the phagocytic activity of THP1 cells and downregulates proinflammatory

cytokine production [Pauley et al, 2011]. Interestingly, mature miR146a is induced in

response to TLR7 and TLR9 stimulation, and type I IFN, as well as LPS stimulation [Tang et

al, 2009], so it is surprising that the expression should be down regulated in SLE. A

functional variant in the promoter of miR-146a that modulates expression and confers

susceptibility to SLE has been identified [Luo et al, 2011]. Further studies are warranted to

understand the expression of miR-146a in SLE patients, particularly when it is considered that

patients with Sjögren’s syndrome have a type I IFN gene signature and increased levels of

miR-146a [Pauley et al, 2011]. MiR-155* and miR-155 also appear to play an important role

in regulating type I IFNs; Mir-155* augments IFNα production by suppressing Interleukin-1

receptor associated kinase M (IRAKM) early following stimulation, whereas mir-155 is

mainly expressed later and down regulates the response by targeting TGF- -activated kinase

1 and MAP3K7-binding protein 2 (TAB2) [Zhou et al, 2010]. However, in this case there is

currently no evidence implying that these microRNAs are aberrantly expressed in SLE.

7. MODULATION OF CELL FUNCTION AND IMMUNE RESPONSES

BY TYPE I IFNS

Historically, the effects of IFNs on cells of the innate immune system were examined in

the context of viral responses. Consequently, there is substantial evidence demonstrating that

type I IFNs have direct effects on NK and CD8 cells to promote the production of IFNγ, the

elimination of virally infected cells and the generation of CD8 memory cells [Biron et al,

1999; Kolumam et al, 2005]. The strong association of type I IFNs in SLE has renewed the

interest in the role of type I IFNs on innate and adaptive immunity and their role in the

pathogenesis of autoimmune diseases. Type I IFNs appear to be able to influence the

development, activation and differentiation of a broad range of cell types that may influence

the disease pathogenesis in SLE (Figure 4).

7.1. Effects of Type I IFN on Hematopoiesis

Acute exposure to type I IFNs promotes the proliferation of dormant hematopoietic stem

cells (HSC) and facilitates the regeneration of immune cells following an infection [Essers et

al, 2009]. It is noteworthy that HSCs express a broad range of TLRs and constitutively

produce low levels of type I IFNs, and have the inherent potential to significantly alter

immune cell homeostasis. For example, TLR4 stimulation of HSC favors the development of


myeloid cells over lymphoid cells [Nagai et al, 2006], whereas TLR9 stimulation of lymphoid

progenitors drives the development of dendritic cells at the expense of B cells [Welner et al,

2008]. Moreover, HSCs chronically activated by type I IFNs or TLR ligands become

exhausted and functionally compromised [Esplin et al, 2011]. Importantly, type I IFNs also

have a profound effect on B cell and T cell lymphopoiesis by inhibiting IL-7-dependent

survival at the pro-B and pro-T stages of differentiation in the bone marrow and thymus

respectively.

Figure 4: The pleiotropic effects of type I IFN

on cells of the immune system

Figure 4. The pleiotropic effects of type I IFN on cells of the immune system. Type I IFNs are

predominantly produced by pDCs. IFN and other type I IFN family members stimulate differentiation

of monocytes to mature dendritic cells. Antigen presentation by dendritic cells in turn enhances the

activity of T effector cells. On CD4 T cells, IFN promotes a Th1 phenotype, while suppressing Treg

function. In addition, type I IFN can enhance the cytotoxic activity of both CD8 T cells and NK cells.

IFN stimulates survival of early pre-T, pre-B cells and mature B cells and promotes the differentiation

of memory B cells to antibody-secreting plasma cells. Within the bone marrow, acute exposure to type I

IFN can promote hematopoietic stem cell (HSC) proliferation, while chronic exposure can lead to stem

cell exhaustion. See text for details.

These effects likely account for the leukopenia and lymphopenia which are common

hematological abnormalities associated with SLE. Considering their effects on hematopoiesis

as previously indicated, it is plausible that TLR ligands, immune complexes and type I IFNs

may be responsible for perturbations in granulocyte differentiation and activation found in

SLE patients. In vitro studies have shown that type I and type II IFNs both induce a strong

tyrosine phosphorylation of STAT1 in mature, but not immature neutrophils [Martinelli et al,

2004]. In vitro, type I IFN inhibits neutrophil apoptosis via PI3K and NFκB signaling [Wang

et al, 2003], and appears to prime mature neutrophils allowing them to form NETs upon

subsequent stimulation with complement and TLR triggering immune complexes [Martinelli

et al, 2004; Garcia-Romo et al, 2011].

7.2. Effects of Type I IFNs on Monocytes and DC

Circulating in the blood with reserves in the red pulp of the spleen, monocytes migrate to

sites of inflammation and differentiate into macrophages and dendritic cells. Tissue

macrophages primarily target microbial antigens or apoptotic material for phagocytosis and

release mediators to recruit and activate other immune cells, and myeloid dendritic cells are

potent antigen-presenting cells that efficiently take up, process and present antigen on MHC


molecules to naïve T cells. Monocytes from SLE patients display a pattern of cell surface

markers that is more consistent with that of mature dendritic cells, with reduced levels of

CD14, increased levels of MHCII and costimulatory molecules CD80, CD86 and CD83, and

the capacity to stimulate allogenic CD4+ T cells in a mixed lymphocyte reaction [Blanco et

al, 2001]. Moreover, monocytes from healthy donors incubated with SLE serum also induced

morphological and functional responses characteristic of dendritic cells, and these effects

were blocked by neutralizing type I IFN antibodies [Blanco et al, 2001]. These dendritic cells

also upregulate the expression of TLR7, and are capable of producing type I IFN in response

to viral stimulation or TLR7-specific ligands [Mohty et al, 2003]. Importantly, DCs

differentiated with SLE sera could also present antigens from dying allogeneic cells and

stimulate the proliferation of autologous T cells indicating that type I IFNs present in SLE

patients likely contribute to the loss of tolerance to self-antigens and the development of

autoimmunity [Blanco et al, 2001; Pascual et al, 2003]. Besides encouraging antigen

presentation, a type I IFN autocrine-paracrine loop is involved in TLR induced IL-12p70 and

IL-6 secretion by DCs [Gautier et al, 2005; Yasuda et al, 2007]. These findings would

indicate that type I IFNs promote presentation of antigen and promote proinflammatory

cytokine induction which would drive CD4+ T cells. However, the effects of type I IFNs may

not be so clear cut, since other studies indicate that type I IFNs inhibit IFNγ induced IL-12

production and the differentiation of Th1 cells [McRae et al, 1998; Nagai et al, 2007].

Moreover, in several experimental and clinical autoimmune settings, treatment with type

I IFN or induction of type I IFNs have been beneficial. In most cases, these conditions are

tissue-specific autoimmune conditions or inflammatory syndromes characterized by

activation of effector Th1 or Th17 responses including arthritis, inflammatory bowel diseases

and multiple sclerosis [Lee et al, 2006; Yarilina et al, 2008; Prinz et al, 2008]. IFNβ is a

common and effective treatment for reducing disease recurrence in multiple sclerosis

[Noseworthy et al, 2000]. The mechanism by which type I IFN affects these pathological

conditions are most likely linked to its immunomodulatory effects, including its ability to

inhibit IL-12 production, augment IL-10 production, to activate regulatory T cells, and to

constrain Th17-cell mediated autoimmune inflammation [Byrnes et al, 2001; Levings et al,

2001; Byrnes et al, 2002; Guo et al, 2008]. Unlike myeloid dendritic cells, pDCs express low

levels of MHC class II molecules and costimulatory molecules so they are likely to have a

diminutive role in promoting CD4+ T cell responses [Grouard et al, 1997; Olweus et al,

1997]. Indeed in vitro and ex vivo studies indicate that pDCs have the intrinsic ability to

prime naïve T cells to differentiate into IL-10 producing T cells, and they appear to play a

critical role in T cell tolerance including mucosal tolerance in the airway, gut, and liver, graft

transplantation, and tumor microenvironment [Liu, 2005]. In vivo studies in which pDCs

were specifically depleted demonstrated that pDCs induce peripheral tolerance by generating

antigen-specific inducible CD4+ FoxP3+ Treg cells that subsequently dampen differentiation

of antigen-specific CD4+ T cells, but pDCs were also shown to negatively regulate the

development of thymic CD4+ FoxP3+ natural T Regs [Takagi et al, 2011]. It was also

recently reported that pDCs may promote central tolerance by transporting peripheral

antigens to the thymus, and this process is inhibited by TLR ligation which down regulates

CCR9 preventing the cells from homing to the thymus [Hadeiba et al, 2012].

In SLE patients, it remains unclear if pDCs exhibit or retain tolerogenic properties in the

presence of type I IFNs and a closer examination of the functional characteristics of pDCs

from SLE patients is generally required. Rather than promoting CD4+ T cell responses, pDCs


appear to be more effective at initiating CD8+ T cell responses by presenting antigen in

association with MHC Class I [Takagi et al, 2011; Cervantes-Barragan et al, 2012]. Indeed,

the role of CD8+ T cell populations in SLE has been largely over-looked. It has been shown

that serum from SLE patients with active disease induce granzyme B expression in cytotoxic

CD8+ T cells, the frequency of these cells correlates with disease activity, and they can kill

target cells and generate nucleosomes and SLE autoantigens in a granzyme B-dependent

manner [Blanco et al, 2005]. Moreover, CD8+ cytotoxic T cells infiltrate the periglomerular

region in patients with severe lupus nephritis and are linked with poor outcome after

induction therapy [Couzi et al, 2007]. So the impact of type I IFNs on cytotoxic T cell

responses may represent an important mechanism by which type I IFNs influence the

development of SLE.

7.3. CD4+ T Cell Subsets

Imbalance in the cytokine profile generated by CD4+ T helper cells have been used to

label the cellular processes underlying different disease states. SLE was considered to be

driven by Th2 (IL-4, IL-5, IL-10) cells on the basis of the clear humoral involvement,

however, later assessments based on blood and kidney biopsies from lupus nephritis patients

are indicative of a strong Th1 (IL-2, IFNγ) signature potentially perpetuated by IL-18, while

SLE patients without renal involvement had a relatively balanced Th1/Th2 profile [Akahoshi

et al, 1999; Calvani et al, 2004]. In more recent years, IL-17 producing Th17 cells have also

been implicated in the pathogenesis of SLE and other autoimmune diseases [Perry et al,

2011]. Increased levels of IL-17 and IL-17 producing T cells occur in SLE patients, and the

levels correlate with diseases activity [Wong et al, 2000; Crispin et al, 2008; Doreau et al,

2009; Mok et al, 2010]. Moreover, SLE patients have increased levels of phosphorylated

STAT3 [Harada et al, 2007], a transcription factor activated by IL-6, IL-21, and IL-23, which

is necessary for the development of Th17 cells [Yang et al, 2007; De Beaucoudrey L. et al,

2008]. Unregulated IFNα production has also been shown to increase proinflammatory

cytokine production including IL-6 and IL-23 which leads to Th17-mediated autoimmunity in

mice [Espinosa et al, 2009]. However, type I IFNs can also act as potent inhibitors of both

Th1 and Th17 inflammatory cell responses. Blockade of TLR9 agonist-induced type I IFNs

promotes inflammatory cytokine IFNγ and IL-17 secretion and CD40L-induced IL-12p70 and

IL-23 by activated human PBMCs [Meyers et al, 2006]. It has also been proposed that the

mechanism by which type I IFNs inhibit Th17 responses is through the induction of IL-27

which suppresses IL-17 production [Guo et al, 2008]. Besides Th17 cells, elevated numbers

of CD3+ CD4- CD8- (DN) TCRα/β T cells (a population derived from CD8+ T cells) are

found in the blood and kidney of SLE patients, are also a significant source of IL-17 and IFNγ

[Shivakumar et al, 1989; Crispin et al, 2008]. These DN T cells augment the production of

pathogenic autoantibodies, and therefore, may play an important role in SLE [Shivakumar et

al, 1989]. It remains to be determined if pDCs or type I IFNs enhance memory and effector

function of these DN T cells, as they do for other CD8+ T cell populations.

Extensive studies have indicated that CD4+ CD25+ Treg cells that express the forkhead-

winged helix protein-3 (FoxP3) are potent suppressors of immune responses, and depletion or

functional defects leads to the development of autoimmunity in mice and humans [Sakaguchi

et al, 2008]. As previously indicated herein, pDCs may directly regulate the generation of


natural and inducible Tregs in mice. The role of Tregs and their associated cytokines in the

regulation of pathogenesis of SLE has been recently reviewed [Okamoto et al, 2011; Miyara

et al, 2011]. Decreased numbers of CD4+ CD25+ Tregs and defective CD4+ CD25+ Treg

activity have both been reported to occur in SLE patients [Crispin et al, 2003; Valencia et al,

2007], and in some murine models of lupus [Chen et al, 2005; Parietti et al, 2008]. This is

somewhat surprising considering that type I IFN and IL-10 can induce the differentiation of

Tregs [Levings et al, 2001]. In contrast, a subpopulation of Fox P3+ Tregs that express ICOS

and secrete IL-10 were found to be increased in untreated SLE patients and correlated with

disease activity [Liu et al, 2011], although the suppressive activity of these cells was not

determined. Other studies from untreated SLE patients indicate that antigen-presenting cells

are responsible for reducing the suppressive function of Tregs, and this was at least in part

mediated by high levels of type I IFN [Yan et al, 2008]. A critical role for IL-2 in the

maintenance of peripheral Tregs has been established, and reduced levels of IL-2 in patients

with SLE provides a plausible explanation for regulatory deficiencies [Linker-Israeli et al,

1983; Setoguchi et al, 2005]. Indeed, selective inhibition of the proliferative capacity of Tregs

by type I IFNs has been attributed to IFN-mediated inhibition of IL-2 production [Golding et

al, 2010]. Besides the effects type I IFNs have on T cell subsets, and despite the T cell

lymphopenia, it is also important to highlight that autoreactive T cells are found in the blood

of SLE patients so T cell tolerance is broken [Lu et al, 1999; Tsokos et al, 2000]. It is also

notable that type I IFNs generally enhance clonal T cell expansion, and yet type I IFN also

sensitizes cells to the Ag-induced cell death [Dondi et al, 2004]. Together these data highlight

the complex ways in which type I IFNs may influence survival, proliferation and

differentiation of T cell subsets, but it still remains unclear how chronic exposure to type I

IFN breaks T cell tolerance in SLE, and what impact neutralization of type I IFNs will have

on T cell homeostasis and disease. It has been hypothesized that neutralization of type I IFNs

during early stages of disease or during remission, when T helper cell mediated inflammation

is absent or minimal, may disrupt the cycle of systemic autoimmune induction and provide

clinical benefit, whereas targeting type I IFNs during advanced stages of disease when there

is substantial ongoing Th1 or Th17 cell-mediated inflammation, may exacerbate the T cell

responses and potentiate end-organ damage [Mangini et al, 2007].

7.4. Effects of Type I IFNs on B Cells and Plasma Cells

Type IFNs may influence B cell biology throughout various stages of development and

many of the resultant abnormalities are apparent in SLE patients. The presence of

autoantibodies targeting a range of nuclear antigens including dsDNA, ribonuclear proteins,

and nucleosomes is a serological diagnostic marker for SLE [Mills, 1994; Hahn, 1998], and is

a clear indication of defective negative selection during B cell development and

differentiation. It is notable that type I IFN gene expression correlates with characteristic

lupus autoantibodies across different ethnic backgrounds, whereas there are no clear

correlations with specific disease manifestations [Weckerle et al, 2011]. This provides the

clearest indication that B cells are the most important targets for type I IFNs in SLE.

Moreover, therapeutic treatment with type I IFN in cancer, chronic viral infections and MS

have been associated with collateral toxic effects characterized by chronic fatigue because of

transient or chronic induction of autoantibodies and autoimmune pathology [Malik et al,


2001; Biggioggero et al, 2010]. Together these observations strongly imply that type I IFNs

are responsible for the breakdown in B cell tolerance in SLE patients. As previously

described type I IFNs are likely responsible for B cell lymphopenia in SLE patients by

impacting IL-7 dependent survival of pro-B cells [Lin et al, 1998]. Importantly, type I IFNs

also impact repertoire selection during early B cell differentiation by altering the sensitivity to

BCR ligation [Demengeot et al, 1997; Vasconcellos et al, 1998]. IFNα and IFNβ, but not

IFNγ inhibit antigen receptor mediated apoptosis in a dose-dependent manner by increasing

the levels of the anti-apoptotic Bcl-2 protein and to a lesser extent Bcl-XL [Su et al, 1999].

Consequently, the frequency of immature B cells with autoreactive specificities exiting the

bone marrow is much greater in SLE patients than normal healthy donors [Wardemann et al,

2003]. Since IFNα promotes the survival of human primary B cells by inhibiting spontaneous

apoptosis in the absence of mitogenic stimulation [Ruuth et al, 2001], type I IFNs likely

promote the survival of circulating immature transitional B cells that are otherwise prone to

apoptosis even in the absence of BCR-signaling [Sims et al, 2005]. This would account for

the increased proportion of B cells with an immature transitional phenotype in the blood of

SLE patients [Sims et al, 2005], and patients with chronic viral infections [Ho et al, 2006].

Besides an increased survival, type I IFN treated peripheral B cells also show enhanced

responses to BCR ligation with increased calcium flux, immunoglobulin internalization,

induction of activation markers and proliferation, and a resistance to Fas-mediated apoptosis.

These characteristics are indicative of a lower threshold of B cell activation and the

capacity to promote hyperactive antibody responses [Braun et al, 2002]. It remains to be

determined to what extent type I IFNs directly influence peripheral B cell tolerance, but B

cells expressing naturally autoreactive BCR encoding the VH4.34 heavy chain V-gene

participate in germinal center (GC) reactions and are expanded in the post-GC IgG memory

cell compartment of SLE but not RA patients [Cappione, III et al, 2005]. Interestingly, it has

been shown that type I IFNs, but not IFNγ, downregulate the key GC transcription factor

BCL6 [Salamon et al, 2012], but this would indicate that type I IFNs would favor the rapid

induction of plasma cells rather than the generation of class-switched high affinity memory B

cells via GC reactions. Indeed, IFNα also induces unabated production of splenic short-lived

PCs in pre-autoimmune lupus prone NZB/NZW F1 mice [Mathian et al, 2011], and an

increased frequency of circulating antibody-secreting cells is the most notable B cell

abnormality in SLE patients [Odendahl et al, 2000]. Plasma cells are transiently increased in

the blood as part of a normal immune response, whereas the increased frequencies detectable

in SLE patients in the absence of any discernible infective agent may be an indicator of a

persistent underlying systemic autoimmune response. Type I IFNs contribute to this active

state by directly promoting B cell activation, plasma cell differentiation and immunoglobulin

production [Neubauer et al, 1985; Braun et al, 2002; Le et al, 2006; Salamon et al, 2012].

Indirectly, IFNα also promotes the expression of IL-6, BAFF and APRIL from dendritic cells

and macrophages which are important B cell growth factors that promote plasma cell

differentiation and survival [Roldan et al, 1991; Litinskiy et al, 2002; Jego et al, 2003;

Ettinger et al, 2007; Mathian et al, 2011]. The upregulation of BAFF may well be an

important function of type I IFN in the pathogenesis of SLE. In mice, IFNα induces BAFF

expression in NZB/W F1 and Balb/c mice [Mathian et al, 2005], and importantly, BAFF is

required for IFNα-accelerated disease in the SLE-prone NZM 2328 mice [Jacob et al, 2011].

Recent clinical data has demonstrated that suppressing B cell differentiation by neutralizing

BAFF provides some clinical improvement in SLE patients [Furie et al, 2011], and


neutralizing type I IFNs in SLE patients reduces BAFF levels [Yao et al, 2009]. Together

these data indicate that type I IFNs play a critical role in the breakdown of B cell tolerance

and the generation of autoantibodies in SLE.

7.5. Effects of Type I IFNS on Endothelial Cells and Macrophages May

Predispose SLE Patients to Cardiovascular Complications

There is a remarkable incidence of premature atherosclerosis, and consequently,

increased rates of cardiovascular associated morbidity and mortality in SLE patients [Manzi

et al, 1997; Karrar et al, 2001]. SLE patients have significantly decreased flow-mediated

dilation of the brachial artery which correlates with increased carotid intima media thickness

[El-Magadmi et al, 2004].

Although elevated levels of circulating immune-complexes, autoantibodies targeting the

endothelium, and C-reactive protein found in SLE patients can all directly activate

endothelium [Tannenbaum et al, 1986; Devaraj et al, 2005], several type I IFN dependent

mechanisms have been identified that may alter endothelial function and contribute to

atherosclerosis [Kaplan et al, 2011]. Type I IFNs clearly impair the production and function

of endothelial precursor cells so the capacity to differentiate into mature endothelial cells to

repair damaged vessels is impeded and likely promotes the development of plaques [Denny et

al, 2007].

Although it remains controversial if type I IFNs are sufficient to induce endothelial

damage, it has been shown that type I IFN producing low density granulocytes found in SLE

patients can induce endothelial cytotoxicity upon contact [Denny et al, 2010]. Increased levels

of circulating apoptotic endothelial cells and the major pro-coagulant, Tissue factor, and high-

density lipoprotein (HDL) are all elevated in patients with SLE and are associated with

subclinical atherosclerosis and an increased propensity for atherothrombotic events [Segal et

al, 2000; Rajagopalan et al, 2004; McMahon et al, 2009]. Infiltration of the arterial wall

subintima by monocytes and their subsequent differentiation and transformation into

cholesterol laden foam cells is an important step in the initiation of an atherosclerotic lesion.

Type I IFN increases adherence of monocytes to endothelial cells [Pammer et al, 2006], and

primes monocytes to upregulate Scavenger receptor A which enhances lipid uptake and

transformation into foam cells [Li et al, 2011]. Plasmacytoid DC have also been isolated from

the carotid lesions where their type I IFN production may promote a local inflammatory

response and destabilize plaques [Niessner et al, 2007], and this may be accentuated by

activated platelets that can directly interact with pDC through CD40L/CD40 interactions

[Duffau et al, 2010; Lood et al, 2010]. Together these data indicate that the effects of type I

IFN may mediate atherosclerosis and cardiovascular disease which are important co-

morbidities associated with SLE.


8. TARGETING TYPE I IFN PATHWAY

IN SLE

Over the last 50 years the standard of care for SLE patients has been largely unchanged

and consists of various immunomodulatory agents including anti-malarials, corticosteroids,

immunosuppressives, as well as non-steroidal anti-inflammatories (Table II). Although the

disease can be effectively managed in most cases, the extended use of corticosteroids and

immunosuppressives that potently inhibit the immune system leads to increased risk of

serious infections and other deleterious side effects that remain a significant health concern.

Consequently SLE remains a disease with high unmet clinical need, and the development of

alternative treatments is an active area of biomedical research. The apparent significance of

type I IFN in SLE has led to a concerted effort among researchers to develop approaches to

target this pleiotropic cytokine (Figure 5). This section of the chapter highlights the current

treatment strategies, emerging therapies and those that target the type I IFN pathway for the

treatment of SLE.

Table II. Summary of current therapeutic strategies for SLE described in this review

Standard Therapies

Antimalarials

Hydroxychloroquine (Plaquenil, Quineprox)

Chloroquine (Aralen)

Quinacrine (Atabrine)

Corticosteroids

Methylprednisolone (Medrol)

Prednisone/prednisolone (Deltasone, Liquid Pred, Meticorten, Orasone, Prednicen-M,

Prednicot, Sterapred, Sterapred DS)

Cortisol/hydrocortisone

Dexamethasone (Decadron, Dexamethasome Intensol, Dexpak Taperpak

Betamethasome (Diprolene, Diprolene AF)

Immunosuppressives

Mycophenolate mofetil (CellCept, Myfortic)

Methotrexate (Rheumatrex, Trexall)

Azathioprine (Azasan, Imuran)

Cyclophosphamide (Cytoxan)

Tacrolimus (Hecoria, Prograf)

B cell modulators Clinical Development

Rituxan (Genentech/Roche) Approved in RA

Benlysta (Human Genome Sciences/GlaxoSmithKline) Approved in SLE

Epratuzimab (Immunomedics, UCB) Phase III in SLE

XmAb5871 (Xencor) Phase I in SLE

Atacicept (Merck/Serono/ZymoGenetics) Phase II in SLE

Type I IFN Pathway Clinical Development

Immune complex interference (FcRs, Nucleases)

SM101 (Suppremol GmbH) Phase II in SLE

RSLV-125 (Resolve Therapeutics) Preclinical development


Table II. (Continued)

TLR antagonists

DV1179 (Dynavax Technologies) Phase II in SLE

IMO-8400 (Idera Pharmaceuticals) Preclinical development

CPG 52364 (Pfizer) Phase II in SLE

Anti-IFNs

Sifalimumab (MedImmune/AstraZeneca) Phase II in SLE

AGS-009 (Argos Therapuetics) Phase I in SLE

Rontalizumab (Genentech/Roche) Phase II in SLE

Medi546 (MedImmune/AstraZeneca) Phase II in SLE

IFNα-Kinoid (Neovacs) Phase II in SLE

JAK inhibitors Tasocitinib (Pfizer) Phase II in RA

INCB28050 (Incyte/Eli Lilly) Phase II in RA

Figure 5: self-amplifying loop of IFN production in SLE

and points for therapeutic intervention

Baff

pDC

monocyte

CD4

T cell

B cell

plasma

cell

apoptotic

cell

immune-complexes

differentiation

survival

antigen

presentation

costimulation

mDC

differentiation

IFNAR

TLRsIFN

IFN

IFN

IFNAR

IFNAR

Jak

Figure 5. Self-amplifying loop of IFN production in SLE and possible points for therapeutic

intervention. Type I IFN produced by activated pDC signals though the IFNAR receptor complex and

Jak-family kinases Jak1 and TYK2. IFN stimulates the production of the B cell survival factor BAFF

from monocytes and also promotes the differentiation of monocytes to mature dendritic cells (mDC),

thus enhancing antigen presentation to T cells. IFN can also act directly on CD4 T cells to promote their

survival. Activated CD4 T helper cells will provide costimulation to B cells and promote affinity

maturation, class switch recombination and plasma cell differentiation. Differentiation of memory B

cells to antibody secreting plasma cells is further enhanced by type I IFN. Antibodies produced from

autoreactive plasma cells can then form nucleic acid containing complexes, which in turn will trigger

type I IFN production from pDC. Potential targets for therapeutic intervention discussed in the text are

highlighted in red.

8.1. Current Therapies in SLE

8.1.1. Antimalarials

Antimalarials are alkaloid compounds derived from the bark of the Peruvian cinchona

tree. Initially used at the end of World War II to treat parasitic infections, antimalarials are

now prescribed for autoimmune diseases such as SLE and RA. Certain SLE manifestations


respond to treatment with antimalarials. In particular, antimalarials are efficacious in relieving

muscle and joint pain, skin lesions and preventing SLE flares [Nayak et al, 1996]. The low

cost and favorable safety profile of antimalarials has resulted in their widespread use for the

treatment of SLE. Recently the mechanism of action of antimalarials in SLE has become

more evident. Given the alkaloid nature of antimalarials, the prevailing concept was that

compounds such as chloroquine prevented the acidification of phagolysosomes which is

considered a requirement for the activation of endosomal TLRs. Indeed bafilomycin A1, and

inhibitor of vacuolar type H+ ATPase, prevents the acidification of lysosomes and subsequent

TLR activation [Hmad Nejad et al, 2002]. However, a recent paper by Kuznik et al has

challenged this mechanism for antimalarials [Kuznik et al, 2011]. The authors report that

antimalarials do not alter the pH of endosomes nor do they inhibit endosomal proteolysis.

Instead, the data shows that antimalarials physically interact with nucleic acids and conceal

the ligand binding epitope for TLRs. As previously discussed, TLR activation may be the

primary type I IFN induction pathway in SLE and antimalarials may act by blocking this

activation.

8.1.2. Corticosteroids

Corticosteroids are another main stay in the treatment of SLE. Corticosteroids can be

subclassified into glucocorticoids and/or mineralocorticoids based upon their specific

receptors, target cells and biological effects. Upon binding to receptors, the steroid receptor

complexes then shuttle into the nucleus where they cause transactivation of genes bearing

specific hormone response elements. Conversely, the steroid receptor complexes are able to

bind to certain transcription factors thus preventing the transcription of target genes, a term

called transrepression.

The overall net effect is the increased expression of anti-inflammatory genes and the

repression of proinflammatory gene induction. Another more immediate effect of steroids has

been categorized by Stahn et al to include nonspecific interactions of glucocorticoids with

cellular membranes, nongenomic effects mediated by the glucocorticoid receptor (GR), and

specific interactions with membrane bound GRs [Stahn et al, 2008]. For SLE, corticosteroids

are prescribed by physicians in varying doses depending on disease activity. Low dose oral

glucocorticoids are often prescribed for maintenance therapy whereas high dose intravenous

therapy over a period of days is used to treat more severe manifestations and flares.

Interestingly, a study by Pascual et al showed that a high dose of methylprednisolone, 30

mg/kg/day for three consecutive days, resulted in the almost complete suppression of the IFN

signature in PBMCs [Bennett et al, 2003]. A proposed mechanism for this observation is the

steroid induced death of pDCs, which are perceived to be the main producers of type I IFN

[Guiducci et al, 2010]. Another study highlighted the usage of the cofactor GRIP1/TIF2 by

both the GR and the IFN ISGF3 transcription complex. As a result, glucocorticoid treatment

may deplete GRIP1/TIF2 resulting in repressed IFN-stimulated gene expression [Flammer et

al, 2010]. From these observations, one of the more important consequences of corticosteroid

treatment could be the reduction in type I IFN mediated disease symptoms and

manifestations.

The profound modulation of the immune system by corticosteroids does not come

without consequences. Corticosteroid therapy results in considerable side effects in many

diverse biological systems. These effects usually are dependent on steroid dose and duration

of treatment. Side effects can include diabetes mellitus, osteoporosis, myopathy and


atherosclerosis [Stahn et al, 2008]. In addition, several studies have shown a higher risk of

infections with those taking high dose corticosteroids [Schacke et al, 2002]. Hence, novel

treatments that allow significant reductions in steroid usage would be welcomed by both

patients and their physicians.

8.1.3. Immunosuppressives

A variety of immunosuppressive agents have been used in the treatment of SLE (see

Table II). On the whole, immunosuppressive agents used in SLE are either anti-metabolites or

alkylating agents. The cytotoxic nature of such agents is mainly restricted to fast dividing

cells such as activated lymphocytes. As such, immunosuppressives are excellent at

suppressing the adaptive immune system. However, immunosuppressives can result in serious

side effects. Consequently their prescription is restricted to the treatment of more severe

symptoms of SLE and lupus nephritis. For example, although mycophenolate mofetil is not

approved for the treatment of SLE, it is widely used for the treatment of lupus nephritis.

8.2. Emerging Therapeutics Approaches for the Treatment of SLE

Previous sections have alluded to the importance of B cells in the development of SLE,

and several therapeutic approaches aim to deplete B cells or otherwise moderate their

differentiation and function. Rituxan (Rituximab; Genentech/Roche), a chimeric antibody that

targets the B cell-specific antigen CD20 for depletion, primarily by antibody dependent cell

mediated cytotoxicity (ADCC), has been used in several open-label investigator trials with

varying success [Sousa et al, 2009; Looney et al, 2010; Terrier et al, 2010]. However, two

pivotal Phase III trials for non-renal SLE (EXPLORER) and lupus nephritis (LUNAR) did

not achieve their primary endpoints [Looney et al, 2010; Merrill et al, 2010]. The failures of

these trials have been a subject of much debate, but it has not deterred clinical development of

other B cell targets.

The anti-CD22 antibody Epratuzumab (Immunomedics, UCB) partially depletes B cells

and also has an immunomodulatory role that is associated with its capacity to internalize

CD22 and induce tyrosine phosphorylation [Carnahan et al, 2003]. In mild to moderately

active SLE patients, BILAG (British Isles Lupus Assessment Score) scores decreased by

50% in all 14 patients at one or more of the four evaluations during the 32 week Phase II

study [Dorner et al, 2006], and Phase III trials are currently ongoing. Xencor has also

developed an antibody XmAb5871 which regulates B cell function by targeting CD19 and

coengaging FcγRIIB to deliver an inhibitory signal [Horton et al, 2011]. Phase I trials to

assess safety and pharmacology have been initiated in SLE and RA. Importantly, in large

pivotal phase III trials BLISS-52 and BLISS-76, Benlysta (Belimumab; Human Genome

Sciences/GlaxoSmithKline), a fully humanized antibody targeting the B cell growth factor,

BAFF, showed an improvement in clinical activity using a newly developed SLE responder

index compared to placebo plus standard therapy [Mok, 2010; Wiglesworth et al, 2010].

Despite concerns over the need for huge trials and unique trial endpoints to demonstrate the

drug’s modest efficacy [Chiche et al, 2012], in March 2011, belimumab was approved for use

in the USA by the FDA for the treatment of active, autoantibody-positive SLE receiving

standard therapy, the first new drug approved for SLE in 57 years. Targeting a similar


mechanism, clinical evaluation of the safety and efficacy of atacicept (Merck/Serono/

ZymoGenetics) is ongoing. Atacicept is an Ig fusion protein of the receptor TACI which

neutralizes both BAFF and APRIL, and therefore has the potential to modify both early B cell

differentiation and survival, as well as impact the survival of plasma cells. It is possible that

this targeted approach may be beneficial if a favorable regime of drug and standard therapy

can be determined that provides an acceptable safety profile [Merrill et al, 2010].

There are several other promising drug targets being evaluated in the clinic such as IL-6,

IL-17, IL-12, IL-23, IFNγ, lymphotoxin-α/β, CD40L, members of the B7 family of co-

stimulators, spleen tyrosine kinase (syk) inhibitors, retinoic acid receptor-α (RARα) and

selective glucocorticoid receptor antagonists (SEGRAs), as well as several therapies targeting

the Type I IFN pathway which in time may provide alternate therapies for the treatment of

SLE [Leishman et al, 2011; Chugh, 2012].

8.3. Clinical Development of Therapies Targeting the Type I IFN Pathway

The data described in previous sections provides a strong rationale for targeting the type I

IFN pathway in SLE (Figure 5). Several different approaches are currently in clinical

development that target the type I IFN pathway (Table II). These approaches include drugs

that interfere with either the uptake of immune complexes or the interactions of the

DNA/RNA components with TLR that induce the induction of type I IFNs, neutralization of

the cytokines and blockade of the IFNAR, as well as small molecule inhibitors that block type

I IFN signaling are briefly outlined below (Figure 5).

8.3.1. Immune Complex Interference (FcRs, Nucleases)

The nucleic acid containing immune complex is an important driver in the induction of

type I IFNs in SLE and consequently represents a target for therapeutic intervention. SM101

(SuppreMol Gmbh), a recombinant, soluble, nonglycosylated version of the low affinity

immunoglobulin receptor Fc RIIB is being developed for the treatment of Idiopathic

Thrombocytopenia (ITP) and SLE. By binding to pathogenic immune complexes in a soluble

form recombinant FcγRIIB prevents immune complexes from triggering surface bound Fc

receptors on immune cells and deposition in target tissues [Werwitzke et al, 2008]. SM101 is

currently in a double blind Phase IIa clinical trial in SLE with results expected in 2013.

Another distinct approach for targeting immune complexes is currently under development by

Resolve Therapeutics. RSLV-125, an undisclosed nuclease linked to the Fc portion of the

IgG1 isotype degrades nucleic acid containing immune complexes preventing their uptake

and subsequent immune activation. The company anticipates filing an Investigational New

Drug (IND) application for a Phase I study to commence in 2012.

8.3.2. TLR Antagonists

IFN induction in SLE is believed to occur via the activation of endosomal TLRs in

pDCs by DNA or RNA containing immune complexes. The endosomal location of the

nucleic acid sensing TLRs renders them unlikely targets for current biologics. To this end,

three pharmaceutical companies are developing small molecule inhibitors of endosomal

TLRs. Dynavax Technologies, in collaboration with GlaxoSmithKline, is developing


DV1179, a bifunctional TLR7 and TLR9 antagonist. DV1179 is an oligonucleotide based

immunoregulatory sequence designed to specifically bind and antagonize the activation of

TLR7 and 9. In 2011, Dynavax initiated a phase I clinical trial in healthy volunteers where

DV1179 was shown to be well tolerated.

A proof of mechanism study in SLE patients is ongoing. Similarly, Idera Pharmaceuticals

is pursuing small molecule antagonists of TLRs. Their lead candidate, IMO-8400, is a TLR7,

8 and 9 antagonist that is in preclinical development for lupus. The company expects to file

an IND application with the FDA sometime in 2012. Finally, Pfizer’s CPG 52364, a

quinazoline derivative, is a selective TLR7, 8 and 9 antagonist that completed a Phase I trial

in healthy volunteers in 2007. Interestingly, Guiducci et al reported that the activation of

TLR7 and/or TLR9 inhibits the immunomodulatory activity of glucocorticoids on pDCs

[Guiducci et al, 2010]. As such, the authors believe that blocking endosomal TLRs will not

only reduce IFN levels but may allow physicians to prescribe lower doses of steroids

resulting in better tolerability.

8.3.3. Anti-IFNs

As outlined above, type I IFNs are an attractive target for therapeutic intervention in SLE.

The concept of antagonizing IFNs is further supported by the finding that SLE patients with

autoantibodies against IFN have reduced type I IFN serum bioactivity and lower disease

activity as compared to patients who do not have anti-IFN autoantibodies [Morimoto et al,

2011]. Several companies are pursuing humanized monoclonal antibodies against IFN

subtypes for the treatment of SLE. Phase I trials of Rontalizumab (Genentech/Roche) and

Sifalimumab (Medi-545, MedImmune/AstraZeneca) have both shown dose-dependent

reduction in type I IFN gene signatures and safety profiles that permitted larger phase II proof

of concept trials to be initiated [Yao et al, 2009; McBride et al, 2009; Merrill et al, 2011].

More recently, Argos Therapeutics also completed a Phase I trial with a humanized IgG4

anti-IFN antibody. Alternatively, the humanized monoclonal antibody Medi-546

(MedImmune/AstraZeneca) provides a more comprehensive approach to neutralizing the

effects of type I IFNs by targeting the type I IFN receptor subunit I (IFNAR1). Currently in

Phase II for SLE, Medi-546 blocks the action of all IFN subtypes as well as other type I

IFNs including IFN . Finally, an innovative approach to targeting IFN has also been

devised by the French biotechnology company Neovacs. Based upon a proprietary technology

platform called Kinoids, the company aims to treat mild to moderate SLE patients. The IFN

kinoid is a vaccine which induces the host to produce polyclonal antibodies against IFN .

Results from a Phase I/II trial demonstrated favorable safety, a reduction in the IFN gene

signature and patients developing neutralizing antibodies against IFN . Importantly, the

levels of anti-IFN antibodies were positively correlated to a reduction in levels of antibodies

to dsDNA, an established biomarker for lupus disease activity [Houssiau et al, 2011].

8.3.4. JAK Inhibitors

Immediately downstream of IFNAR, members of the JAK family are key components of

the type I IFN signaling pathway. As such, both JAK1 and TYK2 would be attractive targets

for the treatment of SLE. Pfizer is currently developing an oral JAK inhibitor known as

tasocitinib. This molecule has selectivity for JAK3 and JAK1 versus JAK2 and has currently

completed a Phase IIb trial in rheumatoid arthritis [Riese et al, 2010]. In addition, the JAK1/2


selective inhibitor INCB28050 (Incyte/Eli Lilly) is also currently in Phase II studies for RA.

The potential use of these selective antagonists in SLE would be an intriguing area of

research.

CONCLUSION

SLE is a debilitating autoimmune disease for patients, and a clinically challenging

responsibility for physicians. Current treatments are mostly effective at controlling milder

forms of the disease. Consequently, there still remains a significant unmet need for alternate

therapeutics that enable significant reductions in the long-term usage of corticosteroids and

better management of more severe forms of the disease, particularly those with kidney

involvement. The genetic and biological data summarized herein indicate that the type I IFN

pathway is strongly associated with the disease, and that it likely plays a central role in the

disease pathogenesis. Type I IFNs modulate the activities of multiple cell types which may

influence different phases of the disease. The available data indicate that the primary

mechanisms by which type I IFNs drive SLE is likely by reducing the threshold of B cell

tolerance and the induction of autoantibodies, and the enhanced differentiation and antigen

presentation by mDC that may promote autoreactive T cell responses. However, it is certainly

plausible that the effects of type I IFNs on innate immune cells and endothelial cells may also

significantly impact the development of the disease. In contrast, it is also possible that type I

IFNs and pDC may promote T cell tolerance and suppress T cell responses. The net effect of

type I IFNs in SLE will ultimately be revealed by the plethora of therapeutic approaches that

are targeting this pathway in on-going clinical trials. The results of which are eagerly

anticipated by the lupus community since they should not only provide a greater insight into

the key regulatory roles of type I IFNs in SLE, but more importantly, will reveal if these

promising approaches are likely to become safe, efficacious therapeutics.

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TYPE INTERFERONS IN SYSTEMIC LUPUS ERYTHEMATOSUS