Best Practice & Research Clinical Rheumatology 31 (2017) 321e333

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Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh

Drivers of the immunopathogenesis in systemic

lupus erythematosus
€ rner a, b, *
Thomas Rose a, b, Thomas Do
a
Department of Rheumatology and Clinical Immunology, Charit €tsmedizin Berlin, Chariteplatz 1,
e Universita
Berlin D-10117, Germany
b
German Rheumatism Research Center, Berlin-Leibniz Institute, Charit
eplatz 1, D-10117 Berlin, Germany

a b s t r a c t
Keywords:
SLE This review summarises a number of current insights into the
B cells pathogenesis of SLE. On the basis of the interaction of environ-
Interferon mental factors within a predisposed host, a chronic autoimmune
TLR process gains function with a positive feed-forward loop between
Etiopathogenesis innate and adaptive immunity. A current focus of SLE pathogenesis
IL-2 deficiency
is on the enhanced production of certain cytokines, such as type I
Inflammation
interferons and BLyS/BAFF, suggesting continuous plasmacytoid
dendritic and myeloid cell activity together with disturbances of B
lineage cells (increased autoantibodies, including anti-dsDNA and
plasmablasts, which correlate with SLE activity and memory B-cell
abnormalities). Recent studies provided evidence that CD4þ and
CD8þ T cells and B cells are hyporesponsive in SLE, likely reflecting
their ‘post-activation status’. Data of enhanced protein tyrosine
phosphatase activity of lymphocytes in SLE require consideration if
they represent a disease characteristic. Better understanding of the
chronic autoimmune phase is needed in addition to those phases
during flares and will permit improved treatment of SLE.
© 2017 Elsevier Ltd. All rights reserved.

Introduction

Systemic lupus erythematosus (SLE) is a prototypic, systemic autoimmune disease with a wide
clinical spectrum that ranges from typical organ manifestations, such as joints, skin and kidneys to

* Corresponding author. Dept. Medicine/Rheumatology and Clinical Immunology, Charite Universit€

atsmedizin Berlin, Char-
iteplatz 01, 10117 Berlin, Germany.
€rner).
E-mail address: thomas.doener@charite.de (T. Do

https://doi.org/10.1016/j.berh.2017.09.007
1521-6942/© 2017 Elsevier Ltd. All rights reserved.
322 €rner / Best Practice & Research Clinical Rheumatology 31 (2017) 321e333
T. Rose, T. Do

infrequent manifestations, e.g. shrinking lung syndrome [1]. The clinical heterogeneity of SLE is
accompanied by complex disturbances in the immune system, with the hallmark of characteristic
autoantibodies and an enhanced type I interferon (IFN) and B-cell activating factor (BAFF)/B
lymphocyte stimulator (BlyS) system [2]. A number of alterations in SLE have been targeted in clinical
trials in the last decade, but so far, only belimumab obtained FDA and EMA approval [3]. Owing to the
various abnormalities in the innate and adaptive immune system, unspecific inhibition with NSAID,
glucocorticoids, antimalarials, methotrexate, cyclophosphamide or mycophenolate mofetil remains
the first choice to control lupus activity. Prior successes and failures of certain targeted therapies in SLE,
however, have permitted deeper insights into the mechanisms of the disease. For example, as IFNs have
pleiotropic effects on the immune system, anifrolumab, a monoclonal antibody against the IFN re-
ceptor, holds promise as another targeted immune therapy and is in advanced development followed
by many other [3].
SLE pathogenesis can only be incompletely explained by a single cause, and it is believed that a
complex interplay of environmental factors (e.g. sex hormones, UV light and smoking), genetic and
epigenetic factors contributes to SLE pathology. The idea of a complex interplay of various factors led to
the concept of an ‘exposome’ affecting healthy but genetically predisposed individuals [4] (Fig. 1). This
concept has been addressed in Gene, Environment Association Studies [5] that will provide further
insights in the interaction between host and environment.

Environmental risk factors

Environmental factors, such as exposure to silicates, smoking, UV light and certain medications;
vitamin D deficiency; viral infections; and oestrogens are considered potential risk factors in the

Fig. 1. Scheme of the potential positive forward loop in the pathogenesis of SLE (adapted from Ref. [2]). Certain environmental
factors are able to induce immune activation in a predisposed host (relevant genetic risk factors of certain immune cells are shown).
Upon activation, enhanced production of type I interferon and formation of immune complexes by anti-RNP autoantibodies (and
other specificities) lead to continuous activation of a circuit and/or network of the depicted cells. As a result, chronic and acutely
enhanced immune activation arrive at tissue and/or organ damage in SLE.
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T. Rose, T. Do 323

development of lupus. The National Institute of Environmental Health Science Expert Panel reviewed
and evaluated environmental influences on autoimmunity and found evidence for silica exposure and
a likely association for smoking as contributors to SLE development [6].
In the last decade, vitamin D with its broad effects on the immune system has been studied
extensively in autoimmune diseases [7]. Sun exposure is important for vitamin D production. As 80% of
patients with SLE show a photosensitivity and consequently protect themself from UV-light exposure,
vitamin D deficiency was found in most SLE patients [8]. As such, the role of vitamin D and SLE is
complex. Few studies investigated vitamin D deficiency as a risk factor for the development of SLE, and
up to now there is no clear answer to this question. In addition, an association between vitamin D
receptor single-nucleotide polymorphisms and a higher long-term cumulative damage in SLE has been
reported [9]. In this context, 25-OH vitamin D levels were inversely related to lupus disease activity
[10,11], and therefore, a contribution to lupus pathology could not be ruled out. Supplementation of
vitamin D is safe in SLE, but the therapeutic effect on disease activity remains to be delineated because
studies including randomised controlled trials supplementing vitamin D in SLE arrived at inconclusive
results [7,12,13]. However, the use of vitamin D to protect against glucocorticoid-related osteoporosis
may superimpose its effect on lupus activity and make it difficult to discern its real impact in clinical
grounds.
Although frequently taken for granted, it is still a matter of debate whether UV-light exposure is a
risk factor for the induction of SLE [14]. On the one hand, UV-light exposure in SLE is known to
aggravate pre-existing skin manifestation and can cause severe lupus flares with a plausible pathogenic
mechanism: UV-light exposure induces increased apoptosis of keratinocytes, followed by a prolonged
exposure of self-antigens because of known clearance defects that subsequently causes precipitation of
immune complexes (ICs) in the skin (‘lupus band’) and results in the initiation of an inflammation
[2,14]. Sun exposure, on the other hand, leads to higher serum concentration of vitamin D and thus
might be protective [14]. It is also possible that the timing of the UV-light exposure in the context of
other environmental or individual predispositions is important, as known from acquired neonatal
lupus syndrome, in which skin manifestation develops in the majority of cases six weeks postpartum
following UV-light exposure [15].
Bacterial and viral infections, such as EBV, CMV, parvovirus B19, human endogenous retroviruses
and others, have been implicated in the development of SLE where these agents apparently ‘kick-start’
immune activation and result in chronic inflammation [16]. One of the best understood mechanisms of
ongoing autoimmunity is molecular mimicry [17,18]: viral infection can trigger B cells to produce
antibodies that recognise the viral antigen, but can also cross-react with autoantigens, causing a lasting
autoimmune response [2]. It has been shown that the Epstein Barr Virus Antigen 1 (EBNA-1) contains
regions that are homologous to sequences of self-proteins such as Ro60 kDa and snRNP [17]. In SLE,
McClain and colleagues could detect anti-EBNA-1 prior to the detection of anti-Ro. This suggests that
EBV infection started with anti-EBNA-1 and due to similarities to Ro antigen, ‘switched’ to anti-Ro
antibody production (probably after Ro60 kDa exposure due to apoptosis induced by UV light). This
study demonstrated that anti-Ro antibodies cross-react with EBNA-1. Similar findings were also re-
ported for other autoantigens (e.g. Sm and La) and support the idea that certain infections can induce
the development of autoimmunity in predisposed individuals.
Most SLE patients, however, cannot be traced back to a single infection, and thus, disturbed general
immune response mechanisms, such as the activation of the IFN system through toll-like receptors
(TLRs) [19] and cytosolic sensors, are considered to be involved in the induction process. Fever in early
SLE has gained recent awareness [20], reflecting systemic immune activation (not essentially an
infection).
Cells are equipped with membrane-bound receptors and cytosolic sensors that allow the immune
system to detect and fight infections. Membrane-bound pattern recognition receptors such as TLRs
detect pathogen-associated molecular patterns such as viral, bacterial and fungal proteins in the
extracellular department and endosome [19,21].
The early recognition by certain individuals is crucial for the subsequent dendritic cell (DC)
response and type of T-cell response (TH1, 2, 17, Treg) and involvement of B cells [2]. In SLE, the
activation of TLR7 and 9 in plasmacytoid dendritic cells (pDC) through RNA- and DNA-containing
antigens, antibodies and ICs lead to an inflammatory cascade, mainly with a pronounced IFN type I
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T. Rose, T. Do

response [19,22]. Bacterial infections are discussed as contributors of SLE pathology through similar
mechanisms. Endotoxins, such as lipopolysaccharides (LPS) of gram-negative bacteria, can lead to the
secretion of polyreactive antibodies in mice and various cytokines because of TLR4 activation [22e24].
In SLE, elevated LPS serum levels were consistent with a significant overlap in genes induced by LPS/
endotoxin together with the known IFN type I signature [25]. Interestingly, TLR4 was recently
described to be upregulated in skin and renal biopsies of SLE patients, and the level of TLR4 expression
was correlated with lupus disease activity [26,27]. Thus, TLR4 activation has been found in affected
organs of SLE patients [25].
In the last decade, other antiviral mechanisms next to cell-surface-dependent TLR signalling were
discovered, which can also elicit an IFN type I response. After virus invasion into the cell, cytosolic
sensors detect foreign RNA molecules and respond mainly with IFN type I or III production. Different
cytosolic sensors, such as RIG-I-like receptors, are known, which detect viral RNA in the cytosol, cyclic
GMP-AMP synthase, IFN gamma-inducible protein 16 and DNA-dependent activator of IFN-regulatory
factors [21]. However, these sensors can detect other ligands independently of infections and lead to a
comprehensive immune reaction mainly through the stimulation of IFN genes (STING) [21]. Very
recently, a gain-of-function mutation in STING, causing familial chilblain lupus with an activation of the
IFN type I system, has been reported [28]. Interestingly, STING-deficient autoimmune-prone mice
showed an exacerbation of disease by lack of expression of negative regulators controlling immune
activation and hyperresponsiveness to TLR agonists [29]. It has been concluded that TLR and STING
pathways might be cross-regulated [30]. The role of STING in SLE is studied less, but data implicate
STING as a regulator of immune responses [31]; however, how it is involved in lupus warrants further
investigations.

Genetic factors

Family studies could show that monozygotic twins have a ten-fold higher risk to develop SLE than
dizygotic twins [32] and a clear aggregation of SLE in families [33]. This together with the findings in
large-scale genome-wide association studies (GWAS) [34e37] implicate a strong genetic background
for SLE. More than 80 genetic risk loci involved in different immunological pathways affecting the
innate and adaptive immune system such as IC processing, clearance of cellular debris including ICs,
type I IFN and TLR signalling as well as lymphocyte activation are associated with SLE risk (some ex-
amples are shown in Fig. 1) [38]. Noteworthy, more than 50% of the lupus susceptibility genes are
linked to the IFN system [39,40]. In addition to this pathway, gene loci involved in NFkB signalling, DNA
degradation, apoptosis, phagocytosis, neutrophil, and monocyte/macrophage function and signalling
have been identified (reviewed [41]). The most pronounced association, however, was found for HLA-
DR2/DR3, followed by BLK and PTPN22 involved in T- and especially B-cell activation and therefore
adaptive immunity. Current concepts suggest that these genetic abnormalities provide a susceptibility
basis for the induction and chronic phase of SLE related to a positive feed-forward loop with a con-
necting point of antigen presentation between innate and adaptive immunity [2].

Epigenetic

As a substantial proportion of heritability in SLE cannot be explained by GWAS data alone [38],
epigenetic mechanisms, such as DNA methylation, post-translational histone modification and
microRNAs (miRNAs), regulating the gene expression appear to play a role in lupus pathogenesis. Each
cell type might have a specific and dynamic epigenetic profile [42]. The interaction between host and
the presumed environmental factors resurfaces and suggests that they may directly interact on this
level.
Recent data provided evidence that most methylation sites in lupus patients are hypomethylated
and subsequently permit enhanced transcription. In this context, striking hypomethylation of loci
associated with type I IFN signalling was found in monocytes and B- and T-cells from lupus patients,
suggesting that these cells might be hypersensitive to IFN [43]. Apart from IFN activation, the
methylation status of CD4þ T cells in SLE has been found to undergo an epigenetic shift towards an
inflammatory status [44]. Recently, Chen and colleagues also reported alterations in DNA methylation
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T. Rose, T. Do 325

in lupus [45]. However, the nature of epigenetic modulations during the disease course, especially
related to disease activity, remains to be delineated [43,44].
Environmental, dietary and lifestyle factors influence epigenetic modulation [46e48] and may
explain why monozygotic twins develop different epigenetic profiles when they become older [49].
The importance of environmental factors and their impact on the epigenome became apparent in a
transgenic lupus model with a transmethylation micronutrients diet that altered DNA methylation
status [50], indicating the capacity of diet on epigenetic modulation in SLE.
Smoking is considered a key environmental factor in SLE pathogenesis [2, 6] and has also been
shown to affect DNA methylation with long-lasting imprints (for years) that continue even after
smoking cessation [48]. Procainamide and hydralazine are medications that can result in drug-induced
SLE. Both are able to inhibit DNA methylation in T cells and induce autoimmunity [51]. Notably, a
previous study showed that mycophenolic acid used in treating lupus nephritis patients is capable of
modulating the epigenetic status through histone modification [52]. Currently, clinical studies in SLE
are evaluating the impact of histone deacetylase inhibitors (vorinostat and panobinostat target class I,
II and IV HDACs; romidepsin is a selective class I HDAC) [3].
Another possibility of epigenetic modulation is interference with miRNA. These are noncoding RNAs
involved in the regulation of about 90% of protein-coding genes [53]. The complex mode of action of
miRNA is not fully understood, but one potential mechanism is translational repression of miRNA,
leading to a downregulation of gene expression [54]. In autoimmune diseases, many different miRNAs
have been reported to be up- or downregulated [53]. Although we are just beginning to understand the
importance of certain miRNAs in SLE, miRNA(miR)-30a in B cells has been shown to decrease the
expression of Lyn as central protein tyrosine kinase of B-cell receptor signalling. The study arrived at
the hypothesis that low levels of Lyn expression in SLE are due to increased expression of miR-30a,
which may facilitate B-cell proliferation and antibody production [55]. Further studies unravelling
the complexity of miRNAs involved in regulating normal immunity and SLE are warranted.

Immune pathogenic considerations and course of SLE

A better understanding of disease stages in SLE and its various course (Fig. 2) is required not only to
identify a ‘window of opportunity’ of healthy people at risk with the possibility of early intervention
but also to discontinue ongoing/chronic immune disturbances in SLE. In this context, it is important to
differentiate at least four disease stages of an immune disease: subclinical autoimmunity, disease
initiation, chronic maintenance and a number of outcomes, including organ failure or resolution. While

Fig. 2. Scheme of the possible translation scenarios of immune activation into the course of overt and ongoing SLE. The concept
follows principles of an acute defence against infectious agents where usually no chronicity emerges but resolution of immune
activation or detrimental outcomes. Upon preclinical immune activation, subsequent (stochastic) immune challenges lead to acute
SLE manifestation and can take various routes. Depending on individual immune activation, chronic phases of SLE may have flares or
primarily chronic. Finally, uncontrolled disease can lead to organ damage, controlled immunity and disease as well as (infrequently)
resolution of immune activation.
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in SLE, the chronic phase can vary with phases of reactivation and clinical flares or chronic progressive
disease, an ultimate challenge is to achieve the resolution phase that would represent clinical cure.
Studies addressing the development of SLE could delineate first hints of early events. Alterations in
the immune system of diagnosed lupus patients, such as the detection of autoantibodies or an activated
IFN type I system, could be identified years prior to the diagnosis [17,56e59]. In this preclinical phase,
autoantibodies were detected up to 9.4 years prior to SLE diagnosis and could be divided into three
different serologic groups. ANA and anti-Ro appeared very early and were followed by anti-dsDNA or
anti-RNP. The number of autoantibodies in a patient accumulated over time until diagnosis [56].
Similar to autoantibodies, a type I IFN signature has been found close to the time of diagnosis. In detail,
in 20% of investigated cases, an activation of the IFN system was found four years prior to diagnosis and
increased steadily over time to up to 75% at the time of diagnosis [59]. From this, a recent study
suggested a stepwise process in lupus development, starting with autoantibody production and/or an
activation of type II IFN produced by T helper cells followed by an activation of type I IFNs likely
released by plasmacytoid cells upon activation by ICs containing anti-RNP autoantibodies. In contrast
to this model of SLE, an activated type I IFN system could be detected prior to the detection of auto-
antibodies in autoimmune type I diabetes [60].
Lu et al. also studied if specific soluble mediators might precede SLE diagnosis. They found elevated
levels of Th1-, Th2- and Th-17 type cytokines prior to SLE diagnosis and before SLE-associated auto-
antibodies increased. Twenty percent of subsequently diagnosed SLE patients presented 6 years before
clinically overt SLE with elevated levels of IL-5 and IL-6. The combination of autoantibodies, IFN-g, IL-5
and IL-6 levels provided increased predictive accuracy in comparison to ‘ANA only’ from 58% to 84%,
respectively, 3.5 years prior to SLE onset [58].
In a genetically predisposed host, immune activation in a certain environment can lead to an initial
(auto)antigen presentation and the appearance of autoreactive cells on a subclinical level. After this
initiation, additional ‘immunologic hits’ result into the release of pro-inflammatory cytokines, such as
IL-5 and IL-6, as well as IFN-g, and a subsequent expansion and maintenance of autoreactive lym-
phocytes, which subsequently translates into clinically overt disease. At this time, chronic autoim-
munity has been established with immune dysregulation based on tissue damage with clearance
defects, continuous exposure to self-antigens and subsequent formation of ICs by autoantibodies
leading to type I IFN release. Finally, a positive feed-forward loop in chronic autoimmunity [2] with a
self-stimulatory network of IFN production driving SLE pathology has been put forward [2,56e59].

Role of IFN in chronic autoimmunity in SLE

IFNs appear to be pivotal for the maintenance of the chronic inflammation in SLE. This cytokine
subset is known for pleiotropic effects on almost if not all cells of the immune system. IFNs have the
ability to modulate differentiation, proliferation, apoptosis and survival, which appear to be key fea-
tures in cellular abnormalities in lupus pathogenesis [61]. IFNs can be divided into three major classes
(I, II and III). While type III IFNs were recently discovered to play a role in lupus [62], type I and II IFNs
have been studied extensively since their first description in SLE in 1979 [63]. All three types act
through different surface receptors but due to overlapping intracellular downstream signals, a tran-
scriptional overlap of IFN inducible genes has been observed [64,65]. Activated type I IFN signatures
can be found in the majority of lupus patients and in almost all paediatric lupus patients (97%) and
correlate with lupus activity [66e70].
Many efforts have been undertaken to identify reliable IFN biomarkers and target type I IFN acti-
vation. Type I IFN response proteins, such as IP-10, SIGLEC1 (CD169) and CD64, have been established
to monitor type I IFN activation in lupus. IP-10 and SIGLEC1 correlated cross-sectionally and longitu-
dinally with lupus disease activity [68,70e72]. However, IFN biomarkers are not widely used in clinical
practice, although they might have advantages in assessing disease activity compared to laboratory
standards, such as complement factor 3 and anti-dsDNA [70].
Enhanced production of type I IFNs in lupus is mainly caused by pDCs through the activation of TLR
[19,73]. These TLRs are membrane bound and get activated by nucleic acids-associated self-antigens
such as U1snRNP, autoantibodies, interferogenic ICs, and viral and bacterial proteins [19,73]. Increased
apoptosis, clearance deficiencies of apoptotic material, diminished phagocytotic function of
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T. Rose, T. Do 327

macrophages and alterations in the complement system are mainly responsible for the prolonged
exposure of self-antigens to the immune system, IC formation and, finally, continuous TLR activation
[74]. Neutrophils can also contribute to IFN activation by two mechanisms. First, they can become
activated by ICs and anti-RNP antibodies and undergo a defined cell death known as NETosis and expel
neutrophil extracellular traps (NETs) [74e77]. NETs activate pDC, especially when containing oxidised
mitochondrial DNA and enhance further IFN production. Second, TLR 7/8-activated neutrophils have
been shown to impair the clearance of IC by monocytes, which indirectly enhance inflammation
[76e79]. Thus, a number of intrinsic and extrinsic stimulators are able to fuel chronic type I IFN pro-
duction in SLE, which likely fluctuate with disease activity and have further consequences on various
immune cells.

Effects of IFN on the immune system

As enhanced type I IFN is a key characteristic of SLE, its consequences on other parts of the immune
system deserve consideration. In this context, each cell type responds to IFN but in a different manner.
This is related to different IFN receptor expression densities on certain cell types and likely more
pronounced in genetically predisposed hosts. Each type I IFN subtype activates the IFN receptor
differently and induces upregulation of MHC I and II molecules that facilitate immune response by
antigen presentation [75,80,81], and class II molecules are outstanding genetic risk factors [2]. Antigen
presentation is further enhanced by type I IFN because of specific effects on monocytes that develop
patterns of surface markers similar to myeloid DCs. Furthermore, these cells express costimulatory
molecules for cellecell interactions (CD80, CD86 and CD83) [82]. In this context, type I IFN-activated
DCs can activate naive T cells and subsequently drive B-cell activation and their differentiation and
growth [83e85].
Notably, IFN has several indirect and direct effects on B cells. IFN production by pDCs has been
found enhanced when co-cultured with B-cells [73]. IFN type I molecules and the B-cell compart-
ment are interconnected. BAFF (also known as BlyS) is known as a crucial B-cell survival factor with
implications in SLE [86]. Lopez et al. could show that IFNalpha induces the production of intracellular
Blys in monocytes of healthy donors and enhances the release of Blys [87]. Corresponding to IFN
activation in SLE, increased Blys in the extracellular compartment can be readily detected in SLE,
suggesting that the production of these cytokines is interrelated [87]. A study by Yao et al. investi-
gated downstream signalling effects of an anti-IFN monoclonal antibody and provided evidence that
BLyS was downregulated under anti-IFNalpha treatment, again supporting that BLyS production is
regulated by type I IFN [89].
IFNalpha/beta exposure of mature B cells is associated with enhanced sensitivity of BCR engage-
ment [90] and induces hyperresponsiveness of a B-cell memory-like phenotype (identified by phos-
phorylated Syk) [91,92]. Moreover, IFN induces the differentiation of B cells to plasmablasts, which in
response to IL-6 are able to become Ig-secreting plasma cells [85,93]. Li et al. found that IFN expression
correlated directly with IgG autoantibodies, whereas IgM autoantibodies correlated inversely. This
suggests that the class-switch from IgM to IgG can be facilitated by these cytokines [94]. Furthermore, a
cell-specific type I IFN signature could be detected in plasma cells and plasmablasts of SLE patients [95].
As BLyS/BAFF and type I IFN are largely produced by different myeloid lineage cells, there is a possibility
that abnormal activity of these cells is fundamental in SLE, but further studies are necessary to
delineate the complexity of lupus pathology [90].

B cells in SLE

The production of autoantibodies is a hallmark in lupus pathology. ANA positivity has recently
been put forward as entry criterion for the classification of SLE [20] consistent with the notion that
autoreactive plasma cells is a conditio sine qua non for this disease. There is evidence that plasma cells
and B cells play different roles in SLE and therefore can be considered as ‘two immunopathogenic
engines’ [3].
B-cell development is normally tightly controlled, and intrinsic defects through checkpoint ab-
normalities are discussed as causes of SLE. In healthy subjects, autoreactive antibodies are deleted
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T. Rose, T. Do

from the B-cell repertoire in the bone marrow and in later stages of B-cell development in the pe-
riphery [96]. In lupus patients, self-reactive naïve B cells are not removed, and increased numbers of
circulating mature naive autoreactive B cells are detectable [97]. While in healthy donors, poly-
reactive antibodies account for 6% of circulating antibodies, they comprise about 1/3 in SLE [97]. The
underlying causes are most likely altered central tolerance mechanisms controlling early stages of B-
cell development in the bone marrow and defects of peripheral tolerance at later stages. The latter is
mainly operative in secondary lymphoid organs or bypassed in extrafollicular structures [98]. Central
mechanisms consist of receptor editing and induction of apoptosis and anergy, while peripheral
mechanisms comprise especially circumvention of selection [99]. Both central and peripheral se-
lection seem to be abnormal in SLE [100,101]. In detail, B-cell abnormalities in SLE are the expansion
of circulating plasmablasts [102] and CD95þCD27-IgD-, CD21low [103] or CD27-/IgD-B cells
[104e106] correlating with disease activity. Conversely, activity-independent B-cell disturbances
comprise increased memory B cells [107] and detection of memory-like B cells [91] together with
polyclonal hypergammaglobulinaemia. Other differences, such as defective B-cell selection,
abnormal germinal centre and increased extrafollicular responses, enhanced somatic hyper-
mutation, and a disturbed peripheral B-cell compartment, have been reported in SLE
[91,99,102,107,108], but it remains to be delineated if these are primary abnormalities or reflections of
an overactivated immune system in SLE. In this context, a higher frequency of pre-immune B cells
(transitional, pre-naïve and naïve B cells), antigen-experienced CD27þIgD memory B cells, atypical
CD27-Sykþþ memory-like B cells and plasmablasts/plasma cells have been found in the blood of
lupus patients [91,102,107,108]. As the abnormalities of the T- and B-cell system can be restored by
autologous stem-cell transplantation including normalization of the disturbed lymphocyte com-
partments, an acquired rather than an intrinsic defect of B and T cells appears to be involved [109].
Recent data on certain B-cell functions in SLE, such as cytokine/chemokine production and BCR
responses, have revealed new and rather unexpected insights. Several risk genes in BCR downstream
signalling have been associated with SLE [2]. The BCR is a crucial regulator of negative and positive
selection and a continuous BCR sensing is critical for B-cell survival. In this regard, ablation of the BCR
resulted in B-cell death by upregulation of CD95 and downregulation of MHC in a preclinical mouse
model [110]. Initial SLE studies reported enhanced BCR responses by detecting Ca2þ influx, global
phosphorylation of tyrosine and inositol phosphate metabolites, supporting the idea of B-cell hyper-
activity [111]. Defective PTEN regulation of BCR signals by miRNAs were considered to contribute [112].
However, the longstanding concept of B-cell hyperresponsiveness has been challenged by recent ev-
idence, showing diminished BCR and TLR responses [113,114]. Here, reduced levels of Syk, phosphor-
ylated Syk (pSyk), PLC-g2 (p-PLC-g2) and Ca2þ influx upon BCR activation and a reduced cytokine
response upon TLR9 activation have been identified. The reduced functional capacity of B cells has been
taken as a reflection of a post-activation status [113], very similar as reported for reduced CD4þ T-cell
responses [116] or transcriptome data from CD8þ T cells ([117], where also the term ‘exhausted’ has
been used).
Cytokines, such as Blys and/or type I IFN, are potential factors able to modulate lymphocyte re-
sponses. For example, Blys crucial for B-cell survival promotes direct phosphorylation of BCR signalling
molecules such as spleen tyrosine kinase (Syk) through BAFF receptors [118], whereas IFN type I in-
creases the sensitivity of the BCR. Thus, both cytokines might have also a capacity to fine-tune BCR
signalling [86,90,97]. The different effects of type I IFN and BLyS/BAFF on BCR signalling indicate that
different factors modulate immune activation that likely differs during flaring/active and chronic
disease. It is therefore important to study not only active but also chronic SLE because the latter will
also provide important insights into disease characteristics and therapeutic guidance.

T cells in SLE

T cells contribute to SLE pathogenesis in various ways, such as by directing the type of inflammation
based on their instruction by DC through the induction of certain cytokines, by amplification of re-
sponses including activation of autoreactive B cells and by subsequent autoantibody production. Here,
especially CD4 T-cells are of central importance, which can also be found in urine of patients with
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T. Rose, T. Do 329

active lupus nephritis [119]. CD4þ T cells can occur in various subsets, such as follicular T helper cells
(Tfh), regulatory T cells (Treg), Th17-, Th1- and Th2 cells.
Tfh cells are essential for germinal centre induction, proliferation, isotype-switching and somatic
hypermutation and were found to be elevated in peripheral blood from SLE patients. These cells ex-
press both PD-1 and CXCR5 and produce the key cytokine IL-21, which provokes B cells to differentiate
into memory B cells and plasmablasts as typically found in SLE [120,121].
Increased numbers of Th-17 with an imbalance to reduced Tregs have also been observed in lupus
[122]. IL-17 mediates inflammation, and its production is inversely correlated with IL-2. In this regard,
blockade of IL-2 promotes differentiation of Th17 cells [123]. IL-2 deficiency was described in SLE and
represents another hallmark of this disease. Low-dose IL-2 administration has been shown to rebalance
Treg in mouse models and patients and showed early efficacy in small trials [124,125]. However, recent
data show that exogenous IL-2 cannot completely restore T-cell functions in SLE [116]. Decreased miR-
200a-3p has been described to reduce IL-2 production through zinc finger E-box binding homeobox
(ZEB)1 and C-terminal binding protein 2 (CtBP2) in murine lupus [126]. While data on selectively
targeting T cells in SLE are very limited and abatacept has not provided sufficient success in SLE, the
value of T-cell modulation in lupus pathogenesis needs to be assessed further.
Increased activity of the serine/threonine protein phosphatase 2A (PP2A) has been found in T cells
from patients with SLE that contribute to decreased IL-2 production, increased CREMa expression,
hypomethylation of risk genes and increased IL-17 production. A mouse overexpressing PP2Ac in T
cells resulted in autoimmunity, including elevated IL-17 production [127]. Thus, a possible com-
monality of lupus B and T cells could relate to enhanced PTP activity, which may represent a
mechanism during chronic autoimmunity also consistent with PTPN22 as genetic risk factor. It needs
to be delineated if increased PTP activity is operative in post-activated lymphocytes or represents a
characteristic of SLE.

Concluding remarks

Pathogenic drivers of SLE are multifactorial. Interaction of genetic susceptibility with environ-
mental and potential stochastic factors leads to an early break of immune tolerance with preclinical
autoimmunity. Despite important genetic risk factors affecting almost all parts of the immune
system, defective clearance mechanisms (enhanced apoptosis and neutrophil extracellular traps
(NETosis), nucleic acid debris) lead to activation of innate immunity with significant production of
IFNs (type I and II) and BAFF/BLyS. Subsequently, antigen presentation through the most prominent
genetic risk factor HLA class II (DR2/DR3) results in T and B lymphocyte activation with autoanti-
body production by plasma cells and type I IFN production. Continuous activation of pDCs and
myeloid cells with increased cytokine production connected to enhanced lymphocyte activation
forms a positive feed-forward loop as a key factor for the maintenance of chronic autoimmunity. In
addition, a number of other disturbances, such as epigenetic modulation including abnormal miRNA
expression, reduced IL-2 production but increased IL-17 by CD4þ T cells, diminished global cytokine
production by B cells and reduced BCR responses, and abnormal PTP activity in T and B cells have
been reported recently.
Insights into lupus pathogenesis become of great importance after a number of SLE trials failed [3].
Lessons from those trials with knowledge from preclinical models and translational research in lupus
provide an improved basis for innovative clinical developments.

Conflict of interest statement

No conflicts of interest to declare.

Acknowledgements

The authors thank Martina Bertolo and Anna R. Lisney for critical review of the manuscript. The
authors' work is supported by grants by the DFG (projects Do491/8-2, 10-1, TR130, CRC Immunobone).
330 €rner / Best Practice & Research Clinical Rheumatology 31 (2017) 321e333
T. Rose, T. Do

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