Download Targeting of the immune system in systemic lupus erythematosus

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Targeting of the immune system in
systemic lupus erythematosus
Meera Ramanujam and Anne Davidson*
Systemic lupus erythematosus (SLE) is a complex immune disorder in which loss
of tolerance to nucleic acid antigens and other crossreactive antigens is
associated with the development of pathogenic autoantibodies that damage
target organs, including the skin, joints, brain and kidney. New drugs based on
modulation of the immune system are currently being developed for the
treatment of SLE. Many of these new therapies do not globally suppress the
immune system but target specific activation pathways relevant to SLE
pathogenesis. Immune modulation in SLE is complicated by differences in the
immune defects between patients and at different disease stages. Since both
deficiency and hyperactivity of the immune system can give rise to SLE, the
ultimate goal for SLE therapy is to restore homeostasis without affecting
protective immune responses to pathogens. Here we review recent
immunological advances that have enhanced our understanding of SLE
pathogenesis and discuss how they may lead to the development of new
treatment regimens.
Systemic lupus erythematosus (SLE) is a disease
characterised by loss of B-cell tolerance to
autoantigens, particularly nucleic acids and
their binding proteins. Although autoantibodies
to nuclear antigens are elicited in healthy
individuals
during
protective
immune
responses (Ref. 1) and are present in the serum
of up to 20% of the population, they are not
sufficient to cause autoimmune disease. Clinical
onset of SLE is often preceded by epitope
spreading with development of antibodies to
multiple nuclear antigens (Ref. 2). In addition,
recruitment of inflammatory cells and mediators
to susceptible target organs is required. Multiple
genetic pathways predispose to development of
SLE, some of which are shared by other
autoimmune diseases; usually there are
contributions from three or more susceptibility
alleles in individual patients (Ref. 3). The
disease may be triggered in genetically
susceptible individuals by environmental
factors, including microbial antigens, drugs,
toxins and hormones. Because a single cause for
SLE has not been identified, therapy has relied
on global immunosuppression; however, this
causes significant morbidity and mortality from
unwanted side effects including infections,
osteoporosis,
infertility
and
premature
atherosclerosis.
More than a hundred single genetic defects
affecting the immune system cause SLE-like
disease in mice (Refs 3, 4, 5), suggesting that
Targeting of the immune system in systemic lupus erythematosus
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Feinstein Institute for Medical Research, NS-LIJHS, Manhasset, NY 11030, USA.
*Corresponding author: Anne Davidson, Feinstein Institute for Medical Research, NS-LIJHS,
Autoimmune Laboratory, 350 Community Drive, Manhasset, NY 11030, USA. Tel: +1 516 562
3840; Fax: +1 516 562 2953; E-mail: [email protected]
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Accession information: doi:10.1017/S1462399408000562; Vol. 10; e2; January 2008
& 2008 Cambridge University Press
there are many pathways that can be targeted
therapeutically. The major challenge to
assembling a new therapeutic armamentarium
for SLE is the difficulty in conducting largescale clinical trials in this highly complex
disease. In addition, because of the
heterogeneity of the disease, targeting a
particular immune pathway may not be equally
successful for each patient. Furthermore,
restoration of homeostasis may be difficult to
achieve because insufficient or excessive cell
activation can predispose to autoimmunity. For
example, insufficient B-cell signalling can result
in selection of autoreactive B cells into the naive
B-cell repertoire (Ref. 6), whereas excessive
B-cell signalling can result in the escape of
autoreactive cells during antigenic stimulation
(Ref. 7). In addition, many inflammatory
mediators have pleiotropic effects that are
dependent on the microenvironment and the
cell activation state. Finally, synergistic
combinations of drugs that allow smaller doses
and therefore less toxicity need to be identified.
The innate immune system as a target for
SLE therapy
The innate immune system comprises cells and
soluble molecules that are the first responders
to an immune insult. Receptors on cells of the
innate immune system recognise microbial
components and induce cellular activation and
cytokine release that induce activation and
proliferation of T and B cells. The innate
immune
system
is
also
crucial
for
noninflammatory
clearance
of
apoptotic
material generated from normal cell turnover.
Circulating natural antibodies, complement and
other acute-phase proteins opsonise and help
specialised cells to clear foreign material. A
defect in these functions can give rise to
autoimmunity.
An emerging concept in the pathogenesis of
SLE is that an excessive load of apoptotic
particles containing nuclear antigens or of
immune complexes containing autoantigens can
overcome self-tolerance mechanisms and
trigger autoimmunity (Refs 8, 9). Loss of
tolerance may be due to excessive generation of
such material, deficiencies of circulating
‘natural’ IgM antibodies, complement and other
proteins that are involved in opsonisation and
clearance, or alterations in thresholds for
signalling of the innate immune response
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(Refs 10, 11, 12, 13). One mechanism for the
pathogenicity of increased antigenic or apoptotic
load is through activation of Toll-like receptors
(TLRs) that recognise foreign and endogenous
nucleic acids (Ref. 14). Four TLRs – TLR3, TLR7,
TLR8 and TLR9 – expressed predominantly by
antigen-presenting cells (APCs) and B cells
belong in this category (Ref. 15). There has been
much focus recently on TLR9 (which recognises
bacterial CpG-rich DNA) and TLR7 (which
recognises viral single-stranded RNA), which
are normally sequestered inside endosomes
away from circulating endogenous nucleic acids
(Refs 15, 16). However, these endosomes are
situated adjacent to phagosomes that take up
apoptotic material. In addition, nucleic acids
within immune complexes can be delivered to
TLR-containing endosomes after cellular uptake
via either cell-surface B-cell receptors (BCRs) or
Fc receptors (Refs 17, 18). Blockade of this
process underlies the therapeutic effect of
antimalarial drugs in SLE patients (Ref. 19).
Stimulation of TLR7 and TLR9 leads to
transcription of genes encoding interleukin 6
(IL-6), IL-12, tumour necrosis factor a (TNF-a),
type I interferons (IFNs) and other innate
immune effectors (Refs 20, 21, 22) (Fig. 1).
Polymorphisms
of
the
TLR-induced
transcription factor gene Irf5 are associated with
SLE in humans, indicating the importance of
this pathway in disease (Ref. 23). One
important mechanism by which TLR ligation
might contribute to SLE pathogenesis is by
induction of type I IFNs. IFN-a is
overexpressed in human SLE patients and
accelerates SLE in humans and in some
genetically predisposed strains of mice (Refs 24,
25) (see below). Other functions reported as a
result of TLR engagement include blockade of
suppressor cell function (Ref. 26), maturation of
monocytes into macrophages and dendritic
cells (Ref. 27), and inhibition of shedding of
inducible costimulator (ICOS) ligand from
B cells, resulting in increased T-cell help
through ICOS (Ref. 28).
TLR9 ligands can induce either inflammation or
tolerance, depending on the mode and timing of
delivery (Ref. 29). The recent in vitro finding that
release of type I IFNs following activation of TLR9
ligands is dependent on the presence of the
inflammatory mediator HMGB1 suggests a
mechanism by which inflammation controls the
outcome of TLR9 ligation (Ref. 30). The effect of
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Immune complex
containing
nucleic acid
IgG
IgM
HMGB1
Phagocytosis
Endocytosis
BCR
Fc receptor
RAGE
dsRNA DNA
TLR3
TLR9
b
ssRNA
Endosome
c
TLR7/8
d
Adaptors
e
p38/JNK
NF-κB
IRF1
TNF-α
IL-12
IL-6
Type 1 IFN
g
h
f
Complement
a
Apoptotic
particle
IRF7
IRF5
The innate immune system in systemic lupus erythematosus
Expert Reviews in Molecular Medicine © 2008 Cambridge University Press
Figure 1. The innate immune system in systemic lupus erythematosus. Immune complexes containing
nucleic acid antigens and apoptotic bodies are internalised by B cells via the BCR and Fc receptor, by
dendritic cells via the Fc receptor and by macrophages via Fc receptors and endocytosis. Complexes are
directed to endosomes containing nucleic-acid-binding TLRs. Via recruitment of adaptor molecules, this
leads to activation of transcription factors (such as p38, JNK, NF-kB, IRFs) that drive the production of
inflammatory cytokines. Alterations in many different components of this pathway may induce or offer
protection from SLE. (a) Immune complexes and apoptotic particles are cleared by various molecules
including natural IgM, complement, DNases and serum amyloid P. Deficiencies of these molecules can
cause SLE. (b) An extra copy of TLR7/8 (part of the Yaa locus) accelerates murine SLE. (c) TLR3 deficiency
has no effect on murine SLE and TLR9 deficiency decreases anti-DNA antibodies but does not improve
disease outcome. (d) TLR7 deficiency decreases anti-RNA antibodies and improves disease outcome in
mice. (e) Polymorphisms of IRFs are associated with SLE. (f) TNF-a blockade can induce SLE but has also
been shown to induce remission of established kidney disease. Thus its effects are stage specific. (g) IL-6
blockade delays disease in murine models. (h) Type I IFN signature is observed in active SLE patients.
Deficiency of type I IFN receptor prevents disease in some SLE models but administration of type I IFN is
protective in others. Polymorphism of IFN-receptor-associated signalling molecule Tyk2 is associated with
SLE in humans. Abbreviations: BCR, B-cell receptor; HMGB, high-mobility group box 1; IFN, interferon; IRF,
interferon regulatory factor; JNK, Jun kinase; RAGE, receptor for advanced glycation end product; TLR, Tolllike receptor.
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TLR9 deficiency in murine models of SLE is strain
dependent. Although the titres of anti-doublestranded DNA and nucleosome antibodies are
decreased in autoimmune-prone TLR9-deficient
mice (Ref. 31), protection has been observed in
some
mice
(Ref.
32)
but
increased
autoantibodies to RNA antigens and increased
mortality have been observed in others
(Ref. 33). By contrast, TLR7 clearly contributes
to SLE pathogenesis. TLR7-deficient SLE-prone
mice fail to mount antibodies to ribonuclear
antigens and have a more moderate disease
course than their wild-type counterparts
(Refs 31, 34). Given this emerging knowledge, it
has therefore been of much interest that the Ylinked Yaa gene – an accelerator of SLE in the
BXSB male mouse – was found to be a
reduplication of part of the X chromosome
containing Tlr7 and Tlr8 (Ref. 35). NZW/BXSB
mice express high titres of antibodies to RNA
and have a marked expansion of the B-cell,
monocyte and dendritic cell lineages that
express TLR7 (Ref. 36). Immune complexes
containing RNA are potent stimulators of TLR7
and TLR8, especially in the presence of IFN-a
and can therefore amplify and perpetuate
disease. Further complexity is added by the
differential expression of TLR7, TLR8 and TLR9
in different cell types and their ability to
crossregulate each other (Ref. 14).
Oligodeoxynucleotide inhibitors of TLR
signalling (ODNs) containing methylated DNA
or DNA containing CCGG or TTAGGG motifs
have recently been developed and inhibit IFN-a
production in response to immune complexes or
viruses (Ref. 15). Synthesis of inhibitors with
dsDNA-like structure may be selective for
autoreactive cells because these are preferentially
taken up into anti-dsDNA-secreting B cells via
the BCR (Ref. 37). Administration of ODNs to
SLE-prone mice results in delay in both the
onset and progression of SLE nephritis (Ref. 38).
Interestingly, in a mouse model of SLE, an
inhibitor of both TLR7 and TLR9 did not add
clinical benefit to the effects of specific TLR7 or
TLR9 inhibitors and had less effect on antidsDNA titres than TLR9 inhibition alone
(Ref. 39). Since much of the effect of TLR9
ligation is mediated by IFN-a, inhibition of this
cytokine is also currently being tested in human
clinical trials.
Another important component of the innate
immune system is the Fc receptor family, which
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regulates responses to immune complexes
(Ref. 40). Four different classes of human IgG
Fc receptors have been identified, with differing
affinities for IgG and for specific IgG isotypes
and with differential expression on particular
lymphoid cell types. FcRI, FcRIIA and FcRIIIA
are activating receptors that are broadly
expressed on cells of the haematopoietic
lineage. FcRIIB is an inhibitory receptor
expressed on all immune cells and is the only
Fc receptor expressed on B cells. FcRIIB inhibits
B-cell responses to immune complexes and
helps terminate humoral immune responses
once there is antibody excess over antigen.
Expression of FcRIIB is constitutively low in
several mouse models of SLE and the disease
can be reversed in these mice by inducing only
40% more FcRIIB expression on B cells (Ref. 41).
Polymorphisms of FcRIIB are associated with
human SLE, but also with protection from
infectious diseases (Ref. 42). In addition,
humans with SLE fail to upregulate FcRIIB on
memory and plasma cells, a defect that is partly
genetically determined and partly acquired
(Refs 43, 44). Complete absence of FcRIIB in
mice leads to autoimmunity and SLE-like
disease in a strain-specific manner (Ref. 45).
Analysis of these mice has indicated that FcRIIB
regulates B-cell tolerance in the periphery,
acting as a brake on the differentiation of
autoantibody-producing plasma cells (Ref. 46).
FcRIIIA and its newly described mouse
homologue FcRIV are intermediate-affinity
receptors that recognise immune complexes but
not monomeric IgG. These receptors are
thought to be the activating receptors for
immune complexes in vivo, because highaffinity Fc receptors are already occupied with
monomeric Ig (Ref. 40). Polymorphisms of
FcRIIIA that lower antibody-binding affinity are
associated with susceptibility to SLE nephritis
and with poorer responses to therapy with
B-cell-depleting agents. Low-affinity binding
FcRIIA polymorphisms have also been
associated with SLE and with antiphospholipid
syndrome (Refs 47, 48). These polymorphisms
of activating receptors may result in decreased
immune complex clearance.
The relative expression of activating and
inhibitory Fc receptors influences the outcome
of immune-complex stimulation of cells, as
does the isotype of the antibodies in the
complexes. During inflammation, FcRIIB is
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downregulated whereas activating Fc receptors are
upregulated, resulting in activation of immune
cells (Ref. 40). This may contribute to the failure
of upregulation of FcRIIB on B cells in patients
with active SLE. One proposed mechanism of
action of intravenous immunoglobulin is that it
upregulates FcRIIB, thus altering the balance of
activating to inhibitory receptors (Ref. 49). This
effect appears to be dependent on a sialic-acidbearing IgG glycoform that acts through an as
yet unidentified receptor (Ref. 49). Further
understanding of this pathway may lead to
novel therapies for SLE based on modulating
FcR function.
Targeting activation of the acquired
immune response in SLE
Triggering of the innate immune system by
exposure to exogenous antigen is crucial for the
activation of antigen-specific T and B cells and
their subsequent clonal proliferation and
differentiation into memory cells. Pathogenic
autoantibodies in SLE are isotype switched and
somatically mutated – functions dependent on
T-cell help (Ref. 50). Self-tolerance of T cells is
maintained by many mechanisms, including
sequestration from self-antigen, deletion of
highly self-reactive cells in the thymus, and
peripheral regulation either by APCs that have
not been activated by innate mechanisms or by
other regulatory cell subsets (Refs 51, 52). Very
little is known about the antigenic specificity
of T cells in SLE. Therefore, T-cell-directed
therapies for SLE have focused on non-antigenspecific pathways. Although the specificity of
the T-cell response is provided by the
interaction of the major histocompatibility
complex (MHC)– peptide complex with the
T-cell receptor (TCR), T-cell activation requires
a second set of costimulatory signals between
T cells and APCs. The last decade has seen the
identification of many costimulatory receptor –
ligand pairs that are potential therapeutic targets.
CD28– B7 family members
CD28 is constitutively expressed on T cells and is
upregulated upon T-cell activation. CD28
engagement by its ligands CD80 and CD86 (B7-1
and B7-2) amplifies signals through the
TCR and stabilises the immunological synapse,
thus lowering the threshold for naive T-cell
activation, and facilitating entry into the cell
cycle and secretion of IL-2 (Refs 53, 54).
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Engagement of the TCR in the absence of CD28
costimulation may lead to cell death or
induction of anergy (Refs 55). This maintains
tolerance to self-antigens that are usually
chronically encountered in the absence of
costimulatory signals. The CD28-homologous
molecule CTLA4 has much higher affinity for
CD80 and CD86 and serves as a negative
regulator of T-cell function. CTLA4, unlike
CD28, signals through CD80 and CD86 to
induce several regulatory molecules including
indoleamine 2,3-dioxygenase (IDO), an enzyme
that helps maintain tolerance through
alterations in tryptophan metabolism (Refs 56,
57). A recently identified polymorphism of
CTLA4 is associated with autoimmunity in
humans (Ref. 58).
Blockade of CD28 is achieved by administration
of the extracellular domain of CTLA4 fused to
immunoglobulin heavy chain (CTLA4Ig,
Abatacept) (Ref. 54). CTLA4Ig acts both as a
competitive antagonist of B7– CD28 interactions
and as an inducer of regulatory pathways in
APCs. CTLA4Ig may also alter expression of
adhesion molecules and chemokine receptors,
resulting in inhibition of traffic of inflammatory
cells to target organs (Ref. 59), and prevents the
upregulation of ICOS (Ref. 36). However, under
some circumstances, administration of CTLA4Ig
might be detrimental. For example, although
CTLA4Ig can induce T-cell deletion and anergy,
it may prevent tolerance induction in
circumstances where signalling through CTLA4
is necessary to establish active tolerance (Ref. 60).
CTLA4Ig and its higher-affinity mutant
LEA29Y (Belatacept) have been successfully
used in patients with psoriasis, rheumatoid
arthritis and transplantation (Refs 54, 61). In
mice, CTLA4Ig prevents the onset of SLE
(Ref. 62) but does not reverse active
inflammation (Ref. 63). For this reason,
combination therapies have been tested.
Administration of CTLA4Ig with concomitant
CD40 or CD40L blockade to SLE-prone mice is a
highly synergistic regimen that prevents the
onset of SLE for many months after a short
course of treatment. This is due to long-lasting
blockade of T-cell help for autoreactive B cells
(Ref. 64). Dual treatment with a single dose of
the alkylating agent cyclophosphamide and
continuous CTLA4Ig is highly synergistic for the
treatment of active SLE nephritis in mice and
induces complete remission of histological
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changes in the kidney. The mechanism for this
effect is not completely understood, but includes
depletion of activated T and B cells, together
with altered renal chemokine and chemokine
receptor expression, and consequent dampening
of the inflammatory response to glomerular
immune-complex deposition (Ref. 65). Clinical
trials of Abatacept in active SLE and in
combination with cyclophosphamide in SLE
nephritis have been initiated.
B7– CD28 interactions are essential for
activation of naive T cells, but have a lesser role
in regulating effector responses and responses
outside secondary lymphoid organs. Expression
of other B7 family members allows regulation
of effector T cells at peripheral sites (Ref. 66)
(Fig. 2). ICOS is a CD28-like molecule that is
expressed on activated and memory T cells and
preferentially
induces
IL-4
and
IL-10
production (Ref. 67). ICOS is highly expressed
on IL-10-expressing effector cells (Ref. 68) and
on IL-21-secreting CXCR5-positive follicular
T-helper (Th) cells located in the apical zone of
germinal centres where somatic mutation
occurs (Ref. 69). Ligation of ICOS results in
upregulation of CD40L on T cells, which
costimulates immunoglobulin synthesis and
differentiation of B cells to memory and plasma
cells (Ref. 70). Dramatic defects of the humoral
immune response occur in ICOS-deficient mice
and humans as well as defects in IL-10 and
IL-17 production (Refs 71, 72). Antagonism of
ICOS during the effector phase of Th2-mediated
disease attenuates inflammation in murine
models (Ref. 72). The ICOS ligand B7RP-1 is
expressed on B cells and macrophages and in
inflamed tissues. ICOS expression is increased
on T cells from SLE-prone mouse strains,
particularly mice that bear a Yaa mutation
(Ref. 36) and on T cells in SLE patients (Ref. 73).
Coinhibition
?
––
BTLA
––
PD-1 CTLA4
––
––
Costimulation
CD28
++
ICOS
++
?
++
TCR/CD3
++
B7.2
B7H
B7-H3
MHC
T cell
APC
B7-H4 HVEM
PDL1/2 B7.1
Members of the CD28–B7 family mediate both costimulation and coinhibition
Expert Reviews in Molecular Medicine © 2008 Cambridge University Press
Figure 2. Members of the CD28 –B7 family mediate both costimulation and coinhibition. Two signals are
required for T-cell activation. Signal 1 is mediated through interaction of the T-cell receptor (TCR) with MHC/
peptide complex shown in blue. Signal 2 is mediated by non-antigen-specific interactions such as that of B7
with CD28. CD28-like receptors are shown on the surface of the T cell and B7-like ligands (blue) are shown
on the surface of the antigen-presenting cell (APC). Receptors shown in green transduce a positive
(costimulatory) signal to the T cell. Receptors shown in red transduce a negative (coinhibitory) signal to the
T cell. Not all the receptors have been identified (indicated by ?). Abbreviations: BTLA, B and T lymphocyte
attenuator; HVEM, herpesvirus entry mediator; ICOS, inducible costimulator; MHC, major histocompatibility
complex.
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The pathogenic role of ICOS has recently been
highlighted by the development of B-cell
autoimmunity in mice deficient in roquin, a
repressor of ICOS expression (Ref. 74), and by
studies showing that blockade of ICOS ligand
prevents and treats disease in NZB/W SLEprone mice (Ref. 75). Clinical trials of ICOS
blockade in humans with SLE are now under way.
The receptor programmed death 1 (PD-1),
which is expressed on both B and T cells, binds
to two ligands: PDL1, which is widely
expressed on many tissues and PDL2, which is
expressed mainly on activated monocytes. Like
CTLA4, PD-1 transduces a negative signal into
the cell and helps to maintain peripheral
tolerance (Ref. 76). Studies in mouse models of
multiple sclerosis and diabetes have shown that
this effect is mediated via the interaction of
PD-1 with PDL1 but not with PDL2 (Refs 77,
78). PD-1-deficient mice develop spontaneous
strain-specific autoimmunity including SLE
(Ref. 79) and recently a PDCD1 polymorphism
associated with human SLE has been identified
(Ref. 80).
Several other members of the CD28 – B7 family
have been characterised. B and T lymphocyte
attenuator (BTLA), like CTLA4 and PD-1, is a
negative regulator of T-cell responses and its
deficiency results in increased susceptibility to
induced autoimmunity. BTLA is unusual
because it binds herpesvirus entry mediator
(HVEM), a member of the tumour necrosis
factor receptor family (Refs 81, 82). B7-H3 and
B7-H4 bind to unidentified receptors (Ref. 83).
Little is currently known about the role of these
molecules in autoimmune disease pathogenesis;
however, these molecules appear to have their
effects only at low antigen doses.
The TNF –TNFR family
Multiple members of this family mediate
costimulation of T cells and B cells, with 4-1BB,
CD40L and B-cell activating factor (BAFF) being
most relevant to SLE therapies.
4-1BB
The engagement of the T-cell costimulatory
receptor 4-1BB (CD137) paradoxically prevents
germinal centre formation in a T-cell-dependent
fashion. In SLE-prone mice, three doses of an
agonistic anti-4-1BB antibody confers prolonged
inhibitory effects on autoantibody production
starting
1–2
weeks
after
antibody
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administration (Ref. 84). In the chronic graftversus-host
(CGVH)
model
of
SLE,
administration of the anti-4-1BB antibody
resulted in rapid depletion of donor T cells by
activation-induced death (Ref. 85). By contrast,
in the NZB/W model, CD4þ T cells were not
depleted, but cytokine secretion by these cells
was markedly diminished (Ref. 84). Transfer of
either activated T cells or APCs from untreated
mice overcame the T-cell anergy and
precipitated disease. Another hypothesis for the
activity of anti-4-1BB is that T-regulatory cells
(T regs) are generated (Refs 84, 86). Although a
regulatory population of CD8þ cells has been
described, it is clear that the antibody still
mediates tolerance in CD8-deficient mice
(Ref. 84). Finally, production of IFN-g has been
shown to enhance tolerance in the Murphy
Roths Large (MRL)/lpr model (Ref. 87) but not
in the CGVH model, suggesting that IFN-g is
not essential for tolerance induction (Ref. 85).
This system is interesting because it shows that
long-lasting restoration of tolerance can be
achieved in mice with spontaneous SLE in
which B and T cells are continuously being
activated. Further studies in this system may
reveal the mechanisms for maintenance, loss
and restoration of tolerance in autoimmunity.
CD40L
CD40L is an important costimulatory molecule,
whose expression on activated T cells is
regulated by CD28 and by ICOS (Ref. 83).
Engagement of CD40 on APCs by CD40L
synergises with TLR signalling and results in
increased expression of MHC and B7 molecules
and secretion of IL-12, thus enhancing their
antigen-presenting
function
(Ref.
88).
Engagement of CD40 on B cells delivers a
survival signal and is essential for formation of
the germinal centre and for reactivation of
memory B cells (Refs 89, 90). Absence of CD40
or CD40L in humans results in a profound
humoral
immunodeficiency
(Ref.
91).
Antibodies to CD40L prevent onset and delay
progression of SLE in mouse models (Ref. 92),
but two Phase II human clinical trials failed
because of the unexpected development of
thrombotic events in some of the treated
patients (Ref. 93). Although one of the
anti-CD40L trials failed to show clinical efficacy
at the dose used (Ref. 94), some of the SLE
patients treated with a different anti-CD40L
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antibody showed clinical improvement (Ref. 95).
Mechanistic studies in these patients revealed
that despite unaltered total B-cell numbers,
treatment
diminished
the
number
of
autoantibody-producing B cells (Refs 95, 96, 97).
It has been suggested that the effect of antiCD40L is due to specific B-cell unresponsiveness
rather than T-cell anergy, because tolerance
cannot be broken in mice by transfer of
pathogenic T cells (Ref. 98). However, in humans
with SLE, B cells producing anti-DNA antibody
reappeared after cessation of anti-CD40L,
indicating that tolerance had not been
established (Ref. 96). A striking therapeutic effect
can be observed in mouse models when antiCD40L is combined with CTLA4Ig. This
combination, given for two weeks to SLE-prone
mice, induces a prolonged effect on disease when
given early in the course (Ref. 63), and, more
importantly, maintains B-cell tolerance to
autoantigens without preventing immune
responses to exogenous antigens (Ref. 64).
However, this combination is not effective in the
setting of active nephritis and requires the
addition of a single dose of cyclophosphamide,
which kills activated effector cells (Ref. 65).
Although anti-CD40L antibodies are not safe for
use in humans, antibodies to CD40 have been
recently developed for human use and appear to
be safe for the treatment of B-cell tumours
(Ref. 99). This may allow for a renewed attempt
at CD40 blockade in human SLE.
BAFF
The TNF family member BAFF is a B-cell survival
factor expressed by many different cell types that
binds to three different BAFF receptors (TACI,
BCMA and BAFF-R), which are variably
expressed on the B-cell surface during
development (Refs 100, 101). BAFF-R and TACI
are the predominant receptors on most mature
B cells, except for plasma cells, which express
BCMA (Refs 102, 103). APRIL, a closely
associated ligand of BAFF, binds to TACI and
BCMA and to proteoglycans such as CD138 on
the plasma cell surface; CD138 serves as a
coreceptor to enhance binding of APRIL to
BCMA (Ref. 104). Maintenance of peritoneal
cavity B1 B cells is BAFF independent
(Refs 105, 106) and germinal centre B cells are
only partially dependent on BAFF. Thus BAFFdeficient mice can still develop autoimmunity,
although they do so in a much delayed fashion
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(Refs 107, 108). BAFF transgenic mice on a
nonautoimmune genetic background develop a
form of SLE that is due to production of
autoantibodies by marginal zone and B1 cells
and this depends on B-cell signalling through
TLRs but does not require T cells (Ref. 109).
BAFF levels may control B-cell selection
because competition for BAFF limits selection
of autoreactive B cells into the mature
compartment. Depletion of B cells results in
excess production of BAFF, which may then
decrease the stringency for B-cell selection
(Refs 110, 111). It remains unclear whether the
increased sensitivity of autoreactive B cells to
survival signals mediated through BAFF and
APRIL is applicable to memory cells,
plasmablasts or plasma cells (Ref. 112). Patients
with SLE and other autoimmune diseases have
increased serum levels of BAFF (Refs 113, 114)
and in murine SLE nephritis, BAFF is also
found locally at the site of inflammation where
it is made by activated macrophages and
dendritic
cells
(Ref.
207).
Activated
macrophages express BAFF receptors and thus
may mediate their own survival in an autocrine
fashion (Ref. 115).
BAFF blockade has been achieved either with a
monoclonal anti-BAFF antibody or with soluble
BAFF receptors. BAFF-R-Ig selectively blocks
BAFF, whereas TACI-Ig blocks both BAFF and
APRIL, and therefore is able to deplete plasma
cells that are dependent on APRIL– BCMA
interactions. Despite these differences, both
selective and nonselective BAFF blockers
prevent SLE in mouse models (Ref. 106),
indicating that BAFF is more important than
APRIL in SLE pathogenesis. BAFF blockade
depletes B cells by 50% but does not
significantly decrease the titres or affinity of
autoantibodies, nor does it prevent T-cell
activation. By significantly decreasing B-cell
numbers and spleen size, BAFF blockade
results in a decrease in the total number of
activated T cells and monocytes, thus
decreasing the total inflammatory load and the
capacity of inflammatory cells to migrate to the
kidney. The combination of BAFF blockade and
CTLA4Ig, but not either drug alone, can induce
remission of SLE in NZB/W mice by
mechanisms that are not fully delineated
(Refs 106, 116). A human clinical trial of the
anti-BAFF antibody Belimumab in moderately
active SLE showed only modest clinical effects,
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with failure to meet initial efficacy end points.
However, long-term follow up and post-hoc
analysis of patients that were serologically
active at initiation has shown a greater
sustained improvement in treated patients than
in placebo-treated controls (Ref. 117). More
extensive trials of this agent are in progress.
TACI-Ig is also entering clinical trials in SLE.
B-cell modulation and depletion
SLE is characterised by the production by B cells
of high-affinity pathogenic autoantibodies that
mediate tissue injury. In addition, B cells have
other important functions that can contribute to
disease pathogenesis. Activated autoreactive
B cells that take up autoantigen through their
antigen receptor can function as APCs and
serve to diversify the epitopes of self-antigen
presented to autoreactive T cells. B cells also
produce cytokines involved both in lymphoid
regulation and in inflammatory processes
(Ref. 118). Because autoreactive B cells play a
role in both the inductive and the effector arms
of autoimmune disease, there has been much
interest in B-cell depletion or modulation as a
treatment strategy for autoimmune disease. One
such strategy has been the use of anti-CD20
antibodies.
CD20, a transmembrane protein with four
subunits, is upregulated on most B cells
past the pre-B-cell stage but is absent on plasma
cells (Refs 119, 120). Anti-CD20 monoclonal
antibodies successfully deplete peripheral
human B cells for periods ranging from three
months to more than one year through
mechanisms involving Fc-receptor dependent
killing, complement-dependent killing and
antibody-dependent apoptosis (Refs 121, 122).
Studies in mice show that the kinetics of B-cell
depletion varies between different B-cell
compartments with 90% follicular B cells in the
spleen being depleted within two days of antiCD20 monoclonal antibody administration but
less effect on marginal zone B cells. The
peritoneal cavity (particularly B1) and the
germinal
centre
B-cell
compartments
demonstrate the greatest relative resistance to
anti-CD20 monoclonal antibody treatment
although marginal zone, germinal centre and
peritoneal B1 B cells express comparable levels
of CD20 and appear to have access to the
antibody. These differential sensitivities depend
partly on the number and localisation of
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mononuclear phagocytes within tissues that
mediate antibody-dependent cell-mediated
cytotoxicity (Refs 122, 123, 124). Hence, location
and microenvironment influence the extent of
B-cell depletion (Ref. 123). Because B-cell
depletion causes a compensatory increase in
BAFF levels, blockade of BAFF synergises with
anti-CD20 monoclonal antibody to enhance
B-cell depletion (Ref. 123). A new approach that
may avoid the need for two drugs is the use of a
depleting anti-BAFF-R antibody. This antibody
blocks the effects of BAFF and also depletes
BAFF-R-bearing cells. However, like anti-CD20,
this antibody does not deplete long-lived plasma
cells that no longer express BAFF-R (Ref. 125).
Preliminary clinical experience with a mouse –
human
chimaeric
anti-CD20
antibody
(Rituximab) in patients with SLE (Ref. 126) and
other
autoimmune
diseases
has
been
encouraging (Refs 127, 128, 129), with rapid
resolution of symptoms in some patients that
depends on B-cell depletion but not on
depletion of autoantibodies. Autoantibodies
continue to be produced because plasma cells
do not express CD20. These studies confirm the
role of B cells as important effector cells
independently of their ability to produce
antibodies. The degree of B-cell depletion is
affected by FcRIIIA genotype; there is less
depletion in patients bearing the low-affinity
allele, which is also a SLE-susceptibility allele
(Ref. 130). In addition, the rapid induction of
human antichimaeric antibodies (HACA) has
prevented B-cell depletion in some SLE
patients. A fully human anti-CD20 is now
available and may help solve this problem. In
some patients, remissions are long-lived and
returning B cells are predominantly of the
transitional phenotype with low numbers of
memory B cells (Ref. 131). The reappearance of
memory B cells is also associated with earlier
relapse in rheumatoid arthritis patients treated
with
anti-CD20
(Ref.
132).
Long-term
remissions have been associated with the
absence of antibodies to extractable nuclear
antigens (Ref. 133). Progressive multifocal
leukoencephalopathy has been observed in two
SLE patients that received more than one course
of
anti-CD20
together
with
other
immunosuppressive therapy. Most of the
reports of the efficacy of anti-CD20 in SLE have
been uncontrolled case series in small numbers
of treatment-resistant patients in which the
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drug has been combined with other therapies
including high doses of corticosteroids and
cyclophosphamide. A placebo-controlled Phase
III trial of anti-CD20 in SLE patients is now in
progress.
CD22 is a member of the sialoadhesin (siglec)
family of adhesion molecules that is
coexpressed with the B-cell receptor on mature
B cells and up to the late germinal centre stage
(Refs 129, 134, 135). CD22 has both
immunoreceptor tyrosine activation motif
(ITAM) and immunoreceptor tyrosine inhibitory
motif (ITIM) domains in its intracellular
domain and can act both as a negative regulator
of BCR signalling and as a costimulatory
molecule, depending on the context in which it
is activated (Ref. 136). Because of this
complexity, the precise effect of CD22 upon
BCR signalling in B cells at the various
developmental stages is not fully elucidated.
B cells from CD22-deficient mice have a
shortened lifespan and the mice have reduced
circulating B-cell numbers; however, these mice
also have hyper-reactive B cells and may
develop autoantibodies with age (Ref. 137).
Epratuzumab, a humanised monoclonal antiCD22 antibody, can mediate antibodydependent cellular cytotoxicity and has been
used to treat human B-cell malignancies
(Ref. 138). The rationale for using anti-CD22 in
human autoimmunity is based on the notion
that modulating B-cell function may be safer
than therapies that deplete B cells. However,
given the complexity of CD22 signalling in
B cells and the ability of this molecule to
mediate functions both in a ligand-dependent
and a ligand-independent fashion, it is difficult
to predict what the effect of an anti-CD22
antibody will be in humans with autoimmune
disease. The first clinical trial of epratuzumab
in 14 SLE patients with mild to moderately
active SLE has just been reported (Ref. 139).
Treatment with anti-CD22 appeared to be safe
and resulted in modest B-cell depletion in some
of the patients. Serum levels of IgG and C3
were not altered, and autoantibody levels either
increased or stayed the same. Although clinical
efficacy could not be assessed in this study,
improvements in BILAG (British Isles lupus
assessment group) scores were reported.
Mechanistic studies of patients in this clinical
trial showed preferential targeting of CD27negative naive or transitional B cells that have
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high levels of cell surface CD22 but no decrease
in memory B cells or plasma cells (Ref. 140).
Cell-surface CD22 levels were downregulated by
epratuzumab. Cell culture experiments further
showed that epratuzumab modulated the
abnormal proliferative response of SLE B cells to
TLR or CD40 ligation. An antiproliferative effect
was also observed in vitro when human B-cell
lines were immobilised and stimulated with
anti-IgM (Ref. 141). Further studies will be
needed to determine whether these modest
B-cell effects result in a measurable clinical effect
in controlled trials.
Depletion of autoantibodies or specifically of
autoantibody-producing B cells is another
approach that is currently in development.
Abetimus sodium is a compound consisting of
four double-stranded 20-mer ODNs that binds
to anti-dsDNA antibodies and clears them from
the serum. In mice, this drug has been shown
to decrease splenic autoantibody-producing
B cells, but it is not clear whether this also
occurs in humans. Although the drug depletes
anti-DNA antibodies in SLE patients by 30%,
two Phase III clinical trials have failed to reach
their primary endpoints of decreased time to
renal
flare
and
clinical
benefit
was
demonstrated only using post-hoc analysis of a
patient subset with high-affinity abetimusbinding antibodies at trial initiation (Ref. 142).
Further studies of this agent are in progress.
Other compounds directed specifically at
autoantibody-producing B cells have been
developed and are described in a recent review
(Ref. 143).
Cytokines in SLE – pleiotropic activities
may complicate treatment
Cytokine inhibition has been used successfully
to treat several autoimmune and inflammatory
diseases but has not yet been applied to the
treatment of SLE. One reason is that a number
of pro-inflammatory cytokines are also required
for the active maintenance of tolerance and
their blockade may exacerbate the loss of
tolerance to ubiquitous antigens. For example,
TNF-a blockade enhances the production of
SLE-related autoantibodies. Crosstalk between
innate immune system signals and cytokines
can be dysregulated in a systemic inflammatory
environment and this may result in
proinflammatory functions of cytokines that are
usually anti-inflammatory. For example, IL-10
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usually signals through STAT-3 but in the presence
of type I IFNs it switches to the proinflammatory
STAT-1 (Refs 144, 145). In addition, upregulation
of costimulatory receptors and integrins, and
alteration in the ratio of activating to inhibitory
Fc receptors, can alter the cellular response to
cytokines.
IL-6
IL-6 is a multifunctional cytokine that is critical for
the development and functioning of many
different cells and plays a crucial role in
immune responses and inflammation (Refs 146,
147). In the setting of activation of the innate
immune system, IL-6 dampens T reg function
(Ref. 26). Conversely, IL-6 has a regulatory role
in the resting immune system as it has been
shown to maintain anergy of resting B cells
chronically exposed to self-antigens (Ref. 208).
Excessive secretion of IL-6 is found in many
autoimmune diseases (Ref. 148) including SLE
(Ref. 149), where it induces plasma cell and
effector T-cell differentiation (Refs 26, 150). A
critical role for IL-6 in the pathogenesis of SLE
was demonstrated by the beneficial effects of
IL-6 receptor blockade and the exacerbating
effect of IL-6 in NZB/W F1 mice (Refs 146, 151,
152). A Phase I clinical study using an anti-IL6R
monoclonal antibody (MRA) in SLE has been
completed but the development of dosedependent neutropaenia may complicate the
use of this agent in human SLE (Ref. 153).
TNF-a
TNF-a is a pleiotropic cytokine that can mediate
both cell survival and cell death (Ref. 154). The
importance of this cytokine in maintaining the
balance of the immune system is highlighted by
acceleration of autoimmunity in a TNF-adeficient background (Refs 155, 156) and the
triggering or maintenance of autoimmunity in
the setting of excess TNF-a (Refs 157, 158, 159).
TNF-a antagonists have a remarkable
therapeutic effect in a number of autoimmune
diseases including rheumatoid arthritis and
Crohn disease (Refs 160, 161, 162). However,
TNF-a blockade appears to exacerbate certain
autoimmune diseases (Ref. 163) and has
resulted in the emergence of new autoimmunity
in up to 50% of treated patients with the
development of antinuclear antibodies and
even clinical SLE (Ref. 164). By contrast, TNF-a
is known to be pathogenic in mouse models of
in molecular medicine
nephritis and is produced by intrinsic renal
cells as a result of exposure to inflammatory
cytokines including IL-1 (Ref. 165). Based on
these findings, successful anecdotal use of
TNF-a blockade has been reported in a small
number of patients with refractory SLE nephritis
(Ref. 166). Not surprisingly, autoantibody titres
increased in the treated SLE patients, confirming
that some features of autoimmunity are
exacerbated by this approach. One hypothesis
for this effect is that TNF-a blockade increases
the load of apoptotic cells (Ref. 167). One group
found increased expression of TNFRII on CD4þ
CD25þ T regs of SLE patients. Signalling through
this receptor resulted in loss of suppressive
function of T regs that could be reversed by IL-2
supplementation (Ref. 168). Other hypotheses
include the induction of IFN-a following TNF
blockade and the requirement for TNF-a in
negative regulation of activated T and B cells.
Since TNF-a is made as a soluble and a
membrane protein and can bind to two different
receptors with different functions (Refs 169, 170,
171), there has been recent interest in selective
TNF-a blockade as a strategy for a safer and
more specific therapeutic response (Refs 163, 172).
Type I interferons
Type I IFNs made by plasmacytoid dendritic cells
are implicated in the pathogenesis of SLE
(Refs 173, 174). Their therapeutic use can
induce SLE-like syndromes, and peripheral
blood mononuclear cells from a subset of
patients with SLE display increased expression
of IFN-a-regulated genes (Refs 175, 176). IFN-a
promotes the differentiation of monocytes into
dendritic cells, induces differentiation of CD8þ
T cells and, together with IL-6, induces
differentiation of B cells into plasma cells.
However, the role of IFN-a in autoimmunity is
pleiotropic and absence of IFN-a or its receptor
has had opposite effects in different mouse
models of SLE (Ref. 177). The explanation for
this might lie in genetic differences and/or in
the different effects of IFN-a on resting and
activated dendritic cells. In vitro experiments
have shown that triggering of TLR9 in naive
peripheral blood mononuclear cell cultures
results in an IFN-a-dependent inhibition of
inflammatory Th1 cytokine secretion upon
subsequent activation (Ref. 178). For this
reason, type I IFN therapy has been used to
treat autoimmune diseases such as multiple
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sclerosis. However, if type I interferons are
administered to activated dendritic cells,
proinflammatory cytokines are generated
(Ref. 179). This suggests that the outcome of
treatment with IFN-a antagonists in patients
may be stage dependent and may not always be
predictable. In addition, the recent finding that
the interferon signature can be elicited in
human monocytes in the absence of IFN-a by
ligation of activating Fc receptors, together with
blockade of inhibitory Fc receptors, suggests
that there are multiple pathways for induction
of inflammation by immune complexes
(Ref. 180). Early clinical trials of anti-IFN
antibodies are in process and should more
definitively define the pathogenic role of this
group of cytokines in SLE.
IL-10
IL-10 is increased in patients with active SLE and
correlates with disease activity (Refs 181, 182).
Although IL-10 is classically considered an
anti-inflammatory cytokine, its role in SLE
appears to be an inflammatory one. In the
presence of IFN-g and immune complexes, there
is attenuation of the suppressive functions
of IL-10 mediated by a decrease in expression of
the IL-10 receptor and decreased activation of
JAK-1 (Ref. 183). In the presence of IFN-a there
is a gain of proinflammatory function of IL-10
leading to STAT-1-dependent expression of
genes that are normally induced by IFN-g.
In NZB/W mice, continuous administration of
IL-10 accelerated onset of renal disease and
treatment with an anti-IL-10 monoclonal
antibody delayed disease onset (Ref. 184). By
contrast, in NZM2410 mice, IL-10 was protective
when administered early in disease (Ref. 185).
Similarly, in MRL/lpr mice, IL-10 deficiency
resulted in a more severe disease (Ref. 186). The
differences between these models may be related
to the amount of concomitant inflammation at
the time of IL-10 administration or depletion. In
a pilot open-label short-term study of a mouse
anti-IL-10 monoclonal antibody in a small
number of active SLE patients, disease
improvement was evident at 2 months,
with continued responses over 3–6 months
(Ref. 187).
Interferon g
IFN-g accelerates disease in SLE-prone NZB/W
mice whereas treatment with anti-IFN-g is
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protective (Refs 188, 189). IFN-g – / – MRL/lpr
mice were also protected from early death
with a reduction in the severity of
glomerulonephritis. These studies highlight the
importance of IFN-g in accelerating SLE
development, presumably by increasing MHC
expression and autoantigen presentation to
otherwise quiescent nontolerant anti-self T cells,
and also by promoting local immune and
inflammatory processes (Ref. 190). By contrast,
results in STAT-4- and STAT-6-deficient SLEprone mice showed surprisingly that a decrease
in IFN-g and an increase in IL-4 accelerated SLE
nephritis even though autoantibody titres were
diminished (Ref. 191). This may be due to early
regulatory effects of IFN-g on the development
of Th17 effector cells. IL-17-secreting cells
appear to be critical effector cells in rheumatoid
arthritis and multiple sclerosis (Ref. 192), but
very little is known as yet about the role of this
cytokine in SLE.
The inflammatory process in SLE nephritis
Proliferative glomerulonephritis is the most
severe form of SLE nephritis and is
characterised by mesangial proliferation and
infiltration of the kidney parenchyma by
inflammatory cells. This process is initiated by
deposition of antibodies in the renal glomeruli
but it is increasingly recognised that this is not
sufficient for renal inflammation to occur. In
NZB/W SLE-prone mice deficient in activating
Fc receptors, autoantibody and complement
deposition in glomeruli do not result in renal
damage (Ref. 193). Subsequently it was shown
that the important Fc-receptor-bearing cells are
of haematopoietic origin and that circulating
monocytes bearing the activating receptors are
sufficient to restore disease (Ref. 194). In SLE
patients, polymorphisms of Fc receptors have
been associated with the susceptibility to renal
disease (Ref. 48). Other downstream effector
pathways including chemokines and cell death
molecules are also required to mediate kidney
damage. By contrast, in the MRL/lpr model,
interstitial inflammation can occur in the kidney
without immune-complex deposition and in the
absence of Fc receptors, perhaps indicating that
endothelial activation is sufficient to initiate
inflammatory cell migration into target organs
in this mouse (Refs 195, 196). A model for the
effector
pathways
involved
in
renal
inflammation is shown in Figure 3. Microarray
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analysis of human SLE biopsies has shown
considerable heterogeneity in gene expression
between patients. Infiltration by B cells and
myeloid cells was observed in some patients, as
was evidence of fibrosis. As observed in
peripheral blood specimens, some patients also
had a type I IFN signature in the kidney (Ref. 197).
Invasion of the glomerulus and the interstitium
by inflammatory cells involves different
Mechanism
1 Immune complex
deposition
IgG
chemokines and receptors. In particular, CCR2
and CCR5 mediate glomerular cell invasion
whereas CCR1 mediates interstitial invasion
(Refs 198, 199). Studies of chemokine expression
in the kidneys of NZB/W mice have shown that a
limited panel of chemokines is expressed in the
early stages of nephritis. The onset of proteinuria
coincides with expression of CCR2 and CCR5
ligands and with infiltration and activation of
Therapy
C3
Fc-receptor
Costimulatory blockade
TLR antagonists
Complement inhibitors
A
2 Endothelial activation
Upregulation of selectins
and integrins
B
MØ
3 Leukocyte adhesion
Inflammatory chemokines
Chemokine inhibitors
4 Local chemokine release
CCL2, CCL5,
CCL8, CCL20,
CXCL13, others
5 Chemokine-enhanced
cell infiltration
6 Inflammatory cytokines
7 Proaptotic factors
(e.g. TGF-β, TNF-α, NO)
Upregulation of
chemokine receptors
CTX/costimulatory blockade
B-cell depletion
T cell
B cell
Cytokine antagonists
Transmigration
Caspase inhibitors
INOS inhibitors
8 Irreversible renal death
The events that lead to renal failure in systemic lupus erythematosus
Expert Reviews in Molecular Medicine © 2008 Cambridge University Press
Targeting of the immune system in systemic lupus erythematosus
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Figure 3. The events that lead to renal failure in systemic lupus erythematosus. Disease is initiated by
deposition of immunoglobulin and complement on the glomerular basement membrane. This is followed by
an inflammatory cascade that involves engagement of activating Fc receptors by circulating monocytes,
endothelial activation, chemokine secretion, recruitment of activated lymphocytes and finally release of
proapoptotic factors that result in irreversible renal cell death. Potential therapies (shown in red) may target
this cascade in a stage-specific manner. Abbreviations: B, B cell; T, T cell; MØ, macrophage; NO, nitrous
oxide; TGF-b, transforming growth factor b; TNF-a, tumour necrosis factor a.
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interstitial macrophages that secrete IL-1 and other
inflammatory molecules. With progression of
disease, there is extensive spreading of the
inflammatory response to include multiple
chemokines and cytokines (Ref. 207). These data
suggest that it may be difficult to induce
remission of active nephritis with single
chemokine or cytokine inhibitors but that such
reagents may be useful once most activated cells
have been purged from the kidneys.
Furthermore, these studies predict stage-specific
therapies for SLE nephritis. For example, CCR2
and CCR5 blockade may be useful for treating
the early stages of glomerular disease whereas
IL-1 or TNF-a blockade may be useful for
antagonising the proinflammatory effects of
activated
infiltrating
macrophages.
Since
upregulation of CCR1 occurs only in mice with
established proteinuria, CCR1 blockade may be
effective for treatment of late- rather than earlystage disease. Consistent with this result, a CCR1
antagonist does not affect systemic immune
activation or glomerular damage in SLE-prone
Genetic
susceptibility
MRL/lpr mice but slows progression of
interstitial renal disease and fibrosis (Ref. 198).
As more is learned about the inflammatory
process in the SLE kidney, application of
therapies to prevent renal cell infiltration are
likely to be tested.
Clinical implications and research in
progress
Maintenance of immune homeostasis requires a
finely tuned immune system that needs the
flexibility to respond quickly to pathogens but
does not mount immune responses to selfantigens.
Both
immunodeficiency
and
exaggerated immune responses can predispose
to autoimmunity. In addition, cytokines and cell
receptors that are balanced to maintain
tolerance in the setting of a resting immune
system can mediate inflammatory responses
when the immune system is activated. Multiple
defects of immune tolerance can lead to SLE
and predisposing causes can include both
immunodeficiency in the resting immune
Trigger
Initiation
Progression
End organ damage
Goal
Prevention
Remission
Flare prevention
Re-establish tolerance
Supportive therapy
Target
Naive B cells
and T cells
Activated cells
Inflammatory
mediators
Memory cells
Plasma cells
Fibrosis
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Therapies for systemic lupus erythematosus depend on the stage of disease
Expert Reviews in Molecular Medicine © 2008 Cambridge University Press
Figure 4. Therapies for systemic lupus erythematosus depend on the stage of disease. The various stages
of SLE consisting of a pre-disease period followed by flares and remissions, are associated with differences
in the state of immune activation which may require different therapeutic approaches.
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Table 1. Common mouse models of systemic lupus erythematosus used for
therapeutic studies
Model
(Refs 200, 202)
Defect
Major disease
manifestations
Clinically relevant
autoantibodies
MRL/lpr male
and female
Susceptible genetic
background
Deficiency of Fas
Skin disease
Arthritis
Vasculitis
CNS disease
Nephritis
Anti-DNA
Anti-Sm
Rheumatoid factor
Antiphospholipid
NZB male and
female
Susceptible genetic
background
Haemolytic anaemia
Anti-RBC
ANAs
BXSB male
Susceptible genetic
background
Yaa gene results in TLR7/8
overexpression
Nephritis
Anti-DNA
Antiphospholipid
Anti-Sm/RNP
NZB/W female
Susceptible genetic
background
Nephritis
Anti-DNA
Antiphospholipid
NZW/BXSB
male
Susceptible genetic
background
Yaa gene results in TLR7/8
overexpression
Nephritis
Thrombocytopenia
Antiphospholipid
syndrome
Anti-DNA
Antiphospholipid
Antiplatelet
Anti-Sm/RNP
NZM2410 male
and female
Inbred from NZB/W
Nephritis
(glomerulosclerosis)
Antinucleosome
Anti-DNA
NZM2328
female
Inbred from NZB/W
Nephritis
Anti-DNA
Chronic GVHD
Induced by transplant of
MHC mismatched
lymphocytes
Nephritis
Anti-DNA
Abbreviations: ANAs, antinuclear antibodies; CNS, central nervous system; GVHD, graft-versus-host disease;
MHC, major histocompatability complex; TLR, Toll-like receptor; RBC, red blood cell; RNP, ribonucleoprotein;
Sm, Smith antigen.
system and excessive immune responses in the
activated immune system. For this reason,
restoration of immune homeostasis in SLE
patients poses many challenges. It is
increasingly recognised that therapies for active
disease, characterised by lymphoid cell
proliferation and production of multiple
inflammatory mediators, may need to be
different from therapies that prevent disease
flares or those that might eventually prevent
disease onset in genetically predisposed
individuals (Fig. 4). Despite these difficulties,
many new drugs are being developed for the
treatment of SLE and clinical trials are in
progress.
Preclinical testing of novel therapies in
murine models
As discussed above, immune activation pathways
involved in initiation of SLE may not always be the
same as those that are pathogenic during the
effector phase. Furthermore, inflammatory
environments can alter signalling cascades or
provide redundant survival signals. Because the
clinical effects of new therapeutics may not
always be predictable from in vitro studies or
studies in non-autoimmune mice, it is important
to test these drugs in preclinical models. Many
different mouse models of SLE now exist (Refs 3,
4, 5) and several of these have been extensively
characterised and used for therapeutic studies
Targeting of the immune system in systemic lupus erythematosus
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15
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& 2008 Cambridge University Press
expert reviews
in molecular medicine
Table 2. Therapeutic trials of novel agents for systemic lupus erythematosus
Drug
Mechanism
No. of
patients
Result
Status
Refs
Anti-CD40
ligand
Prevents
costimulation of
B cells and
dendritic cells
by activated
T cells
85
Phase II randomised and
placebo-controlled study of
IDEC-131 for active SLE;
improvements in disease
activity scores were not
achieved
Open-label study of
BG9588; not powered to
assess clinical efficacy but
clinical improvements were
reported
Clinical
trials
stopped
94
Clinical
trials
stopped
95
18
Abetimus
sodium
Unclear;
crosslinks Bcell receptors
and clears antiDNA antibodies
from the serum
213, 317
Two time-to-renal-flare
randomised and placebocontrolled studies; did not
meet primary endpoints;
decreased flares in a subset
of patients upon post-hoc
analysis
Further
Phase III
trials in
progress
142,
203
DNase
Decreases
antigenic load;
may alter
immune
complexes
17
Phase I study showed no
clinical effect
Not in
current use
204
Anti-CD22
(Eprutuzamab)
Modest naive Bcell depletion;
possible B-cell
antiproliferative
effect
14
Not powered to assess
clinical efficacy;
improvements in BILAG
scores reported
On hold
139
Anti-CD20
(Rituximab)
B-cell depletion
of multiple
subsets; spares
plasma cells
.100
Several uncontrolled case
series usually in
combination with other
agents; many reports of
clinical efficacy
Phase III
trial in
progress
126,
133,
205,
206
Anti-IL-10
Cytokine
antagonist
6
Open-label pilot study of a
murine antibody; not
powered to assess clinical
efficacy but sustained
clinical improvements were
reported
Phase I trial
in progress
187
Anti-TNF
(Infliximab)
Cytokine
antagonist
7
Case series reporting use of
infliximab in active SLE; not
powered to assess clinical
efficacy but clinical
improvements were
reported
Phase II
trial of
etanercept
in progress
167
Targeting of the immune system in systemic lupus erythematosus
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(continued on next page)
16
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& 2008 Cambridge University Press
expert reviews
in molecular medicine
Table 2. Therapeutic trials of novel agents for systemic lupus erythematosus
(continued)
Drug
Mechanism
No. of
patients
Result
Status
Refs
Anti-BLySa
(Belimumab)
Blocks B-cell
survival
molecule BLyS
(BAFF); B-cell
depletion;
spares plasma
cells
449
Randomised placebocontrolled trial for active
SLE; did not meet primary
endpoints at 24 weeks but
long-term follow up with
post-hoc analysis of
serologically active patients
showed significantly greater
improvement in treated
patients than placebo
Phase III
trials in
progress
117
a
Published in abstract form only but included here because it is a large Phase III study. Abbreviations: BAFF,
B-cell-activating factor belonging to the TNF family (also known as BLyS, B lymphocyte activator); BILAG, British
Isles lupus assessment; SLE, systemic lupus erythematosus; TNF, tumour necrosis factor.
(Ref. 200) (Table 1). Most have been used for studies
of prevention or treatment of SLE nephritis or of
the effects of treatment on autoantibody
production and immune cell activation. In
addition, the MRL/lpr mouse can be used for
study of vasculitis, arthritis and skin disease,
whereas the NZW/BXSB mouse can be used to
study the effects of therapy on antiphospholipid
syndrome (Ref. 201). It is important to recognise
that murine SLE models have a number of
limitations. First, mouse immune pathways are
not always the same as human pathways.
Second, not all clinical SLE manifestations are
present in each mouse strain. In particular, there
are no good mouse models for the treatment of
the central nervous system manifestations of
SLE. Third, responses to some therapies are
strain dependent and therapies that improve
disease in one model may worsen it in another.
In particular, a number of differences have been
observed in responses to therapy of MRL/lpr
mice and NZB/W mice. Fourth, most mouse
models do not undergo spontaneous disease
remissions, although it is now possible to study
disease relapses after remissions have been
induced with biological therapies. Nevertheless,
animal models allow analysis of basic immune
mechanisms of disease and therapy that are not
possible in human studies and can help direct
appropriate clinical use of new therapeutics.
Clinical trials in human SLE
New agents for which the results of clinical trials
have been published are shown in Table 2. Most
of these trials were Phase II studies and had
insufficient statistical power to assess clinical
efficacy. However, several large Phase III
studies are now in progress and results can be
expected in the next few years. The design of
SLE clinical trials will be of crucial importance
in determining optimal therapies for induction
of disease remission and for maintenance of
disease remission. Much thought is being given
to recruitment of patient populations, disease
activity
measurements,
disease
response
measurements, primary outcome measures and
mechanistic
analyses
of
immunological
responses in treated patients. Most clinical trials
now employ the BILAG, a scoring system that
measures the severity of disease in individual
organ systems. Some drugs are being tested in
remission induction studies whereas others are
being tested in ‘time-to-flare’ studies. The choice
of design will depend on the expected
mechanism of action of each drug. For example,
blockade of inflammatory cytokines or depletion
of whole cell populations would be expected to
induce remission of active disease whereas
therapies that prevent naive cell activation or
modulate B-cell selection would be expected to
have a preventive rather than a remission
Targeting of the immune system in systemic lupus erythematosus
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17
Accession information: doi:10.1017/S1462399408000562; Vol. 10; e2; January 2008
& 2008 Cambridge University Press
expert reviews
in molecular medicine
Plasmacytoid
DC
TLR
ODN
IFN-α
Immune
complexes
Lymphoid
organisation
Anti-IFN-α
ODN
ODN
Peptide-specific therapy
FcR
TLR
Cytokines
B cell
Anti-CD20/CD22
Migration to
target organs
ICOS
Anti-ICOSL
BAFF
APRIL
Antigen
presentation
CD40L/CD40
CD28/B7
TLR
Myeloid
DC
BAFF blockade
CD28/B7
CTLA4Ig/anti-CD40
CD40L/CD40
T cell
Interactions of the innate and acquired immune system amplify immune
responses in systemic lupus erythematosus
Expert Reviews in Molecular Medicine © 2008 Cambridge University Press
Figure 5. Interactions of the innate and acquired immune system amplify immune responses in systemic
lupus erythematosus. Therapeutic interventions for SLE (shown in red) target multiple arms of the immune
system (see Ref. 143 for review). Abbreviations: APRIL, A proliferation inducing ligand; BAFF, B-cellactivating factor belonging to the TNF family; DC, dendritic cell; ICOS, inducible costimulator; IFN-a,
interferon a; ODN, oligodeoxynucleotide; TLR, Toll-like receptor.
induction effect. Testing in preclinical models may
help direct trial design for each new agent.
The range of new drugs being developed
reflects the global nature of the immune defects
in SLE (Fig. 5). Approaches include measures to
decrease antigen load (DNase), measures to
dampen the innate immune system (ODN and
IFN-a blockade), drugs that antagonise
activation of the acquired immune system
(costimulatory blockade, modulation of BCR
signals), blockade of the soluble mediators
derived from the effector arm of the immune
response (cytokine antagonists), protection of
target organs from damage (chemokine
inhibitors, complement inhibitors) and even
depletion of whole cell populations (B-cell
depletion, stem cell transplant). In addition,
there are agents designed to specifically target
autoreactive B cells through induction of antiidiotypic antibodies. The scope of this article
does not allow discussion of all the new drugs
being developed, but for a comprehensive
review see Ref. 143. The challenge will now be
to determine at which stage of disease each
reagent is most likely to be effective and which
reagents will work together. Optimal therapy
will also require continued research that will
eventually
allow
identification
of
the
underlying immune defect in each patient. The
ultimate goal is to selectively correct deficits
that contribute to autoimmunity without
impacting protective immunity.
Acknowledgements and funding
Targeting of the immune system in systemic lupus erythematosus
http://www.expertreviews.org/
M.R. and A.D. are supported by grants from the
NY SLE Foundation, NY Arthritis Foundation,
Lupus Research Institute, Alliance for Lupus
Research and the NIH. M.R. is an Arthritis
Foundation Young Scholar. A.D. is a Kirkland
Lupus Scholar. We thank our panel of peer
reviewers for helpful suggestions in improving
this manuscript.
18
Accession information: doi:10.1017/S1462399408000562; Vol. 10; e2; January 2008
& 2008 Cambridge University Press
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Further reading, resources and contacts
Publications
Wiesendanger, M. et al. (2006) Novel therapeutics for systemic lupus erythematosus. Curr Opin Rheumatol 18,
227-235
This review paper provides a comprehensive summary of new therapeutics being developed for SLE and the
rationale for their use.
Furie, R. (2006) Abetimus sodium (riquent) for the prevention of nephritic flares in patients with systemic lupus
erythematosus. Rheum Dis Clin North Am 32, 149-156
This paper provides a balanced overview of the entire clinical experience with the DNA analogue abetimus
sodium for the treatment of SLE.
Fairhurst, A.M., Wandstrat, A.E. and Wakeland, E.K. (2006) Systemic lupus erythematosus: multiple
immunological phenotypes in a complex genetic disease. Adv Immunol 92, 1-69
A comprehensive review of the genetics of SLE.
Davidson, A. and Aranow, C. (2006) Pathogenesis and treatment of systemic lupus erythematosus nephritis.
Curr Opin Rheumatol 18, 468-475
An up-to-date review of pathogenesis and current therapeutic approaches for SLE nephritis.
Websites
A list of current clinical trials in SLE can be found at:
http://www.clinicaltrials.gov/ct/search;
jsessionid¼7FB635BE3203D66B6A49A25BD493C13B?term ¼SLE
The official site of the Lupus Research Institute and the NY Lupus Foundation:
http://www.lupusny.org/
An NIH summary statement on SLE can be found at:
http://www.niams.nih.gov/hi/topics/lupus/slehandout/index.htm
Features associated with this article
Figures
Figure 1. The innate immune system in systemic lupus erythematosus.
Figure 2. Members of the CD28 –B7 family mediate both costimulation and coinhibition.
Figure 3. The events that lead to renal failure in systemic lupus erythematosus.
Figure 4. Therapies for systemic lupus erythematosus depend on the stage of disease.
Figure 5. Interactions of the innate and acquired immune system amplify immune responses in systemic lupus
erythematosus.
Tables
Table 1. Common mouse models of systemic lupus erythematosus used for therapeutic studies.
Table 2. Therapeutic trials of novel agents for systemic lupus erythematosus.
Targeting of the immune system in systemic lupus erythematosus
http://www.expertreviews.org/
Citation details for this article
Meera Ramanujam and Anne Davidson (2008) Targeting of the immune system in systemic
lupus erythematosus. Expert Rev. Mol. Med. Vol. 10, e2, January 2008, doi:10.1017/S1462399408000562
27
Accession information: doi:10.1017/S1462399408000562; Vol. 10; e2; January 2008
& 2008 Cambridge University Press