Available online at www.sciencedirect.com
`
`Cytokine & Growth Factor Reviews 19 (2008) 41–52
`
`www.elsevier.com/locate/cytogfr
`
`Dendritic cells and cytokines in human inflammatory and
`autoimmune diseases
`
`Patrick Blanco a,b,c,*, A. Karolina Palucka d, Virginia Pascual d, Jacques Banchereau d
`a CHU Bordeaux, 33076 Bordeaux, France
`b CNRS-UMR 5164, 33076 Bordeaux, France
`c Universite´ Bordeaux 2, 33076 Bordeaux, France
`d Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, TX, USA
`
`Abstract
`
`Dendritic cells (DCs) produce cytokines and are susceptible to cytokine-mediated activation. Thus, interaction of resting immature DCs
`with TLR ligands, for example nucleic acids, or with microbes leads to a cascade of pro-inflammatory cytokines and skewing of T cell
`responses. Conversely, several cytokines are able to trigger DC activation (maturation) via autocrine, for example TNF and plasmacytoid DCs,
`and paracrine, for example type I IFN and myeloid DCs, pathways. By controlling DC activation, cytokines regulate immune homeostasis and
`the balance between tolerance and immunity. The increased production and/or bioavailability of cytokines and associated alterations in DC
`homeostasis have been implicated in various human inflammatory and autoimmune diseases. Targeting these cytokines with biological agents
`as already is the case with TNF and IL-1 represents a success of immunology and the coming years will expand the range of cytokines as
`therapeutic targets in autoinflammatory and autoimmune pathology.
`# 2007 Elsevier Ltd. All rights reserved.
`
`Keywords: Dendritic cells; IL-1; IL-12; IL-23; TNF-a; IFN-a
`
`1. Introduction
`
`The immune system is composed of a non-antigen-specific
`innate limb and an antigen-specific adaptive limb [1]. Innate
`immunity, borne by cells such as granulocytes and macro-
`phages and proteins such as complement and cytokines,
`includes a variety of prompt reactions in response to infectious
`agents and other challenges. An excessive response results in
`inflammatory processes. The adaptive immunity, borne by
`lymphocytes,
`is acquired in weeks or months.
`It
`is
`characterized by an exquisite specificity for the eliciting
`antigen as well as memory, which allows a faster and stronger
`response upon re-exposure to the antigen. Adaptive responses
`can be immunogenic, leading to resistance to infections and
`possibly cancer, or tolerogenic avoiding response against self.
`
`* Corresponding author. Tel.: +33 5 57 57 14 70; fax: +33 5 57 57 14 72.
`E-mail addresses: patrick.blanco@chu-bordeaux.fr (P. Blanco),
`Virginip@Baylorhealth.edu (V. Pascual).
`
`1359-6101/$ – see front matter # 2007 Elsevier Ltd. All rights reserved.
`doi:10.1016/j.cytogfr.2007.10.004
`
`Indeed, to efficiently protect us from invading microorgan-
`isms, the adaptive immune system must distinguish self from
`non-self as immune responses against self can create a wide
`repertoire of autoimmune diseases. Anti-self
`immune
`responses are prevented through a variety of mechanisms
`occurring at various levels during the development of the
`immune system [2]. Autoreactive lymphocytes can be
`deleted, rendered anergic or rendered suppressive [3–5].
`Suppressor T cells, also called regulatory T cells, suppress
`autoreactive responses both in an antigen-specific and a non-
`antigen-specific fashion. These immunological events happen
`either in the primary lymphoid organs (bone marrow and
`thymus) and are thus collectively called ‘‘central tolerance’’
`or in the periphery and are then called ‘‘peripheral tolerance’’.
`Clinical autoimmunity arises as a result of an altered balance
`between the autoreactive cells and the regulatory mechanisms
`designed to counterbalance them.
`DCs are specialized to capture and process antigens to
`present their peptides to lymphocytes. They are found in all
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`tissues including blood and lymphoid organs [6–12]. In
`peripheral tissues, DCs are found in an immature stage
`specialized in the capture of antigens. In response to
`microbes, DCs undergo a complex process of maturation
`into antigen-presenting cells. This happens while the DCs
`migrate from the periphery into the draining lymph node
`through the lymphatics. In the steady state, DCs also migrate
`at a low rate without undergoing activation. Then they
`present self-antigens to lymphocytes in the absence of
`costimulation thereby leading to peripheral
`tolerance.
`Various mouse models have demonstrated that DCs bearing
`self-antigens are able to induce autoimmune diseases [13–
`15]. Furthermore alterations of DC homeostasis have been
`directly implicated in various human autoimmune diseases
`including type I diabetes, multiple sclerosis, and systemic
`lupus erythematosus (SLE) [16,17].
`Here we review our current understanding of dendritic
`cell function in tolerance and how cytokines interfere with
`these processes to generate autoimmunity.
`
`2. Dendritic cells
`
`2.1. Dendritic cell maturation
`
`Dendritic cells (DCs) are a heterogeneous family of cells
`of haematopoietic origin that are specialized in the handling
`of antigens, i.e. those from infectious agents and self, and
`their presentation to lymphocytes. Though most of the
`current knowledge relates to the presentation of peptides to
`T cells in the context of MHC classes I and II molecules,
`DCs can present glycolipids and glycopeptides to T cells and
`NKT cells as well as polypeptides to B cells. DCs undergo a
`complex maturation process from antigen-capturing cells
`into antigen-presenting cells. Numerous agents activate DCs
`including: microbes, dying cells, cells of the innate immune
`system and cells of the adaptive immune system. pathogen-
`associated molecular patterns (PAMPs) from microbes [18]
`signal DCs and other cell types through a variety of pattern-
`recognition receptors (PRR) including toll-like receptors
`(TLRs) [19,20]; cell surface C-type lectins receptors (CLRs)
`[21,22] and intracytoplasmic NOD-like receptors (NLRs)
`[23,24]. TLRs have been given the most attention until now
`and appear to be particularly important in the context of
`autoimmunity and most specifically SLE. Distinct DC
`subsets display different TLRs as will be discussed
`hereunder. Lysates of dying cells induce the maturation of
`DCs [25], and some components involved in dying cells
`enhance antigen presentation by DCs leading to T cell
`immunity [25,26]. These endogenous activating molecules
`are collectively called damage-associated molecular pattern
`molecules (DAMPs) [27]. They include heat shock proteins
`(HSPs) [28], high mobility group box 1 protein (HMGB1)
`[29], b-defensin [30] and uric acid [31].
`DCs can secrete a diversified panel of chemokines that
`attract different cell types at different times of the immune
`
`response [32]. They also express a unique set of
`costimulatory molecules which permit the activation of
`naı¨ve T cells and thus allow the launching of primary
`immune response. Through the cytokines they secrete, e.g.:
`IL-12, IL-23 or IL-10 as well as the surface molecules they
`express, e.g.: OX40-L [33] or ICOS-l [34] DCs can polarize
`naı¨ve T cells into Th1, Th2, Treg or Th17.
`
`2.2. Dendritic cell subsets
`
`There are two main pathways of DC ontogeny from
`hematopoietic progenitor cells
`(HPCs). One pathway
`generates myeloid DCs (mDCs); while another generates
`plasmacytoid DCs (pDCs), a subset capable of secreting
`large amounts of type I IFN in response to viral stimulation
`[35,36] (Fig. 1). At least six DC subsets have been described
`in mouse spleen and lymph nodes, including conventional
`DCs (formerly designated myeloid DCs and lymphoid DCs)
`and plasmacytoid DCs [11,37]. They are distinguished
`according to surface markers such as CD11b, CD8a and
`CD11c, as well as by their functions [38–40]. Myeloid DCs
`are found in three compartments: (1) peripheral tissue, (2)
`secondary lymphoid organ and (3) blood. In the skin, two
`distinct types of mDCs are found in two distinct layers.
`Langerhans cells (LCs), which express CD1a and Langerin
`reside in the epidermis, while interstitial DCs (intDCs),
`which express DC-SIGN and CD14 reside in the dermis
`[41]. Plasmacytoid DCs, circulating in the blood and
`secondary lymphoid organs by crossing high endothelial
`venules, express BDCA2, ILT-7 and CD123, and secrete
`large amounts of type I interferons (IFNs) in response to
`viruses and/or TLR7–9 ligands [9]. Blood plasmacytoid DCs
`express TLR1, 6, 7, 9 and 10, but nor TLR4, while blood
`myeloid DCs express TLR1, 2, 3, 4, 5, 6, 7, 8 and 10, but not
`TLR9 [42,43]. Epidermal Langerhans cells isolated from
`skin lack the expression of TLR4 and TLR5, while dermal
`interstitial DCs express many TLRs including TLR2, 4 and 5
`[44]. In the human, CLRs permit to distinguish DC subsets
`with BDCA2 specifically expressed on plasmacytoid DCs
`[45], Langerin expressed on Langerhans cells [46], and DC-
`SIGN expressed on interstitial DCs [47]. Many other C-type
`lectins are more promiscuous, and are, as is the case with
`TLRs, expressed on various cell types including endothelial
`cells and neutrophils. C-type lectins expressed on DCs act as
`anchors for a large number of microbes including viruses,
`bacteria, parasites and fungi, and allow their internalization,
`but they also act as adhesion molecules between DCs and
`other cell types including endothelial cells, T cells and
`neutrophils. Abnormalities in dendritic cell homeostasis
`have been implicated in various human diseases, including
`cancer, autoimmune diseases, allergy and infections.
`
`2.3. Dendritic cells and immune tolerance
`
`Central tolerance, induced in the thymus or bone marrow,
`plays a pivotal role in the prevention of undesired attacks
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`Fig. 1. Dendritic cells are composed of subsets. DC progenitors originate from bone marrow CD34+FLT3+ hematopoietic progenitor cells (HPCs). A myeloid
`pathway generates both Langerhans cells (LCs), found in stratified epithelia such as the skin, and interstitial (int)DCs, found in all other tissues. It also generates
`mDCs circulating in the blood. Upon inflammation monocytes can yield mDCs. Another pathway generates plasmacytoid DCs (pDCs), which secrete large
`amounts of IFN-a/b after viral infection. Activated (mature) mDCs and pDCs traffic to secondary lymphoid organs either via afferent lymphatics (mDCs) or
`blood (pDCs). Langerhans DCs home to cell zones while interstitial DCs home to follicles consistent with their functional specialization, i.e. generation of
`cellular (Langerhans DCs) and humoral (interstitial DCs) immunity, respectively. The origin of resident lymph node DCs remains to be determined.
`
`against self. Anti-self immune responses are prevented
`through a variety of mechanisms occurring at various levels
`of
`the immune system development
`[2]. Autoreactive
`lymphocytes can be either deleted, or rendered anergic or
`rendered suppressive [3–5]. Suppressor T cells also called
`regulatory T cells are also generated which suppress
`autoreactive responses both in an antigen-specific fashion
`and a non-antigen-specific fashion. Many peripheral auto-
`antigens through their expression in thymic medullary
`epithelial cells (a process regulated by the autoimmune
`regulator AIRE) are known to be responsible for the so-called
`negative selection [48]. Moreover, cytokines like thymic
`stromal lymphopoietin (TSLP) produced by epithelial cells of
`thymic Hassall’s corpuscles promote the conversion of
`CD4+CD25-thymocytes into CD4+CD25+Foxp3+ T regula-
`tory cells (Tregs) [49]. Dendritic cells in the thymus are also
`involved in the process of central tolerance [50].
`It is clear, however, that negative selection in the thymus
`does not eliminate all autoreactive cells. Thus, tolerance
`induced in the periphery becomes a very important
`mechanism to maintain control of emerging autoreactivity.
`The mechanisms involved in peripheral tolerance are not
`entirely understood, but there is evidence that ‘‘resting’’
`immature DCs that capture self-antigens in the steady state
`play an important role in this process. Indeed, under these
`conditions, DCs capture apoptotic bodies and/or cellular
`debris arising from normal cell turnover, migrate to draining
`lymph nodes and silence T cells reacting to these antigens
`[51]. The myeloid DC subset appears to be the most potent
`cell able to capture self-apoptotic bodies.
`
`This phenomenon needs to be tightly regulated, as an
`unusual
`load of apoptotic bodies can induce systemic
`autoimmune disease [52]. Indeed, dead cells may also
`contribute to DC maturation, as it has been shown for
`necrotic or late apoptotic cells, but no early apoptotic cells.
`As discussed above, endogenous activating molecules are
`collectively called damage-associated molecular pattern
`molecules [27]. There is evidence that plasmacytoid DCs in
`their resting state are involved in tolerance induction [53–
`55]. pDCs stimulated via CD40 induce IL-10-secreting
`regulatory CD4+ T cells [34] as well as suppressor CD8+ T
`cells [56].
`Recently, the concept that ‘‘immature DCs are tolero-
`genic whereas mature DCs are immunogenic’’ has been
`challenged by several studies showing that fully mature DCs
`can induce tolerance and differentiation of regulatory T cells
`[57–59]. In fact, the integration of different signals by the
`DCs,
`including Ag dose, cytokine milieu at sites of
`inflammation, encountered pathogen etc., will determine
`whether DCs will become tolerogenic vs. immunogenic.
`Possibly, peripheral tolerance is actively maintained by
`‘‘tolerogenic’’ DCs [60]. In addition to deleting T cells,
`tolerogenic DCs induce the differentiation and proliferation
`of T cells with regulatory/suppressor functions [3,61]. Some
`pathogens have a capacity to actively render DCs
`tolerogenic [62]. Although the specific markers of tolero-
`genic DCs are yet to be determined, expression of inhibitory
`immunoglobulin like transcript (ILT) receptors might be
`their feature [63]. In vitro-generated DCs exposed to IL-10
`express ILT-3, which is associated with their tolerogenic
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`functions [64]. Studies in mice suggest that DCs might be
`used in the treatment of autoimmunity through their ability
`to induce regulatory T cells. Thus, repetitive injections of
`‘‘semi-mature’’ DCs induce antigen-specific protection of
`mice from experimental autoimmune encephalomyelitis and
`thyroiditis [57,58]. In NOD mice which spontaneously
`develop diabetes, DCs can induce the generation of Tregs in
`vitro which provide a therapeutic benefit even after onset of
`disease [59]. Indeed, Tregs appear to suppress DCs that
`induce autoimmunity by presenting autoantigens [59,65]. In
`keeping with this, animals which are depleted of Tregs show
`autoimmunity that is associated to expansion of activated
`DCs [66,67]. While immunogenic DCs have been used in
`clinical trials to treat mainly patients with cancer, under-
`standing the mechanisms underlying the tolerogenic
`functions of DCs, such as those generated with IL-10
`[68,69] or those infected with RSV [70], opens new avenues
`for the treatment of autoimmunity or the induction of
`specific tolerance in organ transplants.
`Cytokines secreted to induce a specific immune response
`against an invading pathogen might
`interfere with DC
`homeostasis and induce an autoimmune response that can be
`responsible for
`tissue pathology.
`Indeed, clinical and
`epidemiological studies have suggested a link between
`infectious agents and chronic inflammatory disorders,
`including autoimmune diseases [71].
`
`3. Cytokines, inflammation and autoimmunity
`
`Cytokines represent critical mediators of the autoimmune
`process. They may represent products of DCs and/or induce
`the differentiation of immature DCs into mature DCs that
`can select autoreactive lymphocytes (Fig. 2).
`
`Fig. 2. Cytokines and dendritic cell activation. DCs both produce cytokines
`and are susceptible to cytokine-mediated activation. Thus, exposure to DC
`activators, for example TLR ligands or microbes, triggers secretion of pro-
`inflammatory cytokines including type I interferons (IFN), acute phase
`cytokines such as TNF and IL-6, IL-1 as well as IL-12 family (left panel).
`Several cytokines are able to trigger DCs activation (maturation) either in
`autocrine or paracrine fashion including IL-1, TNF, type I IFNs and TSLP
`(right panel).
`
`3.1. IL-1 and its family
`
`The IL-1 family plays an important role in inflammation
`and host defense. Up to 11 members of this family have been
`identified to date [72,73]. Of those, only five have been
`thoroughly studied: IL-1a, IL-1b, IL-18, IL-1RA and the
`recently reported IL-33. The remaining six (IL-1F5; IL-1F6;
`IL-1F7; IL-1F8; IL-1F9; IL-1F10) have been shown to be
`expressed in various cell types or tissues but their functions
`remain to be determined.
`IL-1a and IL-1b are pro-inflammatory cytokines. Both
`are synthesized as precursor molecules (pro-IL-1a and pro-
`IL-1b) by many different cell
`types. Pro-IL-1a is
`biologically active and needs to be cleaved by calpain to
`generate the smaller mature protein. By contrast, pro-IL-1b
`is biologically inactive and requires enzymatic cleavage by
`caspase-1 in order to become active. IL-1a is primarily
`bound to the membrane whereas IL-1b is secreted and thus
`represents the predominant extracellular
`form of
`IL-1
`(reviewed in Ref. [74,75]). IL-33 is a new member of the
`IL-1 family that is produced as a propeptide requiring
`cleavage by caspase-1. It binds to IL-1R4 (ST2) and
`stimulates T helper 2 (Th2) responses [73]. IL-1 is an
`activator of DCs, though it is not yet clear whether such IL-
`1-activated DCs display unique biological functions [73].
`Interleukin-1 is involved in the pathogenesis of numerous
`diseases with an inflammatory component [76]. This is best
`demonstrated by the therapeutic benefits of treatment of
`patients with IL-1 antagonists such as IL-1-RA. These
`diseases include Systemic onset Juvenile Idiopathic Arthritis
`(SoJIA) [77], which represents up to 20% of chronic
`inflammatory arthritis in childhood. IL-1RA has also shown
`therapeutic efficacy in gout [78], type II diabetes [79] as well
`as a series of hereditary diseases causing periodic
`inflammatory symptoms and grouped under
`the term
`‘‘familial autoinflammatory syndromes’’
`[80]. Whether
`the beneficial effects are due to the inhibition of DC
`activation is not demonstrated.
`
`3.2. IL-6 and its family
`
`The IL-6 family is composed of IL-6, IL-11, leukaemia
`inhibitory factor
`(LIF), oncostatin M (OSM), ciliary
`neurotrophic factor (CNTF), cardiotrophin-1 (CT-1) and
`cardiotrophin-like cytokine (CLC). Members of this family
`display pro- but also anti-inflammatory effects and play a
`central role in hemopoiesis as well as in innate and adaptive
`immune responses.
`Activation of IL-6 signalling is mediated through the IL-
`6/sIL-6R complex, a process known as ‘‘trans-signaliza-
`tion’’ and a unique example of a soluble cytokine receptor
`displaying agonistic effects. IL-6 is secreted by many cell
`types,
`including B and T lymphocytes, monocytes,
`fibroblasts, keratinocytes, endothelial cells, mesenchymal
`cells and certain types of tumor cells. IL-6 induces the
`differentiation of B lymphocytes into plasma cells as well as
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`the proliferation of T lymphocytes, differentiation of
`cytotoxic T cells and IL-2 production. IL-6 also induces
`the differentiation of macrophages and megakaryocytes [81].
`Recently, IL-6 has been described to participate in the
`differentiation of a novel T cell subset, Th17, which displays
`pro-inflammatory functions [82,83]. IL-23 is responsible for
`the expansion of Th17 previously differentiated, while IL-6
`and TGF-b are responsible for the differentiation of Th17
`from their naı¨ve precursors. TGF-b induces Foxp3 which
`leads to the formation of Tregs, while IL-6 inhibits Foxp3
`expression induced by TGF-b, and favors the formation of
`Th17 together with TGF-b [84–86].
`IL-6 is likely to be involved in the pathogenesis of
`inflammatory and autoimmune diseases.
`It plays an
`important role in bone biology by inducing the differentia-
`tion and activation of osteoclasts and it mediates periarti-
`cular destruction of bone and cartilage in experimental
`models of arthritis [87]. IL-6 levels are increased in the
`serum of children with Systemic onset Juvenile Arthritis in a
`disease activity-dependent manner [88], and blocking its
`receptor is emerging as an effective therapy both in SoJIA
`[89] as well as in adult RA [90].
`
`3.3. IL-12 and its family
`
`IL-12, a heterodimeric cytokine produced mainly by
`activated myeloid DCs, plays a pivotal
`role in the
`differentiation and expansion of Th1 cells [91–95]. The
`recent discovery of IL-23 has led to a re-evaluation of
`interleukin-12 biology, as they share a common p40 subunit.
`In animal models, predisposition to autoimmunity can be
`explained by abnormal levels of IL-12 secreted by APCs
`[96]. Furthermore, IL-12 administration has been shown to
`switch tolerance mediated by intravenous or orally
`administered antigens into immunity [97]. In addition
`blocking IL-12 in patients with active Crohn’s disease using
`a specific antibody can induce stable remission [98].
`IL-23 is a cytokine that drives autoimmune diseases,
`including psoriasis and inflammatory bowel diseases
`[99,100]. IL-23 is secreted by human DCs exposed to
`gram-negative bacteria [101]. As mentioned above, IL-23
`promotes the development and expansion of activated CD4+
`T cells that produce IL-17, IL-17F, IL-6 and TNF and are
`called Th17. Their differentiation is inhibited by IFN-
`gamma, IL-4 and IL-2 [102]. Genetic analysis of these Th17
`cells
`identified a unique expression pattern of pro-
`inflammatory cytokines and revealed a unique role in
`different mouse models of autoimmune inflammation [103].
`Given that the levels of IL-23 p19 and IL-17 are elevated in
`human diseases including multiple sclerosis, psoriasis and
`Crohn’s disease, it is possible that these cytokines mediate
`human diseases [104–106]. Indeed, the therapeutic efficacy
`of an IL-12/23 p40 monoclonal antibody in psoriasis has
`recently been established [107]. The Th17 pathway has also
`been implicated in multiple sclerosis (MS) [108]. DCs, i.e.
`monocyte-derived DCs from MS patients, secrete more IL-
`
`23 but equivalent amounts of IL-12 compared to healthy
`controls [104]. Patients with MS also appear to have
`increased numbers of IL-17-expressing cells [109]. Finally,
`a subset of infiltrating T cells express IL-17 in RA synovium
`[110].
`The implication of IL-27 in autoimmunity is less clear as
`this cytokine can have pro- and anti-inflammatory properties
`[111,112].
`
`3.4. TNF-a
`
`TNF-a was among the first cytokines whose dysregula-
`tion was proposed to contribute to the pathogenesis of
`various autoimmune disorders. More importantly, TNF
`blockers have been extensively used and validated as an
`efficacious treatment for RA, Crohn’s disease and psoriasis
`[113,114]. This clearly represents one of the greatest
`successes of immunology though the mechanisms of action
`remain unclear. Inasmuch as TNF induces many cell types,
`including DCs, to secrete pro-inflammatory cytokines, it is
`likely that TNF blocking results in their decreased secretion.
`Alternatively, anti-TNF-a therapy might generate a newly
`differentiated population of Treg cells distinct from natural
`Tregs, which seem to be defective in RA patients [115].
`However, TNF antagonists are not without adverse
`effects, including reactivation of tuberculosis and induction
`of reversible systemic autoimmunity like SLE. In fact TNF
`blockers enhance the production of type I IFNs by pDCs
`exposed to viruses whereas TNF inhibits it. Type I IFNs, as
`described below, have been implicated as
`important
`mediators of autoimmune diseases in humans. Interestingly,
`transcription of type I IFN-inducible genes is observed in
`juvenile arthritis patients treated with TNF blockers. These
`data suggests that TNF represent an endogenous mechanism
`to control IFN production by pDCs [116]. Indeed, TNF
`produced by pDCs in response to viral activation acts as an
`autocrine maturation factor for these cells. Once they
`mature, pDCs are unable to secrete type I IFNs. It is
`therefore conceivable that blocking TNF would keep pDCs
`at an immature stage where they can continue to produce
`type I IFNs. Thus, based on these observations, immunity
`can be viewed as a dynamic system driven by opposite
`vectors, i.e. TNF-type I IFNs. The sum of the vectors yields
`an equilibrium point which allows protective immunity
`when vectors are equal. This dynamic system can
`accommodate the prevalence of either vector to a certain
`extent. However, when one of the vectors prevails beyond a
`certain threshold, the equilibrium point moves into a zone of
`immunopathology, including arthritis when the TNF vector
`prevails and SLE and others when type I IFN production
`prevails (Fig. 3) [16].
`
`3.5. Type I interferons (IFNs)
`
`IFNs (IFN-a/b), major controllers of viral
`Type I
`infections, play a role in several human autoimmune
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`found between the lupus nephritis activity score and the
`number of periglomerular infiltrating CD8+ T lymphocytes.
`No correlation was found, however, with the chronicity
`score. In a similar way, autoreactive CD8+ T lymphocytes
`directed against myelin epitopes are expanded in patients
`with CNS lupus involvement. None of those autoreactive
`cells were found in a control population without neurologic
`involvement or in SLE patients in whom thrombosis was
`responsible for the neurologic symptoms. IFN also appears
`to be associated to other autoimmune diseases including
`myositis [124,125], Sjogren’s syndrome [126,127] and the
`initial phase of psoriasis [128].
`
`3.5.2. IFN-a and B cell activation
`The key role of B lymphocytes in SLE has been known
`for a long time and it has recently been reinforced by the
`observation that
`treatment of patients with the B cell
`depleting CD20 antibody leads to disease improvement
`[129]. Through their direct effect on B cells, type I IFNs
`enhance primary antibody responses to soluble proteins and
`induce the production of all subclasses of IgG in mice [130].
`IFN-a up-regulates CD38, a germinal center B cell and
`plasma cell marker, on B lymphocytes and BAFF (B cell
`activating factor) on monocytes and mDCs. BAFF in turn
`contributes to the survival of autoreactive B lymphocytes
`[131]. In addition, IFN-a promotes the differentiation of
`activated B lymphocytes into plasmablasts. pDCs activated
`with viruses secrete IFN-a and IL-6, which permits
`plasmablasts to become antibody-secreting plasma cells
`[132]. The same effect is observed when pDCs are activated
`with SLE immune complexes containing nucleic acids that
`bind TLRs [133,134]. This could contribute to amplify the
`production of type I IFNs and subsequently the differentia-
`tion of autoreactive plasma cells that would further secrete
`autoantibodies, thus perpetuating this pathogenic loop.
`
`4. Toll-like receptor (TLR) ligands and
`autoimmunity
`
`Infections frequently precede the occurrence of either
`organ-specific or systemic autoimmune diseases. Molecular
`mimicry, however, cannot account for all the autoimmune
`responses that have been linked to infectious diseases. TLRs
`are key components of the innate immune system. These
`receptors activate multiple pathways of inflammation that
`eventually permit to eradicate invading pathogens [135].
`Microbial-derived TLR ligands include a wide range of
`molecules with strong adjuvant activity that can activate
`DCs, macrophages and other APCs [136]. TLRs are
`involved in the pathogenesis of autoimmune disorders
`[14], and endogenous ligands also activate these receptors
`[137–139]. Exposure to TLR3 or TLR7 ligands is required,
`for example, to induce autoimmune diabetes in transgenic
`mice that harbour large numbers of pancreatic islet-reactive
`cytotoxic T cells.
`In this model, TLR-induced local
`
`Fig. 3. Cross-regulation of TNF and IFN-a in autoimmune diseases. TNF
`and IFN-a represent opposite vectors (paths) of immune responses. The sum
`of the vectors yields an equilibrium point, which allows protective immunity
`when vectors are equal. When one of the vectors prevails beyond a certain
`threshold, the equilibrium point moves into a zone of autoimmunity: an
`excess of IFN-a/b is pathogenic in SLE, Sjogren’s, dermatomyositis and
`early stages of psoriasis while excess of TNF is pathogenic in rheumatoid
`arthritis, inflammatory bowel disease (IBD), Crohn’s disease and psoriasis.
`
`diseases, most particularly SLE. Indeed, SLE is the first
`autoimmune disorder where alterations in the type I IFN
`system were reported. In 1979, Notkins and colleagues
`described the presence of IFN activity in the serum of
`patients with SLE [117]. More importantly, induction of
`autoimmunity, including appearance of anti-nuclear anti-
`bodies and occasionally clinical symptoms of SLE, were
`reported during repeated administration of recombinant
`IFN-a to patients with various malignancies or chronic viral
`infection [118]. Recent studies have identified an ‘‘IFN
`signature’’ in the majority of patients with active SLE [119-
`121]. IFN-a in SLE patients is mainly secreted by pDCs and
`understanding what drives its unabated secretion in SLE
`patients remains an area of intense investigation. Type I IFNs
`can contribute to the breaking of tolerance through different
`mechanisms including direct effect on APCs, T cells and B
`cells.
`
`3.5.1. IFN-a and DC alteration
`We have shown that SLE blood constitutes a DC-
`inducing environment, as it promotes the differentiation of
`healthy monocytes into mDCs. The DC-inducing property
`of SLE sera is mainly mediated through IFN-a [122].
`Indeed, blood SLE monocytes display DC-like functions as
`they capture antigens and autoantigens and present them to
`CD4+ and CD8+ T cells. Thus, type I IFN-induced unabated
`DC activation could promote the expansion of autoreactive
`T cells. SLE DCs are characterized by their unique in vitro
`ability to promote the differentiation of CD8+ T lympho-
`cytes in CTLs able to generate nucleosomes and granzyme
`B-dependent autoantigens. Interestingly, terminally differ-
`entiated effector CD8+ T lymphocytes (CCR7, CD45RA+)
`are expanded in the blood of SLE patients and this expansion
`correlates with disease activity as assessed by the SLE
`Disease Activity Index (SLEDAI) [123]. These cells can
`induce direct tissue damage as they represent the main cell
`subset infiltrating the kidney in lupus nephritis, where they
`adopt a periglomerular localization. A direct correlation is
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`production of IFN-a triggers the recruitment of autoreactive T
`cells into the pancreatic islets [140]. TLR3 and TLR9 ligation
`are also key events in the development of autoimmune
`myocarditis by inducing the maturation of DCs pulsed with
`heart-specific self-peptide [14]. In humans, TLR activation
`has been reported as a pathogenic event mainly in the context
`of systemic autoimmune diseases such as SLE. Early studies
`demonstrated that immune complexes were potent stimuli for
`IFN-a secretion by pDCs in an Fc receptor (CD32)-dependent
`manner [141,142]. Indeed, chromatin and/or ribonucleopro-
`tein-containing immune complexes are internalized by pDCs
`via FcgRIIa, reach the endosomal compartment and activate
`IFN-a secretion through TLR9 and/or 7-dependent pathways
`[143,144]. Sera from SLE patients can also induce IFN-a
`secretion in a TLR7/8-dependent manner [133]. Accordingly,
`there is a correlation between the presence of an IFN gene
`signature in blood leukocytes and the detection of auto-
`antibodies directed against ribonucleoproteins in the sera of
`SLE patients [145]. Since INF-a induces the transcription of
`TLR7 itself, a self-amplifying loop could take place at this
`stage as well, thus explaining the above-described correlation.
`The contribution of
`immune complexes and TLR
`signalling to the generation of autoantibodies characteristic
`of SLE has been the purpose of several studies in murine SLE
`models. Chromatin-containing IC activate transgenic auto-
`reactive B cells via sequential engagement of the B cell
`antigen receptor (BCR) and TLR9. In vivo, TLR9 contributes
`to the development of anti-dsDNA antibodies, as lupus-prone
`(Fas-deficient) mice that lack TLR9 on the mixed MRL-B6-
`129 background fail to generate these antibodies [146].
`
`Unexpectedly, in another mouse model (MRL/lpr), TLR9
`deficiency leads to an increased production of autoantibodies
`and a more severe lupus-like disease [147]. Thus, depending
`on the genetic background, TLR9 seems to deliver a
`