The role of dendritic cells in the pathogenesis of systemic lupus erythematosus
© BioMed Central Ltd 2010
Published: 26 April 2010
The etiology of the autoimmune disease systemic lupus erythematosus is not known, but aberrant apoptosis and/or insufficient clearance of apoptotic material have been assigned a pivotal role. During apoptosis, nucleosomes and several endogenous danger-associated molecular patterns are incorporated in blebs. Recent data indicate that apoptotic blebs induce maturation of myeloid dendritic cells, resulting in IL-17 production by T cells. In this review we summarize current knowledge on the role of dendritic cells in the pathogenesis of systemic lupus erythematosus with special emphasis on the uptake of apoptotic blebs by dendritic cells, and the subsequent induction of Th17 cells.
Systemic lupus erythematosus (SLE) is a complex, multiorgan, autoimmune disease. It is characterized by an autoimmune response directed against multiple nuclear components, of which the nucleosome is the major autoantigen . SLE autoantigens cluster in blebs formed at the surface of apoptotic cells . The exact etiology of SLE is still unclear, although insufficient clearance of apoptotic material and/or aberrant apoptosis, in combination with a susceptible genetic background, have been suggested to be involved in SLE development and progression [3, 4]. Multiple SLE-associated autoreactive antibodies, which are found in both SLE patients and lupus mouse models, recognize apoptosis-induced modifications of nuclear autoantigens. It has been demonstrated that the pathogenic autoantibodies result from CD4+ T cell-dependent immune responses. Activation of the autoimmune T helper (Th) cells requires immunogenic antigen presentation by dendritic cells (DCs) . Here, we provide an overview of the role of DCs and their response to apoptotic material in the pathogenesis of SLE.
At the interface of innate and adaptive immunity, DCs play a pivotal role in the regulation of immune responses. DCs are distributed throughout the body for optimal antigen capture and, as the most potent antigen presenting cells, they are well suited to activate (naïve) T cells. On the other hand, immature DCs can promote epitope-specific peripheral tolerance by presenting antigens acquired from dying cells without co-stimulation of T cells. This results in anergy or deletion of self-reactive T cells and the development of regulatory T cells (Tregs) . Depletion of DCs in mice results in breaking of self-tolerance of CD4 T cells and induction of spontaneous autoimmunity , reflecting the importance of DCs in peripheral tolerance. On the other hand, inhibition of apoptosis in mouse DCs by Bim-deficieny leads to overstimulation of T cells by DCs. This overactivation of T cells then results in breakage of self-tolerance and induction of autoimmunity in mice , indicating the ability of DCs to induce autoimmune responses. When an antigen is perceived by DCs as being harmful, T cells recognizing the antigen will be activated. In order to activate T cells, DCs undergo a process called maturation, migrate to secondary lymphoid organs, and present antigens in an immunogenic context to T cells. During the process of maturation, DCs are transformed from predominant antigen-capturing cells towards antigen-presenting cells. DCs thereby increase the expression of antigen-loaded major histocompatibility complex (MHC) molecules, upregulate the expression of co-stimulatory molecules (that is, CD86, CD40) and secrete pro-inflammatory cytokines and chemokines, such as IL-6 and TNF-α . Furthermore, the signature of the secreted cytokines and the molecules expressed on the cell surface (for example, OX40 ligand (OX40L) or ICOS-1 (inducible costimulator-1)) determine the type of T cell polarization, for example, Th1, Th2, Th17, or Treg .
DCs can be divided into several subsets, which display different characteristics and tissue distributions. Discussing all possible DC subsets is beyond the scope of this review, but currently two main types of DC are known: myeloid DCs (mDCs), and plasmacytoid DCs (pDCs) [9, 10]. The number of DCs circulating in blood is relatively low; therefore, in vitro cultured DCs are often used in studies. Human mDCs are predominantly generated by culturing monocytes in the presence of granulocyte-macrophage colony-stimulating factor (GMCSF) and IL-4; these cytokines are also mainly used to generate mDCs from mouse bone marrow. pDCs were previously isolated from blood, but nowadays they can also be generated after culturing human monocytes or mouse bone marrow in the presence of Flt-3 ligand (Flt-3L). An important characteristic of mDCs in the context of SLE is their ability to take up apoptotic and necrotic cell material  and present this to T cells . In contrast to mDCs, pDCs are unable to ingest uncomplexed apoptotic and necrotic material . However, when apoptotic material is in complex with (auto)antibodies, pDCs ingest these complexes. pDCs can produce high amounts of type I IFN (mainly IFN-α) and were, therefore, originally referred to as the natural interferon-producing cells . Interestingly, high levels of IFN-α are found in SLE patients, suggesting the involvement of pDCs in the pathogenesis of SLE .
The activation and maturation of DCs can be accomplished by numerous agents, such as microorganisms, immune complexes, various cells of the innate and adaptive immune system, dying cells, or material derived from dying cells [5, 8, 14]. In the case of microorganisms, pathogen-associated molecular patterns (PAMPs) are recognized by DCs via pathogen recognition receptors (PRRs). These PRRs comprise Toll-like receptors (TLRs), C-type lectin receptors, the intracellular RIG-I-like receptors and NOD-like receptors, of which the TLRs have been studied in most detail [10, 14]. However, TLRs are not solely stimulated by PAMPs, but also by endogenous TLR ligands, which can be released from dying cells and are referred to as danger-associated molecular patterns (DAMPs). Expression of the PRRs varies between the DC types and subsets, and also differs between species. With regard to TLRs, mDCs express most of the known TLRs, whereas pDCs predominantly express TLR7 and 9. Currently, the involvement of TLR triggering by DAMPs in auto-immune diseases, and SLE in particular, is an area of active research . We will address this topic in more detail below.
Insufficient clearance of apoptotic material in SLE
An increased load of apoptotic material has been related to the induction of SLE and the disease severity [3, 4]. This increased load of apoptotic material can, in theory result from aberrant apoptosis and/or insufficient clearance of apoptotic cells [15, 16]. While some limited data support an increased rate of apoptosis in SLE in humans, animal models have shown that aberrant apoptosis, as in mice with defective Fas (lpr) or Fas ligand (gld), results in lymphoproliferation and autoimmunity with SLE-like features. Deregulated apoptosis ultimately leads to increased amounts of apoptotic cells at the wrong time or in a wrong micro-environment. However, an increasing body of evidence indicates that insufficient clearance is probably a more important cause of the increased load of apoptotic material in SLE.
In contrast to the normal situation, where early apoptotic cells are swiftly removed by phagocytosis, insufficient clearance of apoptotic cells and material may result in accumulation of these in tissues, and apoptosis can then proceed to secondary necrosis and to the release of inflammatory stimuli.
Insufficient clearance of apoptotic material results in the release of modified autoantigens that can illicit an immune response
Insufficient clearance of apoptotic material does not directly provide an explanation for the pathogenesis of SLE, since tolerance towards self is not automatically affected. The immune system is constantly in contact with numerous self-antigens, and it harbors multiple mechanisms to prevent autoimmunity [5, 20, 21]. Yet, one can imagine two pathways leading to an immune response against self-antigens. First, self is presented in an immunogenic context by antigen-presenting cells - for example, DCs - to auto-reactive T cells that have escaped central and peripheral tolerance mechanisms. The activated T cells provide the help needed for the subsequent activation of autoreactive B cells presenting the self epitopes. Second, modified or cryptic self is presented in an immunogenic context by DCs to T cells. When B cells ingest modified self that is recognized by their B cell receptor, they will present the peptides derived from this material. The activated T cells recognizing modified peptides can provide the help necessary for the activation of these B cells, resulting in the production of antibodies directed towards modified self. Because the tolerance mechanisms for B cells are less stringent than those for T cells, natural autoreactive B cells specific for unmodified parts of self-antigens are present. In SLE patients, this fraction of autoreactive B cells is probably even larger than in healthy individuals . Since these B cells can present peptides derived from the modified as well as the unmodified parts of the ingested antigen, they can receive help from activated T cells recognizing any one of these peptides. This mechanism of epitope spreading will ultimately result in the activation of various autoreactive T and B cells. We favor an important contribution of this second pathway, where the initial response is directed towards modified self, since it does not require the failure of physiological tolerance mechanisms. Experimental evidence for the involvement of modified self is found in the specificity of autoantibodies that are found in SLE patients. Antibodies from these patients recognize self-antigens that are modified during the process of apoptosis. This is exemplified in one of our own studies showing autoantibodies recognizing apoptosis-modified histone H4 .
Immunogenic presentation of (modified) autoantigens by matured dendritic cells
We recently found that apoptotic blebs can induce maturation of mouse mDCs with the production of high amounts of IL-6 . This effect was not observed with apoptotic cell bodies, the remainder of the dying cell after blebbing has finished. Interestingly, many of the potential endogenous ligands that can activate DCs, including RNA, DNA, and HMGB1, are found in blebs [37, 38]. In addition, HMGB1 remains attached to the nucleosomes that are released from late apoptotic cells . Taken together, the disturbed clearance of apoptotic cells leads to an accumulation of blebs with immunogenic modification of autoantigens. The simultaneous presence of endogenous danger signals and possibly a deficiency of regulatory pathways will enhance the ability of DCs to initiate an immune response to (modified) autoantigens.
The important role of DCs presenting apoptotic material in the pathogenesis of SLE is illustrated by studies showing that administration of mDCs loaded with apoptotic or necrotic cells can induce the formation of antinuclear antibodies in normal mice and in lupus mice [39, 40]. Furthermore, vaccination with these DCs in lupus mice increased the disease severity [39–41].
The involvement of TLRs in the pathogenesis of SLE is supported by the observation that lupus-prone mice deficient in MyD88, a critical adaptor in most TLR signaling, did not develop autoimmune nephritis . Accordingly, lupus-prone mice that are deficient in Sigirr, a negative regulator in TLR signaling, show accelerated disease progression . In TLR9-deficient lupus-prone mice, the generation of anti-DNA and anti-chromatin autoantibodies was impaired , which was, however, dependent on the genetic background. Furthermore, a protective effect of TLR9 signaling has also been described in animal models . In humans, an association between genetic variation in TLR9 and SLE susceptibility could not be demonstrated . The involvement of TLR7 signaling in SLE pathogenesis is especially evident from mouse studies. The generation of autoantibodies recognizing RNA-containing antigens was shown to be TLR7 dependent . Furthermore, the RNA component of the Sm/RNP (Smith antigen/small nuclear ribonucleo-proteins) and SS-A 60 lupus autoantigens contributes to DC maturation in vivo, probably via a TLR7- dependent pathway . Overexpression of TLR7 caused profound DC dysregulation, increased levels of proinflammatory cytokines, such as IL-6 and TNF-α, in sera, SLE autoantibody production and fatal systemic autoimmunity [48, 49]. However, no evidence for increased TLR7 expression was found in SLE patients . When signaling via TLR3, TLR7, and TLR9 was abolished simultaneously in lupus-prone mice, the production of antinuclear antibodies and disease manifestation were markedly reduced . As proposed by Baccala and colleagues , the dependency on TLR signaling may vary with the phase of SLE development. The initiation phase might concern TLR-independent maturation of DCs by apoptotic material and associated nucleic acids. After the formation of autoantibodies an amplification phase can be initiated where Fc receptor-dependent uptake of nucleic-acid-containing immune complexes induces TLR-dependent maturation of DCs. Taken together, evidence for a role for TLRs in the pathogenesis of SLE is mainly derived from animal models, and the relevance in human lupus has still to be shown.
A Th17 polarizing effect of dendritic cells in SLE
As outlined above, the interaction between DCs loaded with antigens derived from apoptotic cells and naive T cells can give rise to various responses of sub populations of T cells. First, when immature DCs present self antigens in a tolerogenic way, autoreactive T cells are deleted or anergized, and regulatory T cells can be activated. The development of regulatory T cells largely depends on the presence of TGF-β. When mature DCs present antigens in an immunogenic way, cytotoxic T cells as well as helper T cells can be activated. Helper T cells have traditionally been divided into type 1 (Th1) and type 2 (Th2) subsets, and until recently many auto immune diseases were associated with a Th1 type of autoimmune response . However, recent data have clearly demonstrated a crucial role for the IL-17 producing Th17 subset in autoimmune diseases . For example, in contrast to the Th1-promoting cytokine IL-12, the Th17- promoting cytokine IL-23 is involved in joint destruction in a rheumatoid arthritis model. Blocking IL-17 with a monoclonal antibody decreased intestinal inflammation significantly in a mouse model for inflammatory bowel disease . In mice, both Th17 and Tregs require TGF-β for their development. However, in the presence of IL-6 the development of Tregs is decreased, and their suppressive function is inhibited , whereas the combination of IL-6 and TGF-β is required for Th17 development . Further more, IL-23 and IL-21 mediate the efficient expansion of the Th17 subset . In humans, the development of Th17 cells appears to be different from mice, although there is no consensus when comparing various studies. Several studies using human cells demonstrated that as well as IL-6 and TGF-β, Th17 cell activation and differentiation can involve IL-1β, IL-21, and IL-23 . Compared to other autoimmune diseases, little is yet known about the role and involvement of Th17 cells in SLE. However, there are several indications that Th17 cells and cytokines involved in activation and expansion of these cells are important. For instance, hyperproduction of IL-17 and IL-23 was observed in SLE patients . Besides producing IFN-γ, expanded double negative T cells from SLE patients were found to produce significant amounts of IL-17. These double negative IL-17-producing T cells were shown to infiltrate kidneys of lupus patients with nephritis . In addition, increased numbers of Th17 cells are associated with disease flares of SLE. During these flares the Treg population was contracted . Lupus mice deficient in TNF receptor 1 and 2 develop accelerated lupus via a Th17-associated pathway . Furthermore, IL-21 signaling was shown to be important in disease pathogenesis in lupus-prone mice . Effective peptide tolerance therapy in lupus mice was associated with reduced numbers of Th17 cells and expansion of Tregs. DCs from tolerized mice, especially pDCs, were altered and produced increased levels of TGF-β and decreased levels of IL-6 after stimulation with nucleosomes, a condition favoring the expansion of Tregs . In conclusion, several lines of evidence support that Th17 cells and related cytokines are important in the pathogenesis of SLE.
As described above, mDCs that are co-cultured with nucleosomes, nucleosomes modified during apoptosis, or apoptotic blebs gain a mature phenotype and produce high concentrations of IL-6. In addition, we found that when mouse mDCs matured by apoptotic blebs are used as stimulator cells in an allogeneic mixed leukocyte reaction, they induce IL-17 production by responder splenocytes . This suggests that the TGF-β-facilitated induction of Tregs under non-inflammatory conditions can be diverted to Th17 activation and development when mDCs produce high levels of IL-6 after interaction with nucleosomes or blebs released from apoptotic cells.
Based on this model we postulate that DCs play a pivotal role in the initiation and progression of SLE. Although SLE patients are often treated with rather unspecific immunosuppressive drugs, the data presented here suggest that specific interference in the maturation of DCs, TLR signaling, or the development of certain T cell subsets might become attractive treatment goals. For example, hydroxychloroquine, which inhibits signaling via TLR3, 7, 8 and 9 by blocking the acidification of endosomes, is a well known effective drug in the treatment of SLE patients . Furthermore, inhibition of TLR7 and 9 was recently shown to ameliorate the disease manifestations in lupus-prone mice . Further knowledge of the role of endogenous apoptotic (modified) compounds and their receptors in the maturation of DCs and the activation of specific T cell subsets, such as Th17 cells, may reveal novel targets for the specific treatment of SLE.
danger-associated molecular pattern
high-mobility group box 1 protein
myeloid dendritic cell
pathogen associated molecular pattern
plasmacytoid dendritic cell
pathogen recognition receptor
receptor for advanced glycation end products
systemic lupus erythematosus
tumor growth factor
tumor necrosis factor
regulatory T cell.
- Lu L, Kaliyaperumal A, Boumpas DT, Datta SK: Major peptide autoepitopes for nucleosome-specific T cells of human lupus. J Clin Invest. 1999, 104: 345-355. 10.1172/JCI6801.PubMed CentralView ArticlePubMedGoogle Scholar
- Casciola-Rosen LA, Anhalt G, Rosen A: Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med. 1994, 179: 1317-1330. 10.1084/jem.179.4.1317.View ArticlePubMedGoogle Scholar
- Gaipl US, Munoz LE, Grossmayer G, Lauber K, Franz S, Sarter K, Voll RE, Winkler T, Kuhn A, Kalden J, Kern P, Herrmann M: Clearance deficiency and systemic lupus erythematosus (SLE). J Autoimmun. 2007, 28: 114-121. 10.1016/j.jaut.2007.02.005.View ArticlePubMedGoogle Scholar
- Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR: Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum. 1998, 41: 1241-1250. 10.1002/1529-0131(199807)41:7<1241::AID-ART15>3.0.CO;2-H.View ArticlePubMedGoogle Scholar
- Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature. 1998, 392: 245-252. 10.1038/32588.View ArticlePubMedGoogle Scholar
- Ohnmacht C, Pullner A, King SB, Drexler I, Meier S, Brocker T, Voehringer D: Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med. 2009, 206: 549-559. 10.1084/jem.20082394.PubMed CentralView ArticlePubMedGoogle Scholar
- Chen M, Huang L, Wang J: Deficiency of Bim in dendritic cells contributes to overactivation of lymphocytes and autoimmunity. Blood. 2007, 109: 4360-4367. 10.1182/blood-2006-11-056424.PubMed CentralView ArticlePubMedGoogle Scholar
- Blanco P, Palucka AK, Pascual V, Banchereau J: Dendritic cells and cytokines in human inflammatory and autoimmune diseases. Cytokine Growth Factor Rev. 2008, 19: 41-52. 10.1016/j.cytogfr.2007.10.004.PubMed CentralView ArticlePubMedGoogle Scholar
- Dalgaard J, Beckstrom KJ, Jahnsen FL, Brinchmann JE: Differential capability for phagocytosis of apoptotic and necrotic leukemia cells by human peripheral blood dendritic cell subsets. J Leukoc Biol. 2005, 77: 689-698. 10.1189/jlb.1204711.View ArticlePubMedGoogle Scholar
- Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004, 5: 987-995. 10.1038/ni1112.View ArticlePubMedGoogle Scholar
- Inaba K, Turley S, Yamaide F, Iyoda T, Mahnke K, Inaba M, Pack M, Subklewe M, Sauter B, Sheff D, Albert M, Bhardwaj N, Mellman I, Steinman RM: Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J Exp Med. 1998, 188: 2163-2173. 10.1084/jem.188.11.2163.PubMed CentralView ArticlePubMedGoogle Scholar
- Ito Y, Aoki H, Kimura Y, Takano M, Shimokata K, Maeno K: Natural interferonproducing cells in mice. Infect Immun. 1981, 31: 519-523.PubMed CentralPubMedGoogle Scholar
- Theofilopoulos AN, Baccala R, Beutler B, Kono DH: Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005, 23: 307-336. 10.1146/annurev.immunol.23.021704.115843.View ArticlePubMedGoogle Scholar
- Marshak-Rothstein A: Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006, 6: 823-835. 10.1038/nri1957.View ArticlePubMedGoogle Scholar
- Nakou M, Knowlton N, Frank MB, Bertsias G, Osban J, Sandel CE, Papadaki H, Raptopoulou A, Sidiropoulos P, Kritikos I, Tassiulas I, Centola M, Boumpas DT: Gene expression in systemic lupus erythematosus: bone marrow analysis differentiates active from inactive disease and reveals apoptosis and granulopoiesis signatures. Arthritis Rheum. 2008, 58: 3541-3549. 10.1002/art.23961.PubMed CentralView ArticlePubMedGoogle Scholar
- Munoz LE, van Bavel C, Franz S, Berden J, Herrmann M, Vlag van der J: Apoptosis in the pathogenesis of systemic lupus erythematosus. Lupus. 2008, 17: 371-375. 10.1177/0961203308089990.View ArticlePubMedGoogle Scholar
- Sturfelt G, Truedsson L: Complement and its breakdown products in SLE. Rheumatology (Oxford). 2005, 44: 1227-1232. 10.1093/rheumatology/keh719.View ArticleGoogle Scholar
- Russell AI, Cunninghame Graham DS, Shepherd C, Roberton CA, Whittaker J, Meeks J, Powell RJ, Isenberg DA, Walport MJ, Vyse TJ: Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum Mol Genet. 2004, 13: 137-147. 10.1093/hmg/ddh021.PubMed CentralView ArticlePubMedGoogle Scholar
- Chitrabamrung S, Rubin RL, Tan EM: Serum deoxyribonuclease I and clinical activity in systemic lupus erythematosus. Rheumatol Int. 1981, 1: 55-60. 10.1007/BF00541153.View ArticlePubMedGoogle Scholar
- Kyewski B, Klein L: A central role for central tolerance. Annu Rev Immunol. 2006, 24: 571-606. 10.1146/annurev.immunol.23.021704.115601.View ArticlePubMedGoogle Scholar
- Lee JW, Epardaud M, Sun J, Becker JE, Cheng AC, Yonekura AR, Heath JK, Turley SJ: Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol. 2007, 8: 181-190. 10.1038/ni1427.View ArticlePubMedGoogle Scholar
- Yurasov S, Wardemann H, Hammersen J, Tsuiji M, Meffre E, Pascual V, Nussenzweig MC: Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med. 2005, 201: 703-711. 10.1084/jem.20042251.PubMed CentralView ArticlePubMedGoogle Scholar
- Dieker JW, Fransen JH, van Bavel CC, Briand JP, Jacobs CW, Muller S, Berden JH, Vlag van der J: Apoptosis-induced acetylation of histones is pathogenic in systemic lupus erythematosus. Arthritis Rheum. 2007, 56: 1921-1933. 10.1002/art.22646.View ArticlePubMedGoogle Scholar
- Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MA, Nacken W, Foell D, Poll van der T, Sorg C, Roth J: Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med. 2007, 13: 1042-1049. 10.1038/nm1638.View ArticlePubMedGoogle Scholar
- Gurung P, Kucaba TA, Ferguson TA, Griffith TS: Activation-induced CD154 expression abrogates tolerance induced by apoptotic cells. J Immunol. 2009, 183: 6114-6123. 10.4049/jimmunol.0901676.PubMed CentralView ArticlePubMedGoogle Scholar
- Propato A, Cutrona G, Francavilla V, Ulivi M, Schiaffella E, Landt O, Dunbar R, Cerundolo V, Ferrarini M, Barnaba V: Apoptotic cells overexpress vinculin and induce vinculin-specific cytotoxic T-cell cross-priming. Nat Med. 2001, 7: 807-813. 10.1038/89930.View ArticlePubMedGoogle Scholar
- Fransen JH, Hilbrands LB, Ruben J, Stoffels M, Adema GJ, Vlag van der J, Berden JH: Mouse dendritic cells matured by ingestion of apoptotic blebs induce T cells to produce interleukin-17. Arthritis Rheum. 2009, 60: 2304-2313. 10.1002/art.24719.View ArticlePubMedGoogle Scholar
- Rovere P, Vallinoto C, Bondanza A, Crosti MC, Rescigno M, Ricciardi-Castagnoli P, Rugarli C, Manfredi AA: Bystander apoptosis triggers dendritic cell maturation and antigen-presenting function. J Immunol. 1998, 161: 4467-4471.PubMedGoogle Scholar
- Lotze MT, Tracey KJ: High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005, 5: 331-342. 10.1038/nri1594.View ArticlePubMedGoogle Scholar
- Urbonaviciute V, Fürnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, Bianchi ME, Kirschning C, Wagner H, Manfredi AA, Kalden JR, Schett G, Rovere-Querini P, Herrmann M, Voll RE: Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med. 2008, 205: 3007-3018. 10.1084/jem.20081165.PubMed CentralView ArticlePubMedGoogle Scholar
- Means TK, Latz E, Hayashi F, Murali MR, Golenbock DT, Luster AD: Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest. 2005, 115: 407-417.PubMed CentralView ArticlePubMedGoogle Scholar
- Boule MW, Broughton C, Mackay F, Akira S, Marshak-Rothstein A, Rifkin IR: Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. J Exp Med. 2004, 199: 1631-1640. 10.1084/jem.20031942.PubMed CentralView ArticlePubMedGoogle Scholar
- Decker P, Singh-Jasuja H, Haager S, Kotter I, Rammensee HG: Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation. J Immunol. 2005, 174: 3326-3334.View ArticlePubMedGoogle Scholar
- Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, Parroche P, Drabic S, Golenbock D, Sirois C, Hua J, An LL, Audoly L, La Rosa G, Bierhaus A, Naworth P, Marshak-Rothstein A, Crow MK, Fitzgerald KA, Latz E, Kiener PA, Coyle AJ: Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007, 8: 487-496. 10.1038/ni1457.View ArticlePubMedGoogle Scholar
- Chen GY, Tang J, Zheng P, Liu Y: CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science. 2009, 323: 1722-1725. 10.1126/science.1168988.PubMed CentralView ArticlePubMedGoogle Scholar
- Sánchez E, Abelson AK, Sabio JM, González-Gay MA, Ortego-Centeno N, Jiménez-Alonso J, de Ramón E, Sánchez-Román J, López-Nevot MA, Gunnarsson I, Svenungsson E, Sturfelt G, Truedsson L, Jönsen A, González-Escribano MF, Witte T, German Systemic Lupus Erythematosus Study Group, Alarcón-Riquelme ME, Martín J: Association of a CD24 gene polymorphism with susceptibility to systemic lupus erythematosus. Arthritis Rheum. 2007, 56: 3080-3086. 10.1002/art.22871.View ArticlePubMedGoogle Scholar
- Lane JD, Allan VJ, Woodman PG: Active relocation of chromatin and endoplasmic reticulum into blebs in late apoptotic cells. J Cell Sci. 2005, 118: 4059-4071. 10.1242/jcs.02529.View ArticlePubMedGoogle Scholar
- Moss DK, Betin VM, Malesinski SD, Lane JD: A novel role for microtubules in apoptotic chromatin dynamics and cellular fragmentation. J Cell Sci. 2006, 119: 2362-2374. 10.1242/jcs.02959.PubMed CentralView ArticlePubMedGoogle Scholar
- Bondanza A, Zimmermann VS, Dell'Antonio G, Dal Cin E, Capobianco A, Sabbadini MG, Manfredi AA, Rovere-Querini P: Cutting edge: dissociation between autoimmune response and clinical disease after vaccination with dendritic cells. J Immunol. 2003, 170: 24-27.View ArticlePubMedGoogle Scholar
- Ma L, Chan KW, Trendell-Smith NJ, Wu A, Tian L, Lam AC, Chan AK, Lo CK, Chik S, Ko KH, To CK, Kam SK, Li XS, Yang CH, Leung SY, Ng MH, Stott DI, MacPherson GG, Huang FP: Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains. Eur J Immunol. 2005, 35: 3364-3375. 10.1002/eji.200535192.View ArticlePubMedGoogle Scholar
- Bondanza A, Zimmermann VS, Dell'Antonio G, Cin ED, Balestrieri G, Tincani A, Amoura Z, Piette JC, Sabbadini MG, Rovere-Querini P, Manfredi AA: Requirement of dying cells and environmental adjuvants for the induction of autoimmunity. Arthritis Rheum. 2004, 50: 1549-1560. 10.1002/art.20187.View ArticlePubMedGoogle Scholar
- Sadanaga A, Nakashima H, Akahoshi M, Masutani K, Miyake K, Igawa T, Sugiyama N, Niiro H, Harada M: Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice. Arthritis Rheum. 2007, 56: 1618-1628. 10.1002/art.22571.View ArticlePubMedGoogle Scholar
- Lech M, Kulkarni OP, Pfeiffer S, Savarese E, Krug A, Garlanda C, Mantovani A, Anders HJ: Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens. J Exp Med. 2008, 205: 1879-1888. 10.1084/jem.20072646.PubMed CentralView ArticlePubMedGoogle Scholar
- Christensen SR, Kashgarian M, Alexopoulou L, Flavell RA, Akira S, Shlomchik MJ: Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med. 2005, 202: 321-331. 10.1084/jem.20050338.PubMed CentralView ArticlePubMedGoogle Scholar
- Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ: Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity. 2006, 25: 417-428. 10.1016/j.immuni.2006.07.013.View ArticlePubMedGoogle Scholar
- De Jager PL, Richardson A, Vyse TJ, Rioux JD: Genetic variation in toll-like receptor 9 and susceptibility to systemic lupus erythematosus. Arthritis Rheum. 2006, 54: 1279-1282. 10.1002/art.21755.View ArticlePubMedGoogle Scholar
- Kelly-Scumpia KM, Nacionales DC, Scumpia PO, Weinstein JS, Narain S, Moldawer LL, Satoh M, Reeves WH: In vivo adjuvant activity of the RNA component of the Sm/RNP lupus autoantigen. Arthritis Rheum. 2007, 56: 3379-3386. 10.1002/art.22946.View ArticlePubMedGoogle Scholar
- Deane JA, Pisitkun P, Barrett RS, Feigenbaum L, Town T, Ward JM, Flavell RA, Bolland S: Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation. Immunity. 2007, 27: 801-810. 10.1016/j.immuni.2007.09.009.PubMed CentralView ArticlePubMedGoogle Scholar
- Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S: Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science. 2006, 312: 1669-1672. 10.1126/science.1124978.View ArticlePubMedGoogle Scholar
- Kelley J, Johnson MR, Alarcon GS, Kimberly RP, Edberg JC: Variation in the relative copy number of the TLR7 gene in patients with systemic lupus erythematosus and healthy control subjects. Arthritis Rheum. 2007, 56: 3375-3378. 10.1002/art.22916.View ArticlePubMedGoogle Scholar
- Kono DH, Haraldsson MK, Lawson BR, Pollard KM, Koh YT, Du X, Arnold CN, Baccala R, Silverman GJ, Beutler BA, Theofilopoulos AN: Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus. Proc Natl Acad Sci USA. 2009, 106: 12061-12066. 10.1073/pnas.0905441106.PubMed CentralView ArticlePubMedGoogle Scholar
- Baccala R, Hoebe K, Kono DH, Beutler B, Theofilopoulos AN: TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat Med. 2007, 13: 543-551. 10.1038/nm1590.View ArticlePubMedGoogle Scholar
- Korn T, Bettelli E, Oukka M, Kuchroo VK: IL-17 and Th17 Cells. Annu Rev Immunol. 2009, 27: 485-517. 10.1146/annurev.immunol.021908.132710.View ArticlePubMedGoogle Scholar
- Pasare C, Medzhitov R: Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science. 2003, 299: 1033-1036. 10.1126/science.1078231.View ArticlePubMedGoogle Scholar
- Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW: Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol. 2008, 127: 385-393. 10.1016/j.clim.2008.01.019.View ArticlePubMedGoogle Scholar
- Crispin JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, Kyttaris VC, Juang YT, Tsokos GC: Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol. 2008, 181: 8761-8766.PubMed CentralView ArticlePubMedGoogle Scholar
- Yang J, Chu Y, Yang X, Gao D, Zhu L, Yang X, Wan L, Li M: Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009, 60: 1472-1483. 10.1002/art.24499.View ArticlePubMedGoogle Scholar
- Jacob N, Yang H, Pricop L, Liu Y, Gao X, Zheng SG, Wang J, Gao HX, Putterman C, Koss MN, Stohl W, Jacob CO: Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway. J Immunol. 2009, 182: 2532-2541. 10.4049/jimmunol.0802948.PubMed CentralView ArticlePubMedGoogle Scholar
- Bubier JA, Sproule TJ, Foreman O, Spolski R, Shaffer DJ, Morse HC, Leonard WJ, Roopenian DC: A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc Natl Acad Sci USA. 2009, 106: 1518-1523. 10.1073/pnas.0807309106.PubMed CentralView ArticlePubMedGoogle Scholar
- Kang HK, Liu M, Datta SK: Low-dose peptide tolerance therapy of lupus generates plasmacytoid dendritic cells that cause expansion of autoantigen-specific regulatory T cells and contraction of inflammatory Th17 cells. J Immunol. 2007, 178: 7849-7858.View ArticlePubMedGoogle Scholar
- Frisoni L, McPhie L, Colonna L, Sriram U, Monestier M, Gallucci S, Caricchio R: Nuclear autoantigen translocation and autoantibody opsonization lead to increased dendritic cell phagocytosis and presentation of nuclear antigens: a novel pathogenic pathway for autoimmunity?. J Immunol. 2005, 175: 2692-2701.View ArticlePubMedGoogle Scholar
- Lovgren T, Eloranta ML, Bave U, Alm GV, Ronnblom L: Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum. 2004, 50: 1861-1872. 10.1002/art.20254.View ArticlePubMedGoogle Scholar
- Tovey MG, Lallemand C, Thyphronitis G: Adjuvant activity of type I interferons. Biol Chem. 2008, 389: 541-545. 10.1515/BC.2008.051.View ArticlePubMedGoogle Scholar
- van Bavel CC, Fenton KA, Rekvig OP, Vlag van der J, Berden JH: Glomerular targets of nephritogenic autoantibodies in systemic lupus erythematosus. Arthritis Rheum. 2008, 58: 1892-1899. 10.1002/art.23626.View ArticlePubMedGoogle Scholar
- Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA: Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010, 69: 20-28. 10.1136/ard.2008.101766.View ArticlePubMedGoogle Scholar
- Barrat FJ, Meeker T, Chan JH, Guiducci C, Coffman RL: Treatment of lupusprone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur J Immunol. 2007, 37: 3582-3586. 10.1002/eji.200737815.View ArticlePubMedGoogle Scholar