- Email: [email protected]
Can dendritic cells still be tamed in systemic lupus erythematosus?
Clinical Immunology (2012) 143, 4–5 available at www.sciencedirect.com
Clinical Immunology www.elsevier.com/locate/yclim
EDITORIAL
Can dendritic cells still be tamed in systemic lupus erythematosus? Dendritic cells (DC) are professional antigen-presenting cells (APC) which have the unique ability to induce and sustain immune responses. DC constitute a complex and plastic system of cells, which comprise several subsets that are at different stages of maturation. Immature, antigen-capturing DC in peripheral tissues sense pathogens, tissue necrosis, and local inflammation. These “danger” signals induce DC to undergo a maturation process while migrating into T cell areas of draining lymph nodes. There, they present processed antigens to T cells resulting in T cell proliferation and activation [1]. There is now evidence that immature DC during steady state conditions capture self-antigens and present them to T cells that lead to inactivate potentially self-reactive T cells (anergy) and/or to promote the development of regulatory T cells [2]. This process has been shown as a key event of the so called peripheral tolerance. In contrast, if antigen-loaded DC undergo maturation, they induce antigen-specific immunity [3]. Thus unabated DC activation may skew self-antigen presentation from tolerance to autoimmunity [4]. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiorgan involvement characterised by an immune response against nuclear components that may induce tissue damages. The pathogenesis of this disease remains largely unknown even if environmental triggers as well as immunological factors in the context of susceptibility genes might play an important role [5]. Following the assumption that an ill-regulated DC maturation process would lead to the activation of T cells in the presence of self antigens, the phenotype and function of SLE-derived DC have been the focus of several studies. In this issue, Crispin et al., add to the accumulating evidence indicating that alterations in DC homeostasis are a key feature of SLE pathogenesis [6]. Blood DC contain two DC subsets, a CD11c− one and a CD11c + one. The CD11c− subset called plasmacytoid DC (pDC), comes from an independent, possibly lymphoid-related differentiation pathway. The CD11c+ subset follows a myeloid differentiation pathway and is called myeloid DC (mDC) where monocytes serve as the reservoir of precursors [7]. Notwithstanding, several studies have analysed DC phenotype in patients with lupus, but not surprisingly, their results are conflicting.
1521-6616/$ - see front matter © 2012 Published by Elsevier Inc. doi:10.1016/j.clim.2012.01.006
Earlier reports stated that mDC from patients with SLE display normal or even low levels of co-stimulatory molecules and are poor to normal stimulators in allogenic mixed lymphocyte reactions [8,9]. However, recent studies have reported an overstimulated phenotype and function of SLE monocytes and DC. Ding et al. reported that monocytes from SLE patients undergo an accelerated differentiation process into mDCs and express abnormally high levels of co-stimulatory molecules [10]. In addition, Blanco et al. showed that monocytes in SLE patients were acting as dendritic cells [11]. It also appeared that some of the DC defects were associated with clinical features. For example, increased levels of CD86 correlated with disease activity as well as with nephritis [10]. Accordingly, Decker et al. reported that monocyte-derived DC from SLE patients are characterised by an abnormally high expression of CD86 and produce increased levels of IL-6 upon stimulation [12]. In this study, Crispin et al. examine circulating mDC phenotype in SLE patients [6]. The authors found that patients with SLE had a tendency to have more DC than normal subjects and had significantly more monocytes which are mDC precursors. They looked at the activation status of DC and found that peripheral blood DC bear increased levels of CD80 and CD86 in patients with SLE compared to healthy controls suggesting that SLE DC are characterised ex vivo by an overstimulated phenotype which is in accordance with some previous reports. They did not observe any correlation to disease activity as well as direct link with the underlying immunosuppressive regimen. Factors present in SLE sera, including IFN-α, CD40L, free nucleosomes and autoantibody-DNA complexes cause differentiation and activation of normal DC and stimulate them to produce inflammatory cytokines including IFN-α [11,13–16]. The ex vivo phenotype differences between SLE DC and control DC could result from intrinsic or extrinsic factors to the monocyte/DC. To this end, Crispin et al. used an interesting in vitro system in which they isolated monocytes from SLE patients and healthy controls and incubated them in the presence of GM-CSF and IL-4. The authors found that DC derived in vitro from SLE monocytes compared to healthy monocytes DCs were normal according to their phenotype assessed by the expression of MHC class II molecules and
Editorial costimulation markers as well the stimulation capacity measured as T cell proliferation. These findings suggest that the inflammatory environment found in patients with lupus play an important role in DC maturation and activation. Activation of DC is driven by a variety of stimuli. When stimulated by microbial products, inflammatory cytokines, or T cell-derived signals, DC undergo maturation and become powerful APC [1]. Recent findings suggest that pathogen-associated-nucleic acids can exacerbate SLE pathology through stimulation of Toll-like receptors (TLRs) [17] and it has been shown that self nucleic acids found in apoptotic cells and necrotic acids can activate DC in a TLR and FcγR dependent manner [18–20]. Crispin et al. found that the expression of TLR2 and TLR4 downstream of maturation stimuli dropped in DC from normal controls but remained high or even increased in SLE DC suggesting that intrinsic cellular defects may be involved in alterations of DC homeostasis during SLE. During steady state conditions, DC contribute to the preservation of immune tolerance by presenting antigens to T cells in non-inflammatory conditions. It is well known that IL-10 promotes a tolerance-inducing phenotype in DC [21,22]. Crispin et al. in their paper demonstrate that IL-10 treated SLE-derived DC are able to induce unresponsiveness to allogenic antigens when cultured with normal T cells suggesting that their “tolerogenic” capacity is preserved. Therefore, targeting immature DC might represent a worth testing therapeutic approach in SLE.
Conflict of interest statement
5
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
The authors declare that there are no conflicts of interest.
References [1] J. Banchereau, F. Briere, C. Caux, J. Davoust, S. Lebecque, Y.J. Liu, B. Pulendran, K. Palucka, Immunobiology of dendritic cells, Annu. Rev. Immunol. 18 (2000) 767–811. [2] R.M. Steinman, D. Hawiger, K. Liu, L. Bonifaz, D. Bonnyay, K. Mahnke, T. Iyoda, J. Ravetch, M. Dhodapkar, K. Inaba, M. Nussenzweig, Dendritic cell function in vivo during the steady state: a role in peripheral tolerance, Ann. N. Y. Acad. Sci. 987 (2003) 15–25. [3] R.M. Steinman, Decisions About Dendritic Cells: Past, Present, and Future. Annu Rev Immunol. [4] P. Blanco, A.K. Palucka, V. Pascual, J. Banchereau, Dendritic cells and cytokines in human inflammatory and autoimmune diseases, Cytokine Growth Factor Rev. 19 (2008) 41–52. [5] G.C. Tsokos, Systemic lupus erythematosus. N Engl J Med 365 2110-21. [6] J.C. Crispin, M.I. Vargas-Rojas, A. Monsivais-Urenda, J. Alcocer-Varela, Phenotype and function of dendritic cells of patients with systemic lupus erythematosus, Clin. Immunol. 143 (2012) 45–50. [7] V. Pascual, J. Banchereau, A.K. Palucka, The central role of dendritic cells and interferon-alpha in SLE, Curr. Opin. Rheumatol. 15 (2003) 548–556. [8] C. Scheinecker, B. Zwolfer, M. Koller, G. Manner, J.S. Smolen, Alterations of dendritic cells in systemic lupus erythematosus: phenotypic and functional deficiencies, Arthritis Rheum. 44 (2001) 856–865. [9] M. Koller, B. Zwolfer, G. Steiner, J.S. Smolen, C. Scheinecker, Phenotypic and functional deficiencies of monocyte-derived
[19]
[20]
[21]
[22]
dendritic cells in systemic lupus erythematosus (SLE) patients, Int. Immunol. 16 (2004) 1595–1604. D. Ding, H. Mehta, W.J. McCune, M.J. Kaplan, Aberrant phenotype and function of myeloid dendritic cells in systemic lupus erythematosus, J. Immunol. 177 (2006) 5878–5889. P. Blanco, A.K. Palucka, M. Gill, V. Pascual, J. Banchereau, Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus, Science 294 (2001) 1540–1543. P. Decker, I. Kotter, R. Klein, B. Berner, H.G. Rammensee, Monocyte-derived dendritic cells over-express CD86 in patients with systemic lupus erythematosus, Rheumatology (Oxford) 45 (2006) 1087–1095. P. Duffau, J. Seneschal, C. Nicco, C. Richez, E. Lazaro, I. Douchet, C. Bordes, J.F. Viallard, C. Goulvestre, J.L. Pellegrin, B. Weil, J.F. Moreau, F. Batteux, and P. Blanco, Platelet CD154 potentiates interferon-alpha secretion by plasmacytoid dendritic cells in systemic lupus erythematosus. Sci Transl Med 2 47ra63. P. Decker, H. Singh-Jasuja, S. Haager, I. Kotter, H.G. Rammensee, Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation, J. Immunol. 174 (2005) 3326–3334. M.W. Boule, C. Broughton, F. Mackay, S. Akira, A. Marshak-Rothstein, I.R. Rifkin, Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatinimmunoglobulin G complexes, J. Exp. Med. 199 (2004) 1631–1640. T.K. Means, E. Latz, F. Hayashi, M.R. Murali, D.T. Golenbock, A.D. Luster, Human lupus autoantibody–DNA complexes activate DCs through cooperation of CD32 and TLR9, J. Clin. Invest. 115 (2005) 407–417. H.J. Anders, D. Zecher, R.D. Pawar, P.S. Patole, Molecular mechanisms of autoimmunity triggered by microbial infection, Arthritis Res. Ther. 7 (2005) 215–224. F.J. Barrat, T. Meeker, J. Gregorio, J.H. Chan, S. Uematsu, S. Akira, B. Chang, O. Duramad, R.L. Coffman, Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus, J. Exp. Med. 202 (2005) 1131–1139. K. Yasuda, C. Richez, M.B. Uccellini, R.J. Richards, R.G. Bonegio, S. Akira, M. Monestier, R.B. Corley, G.A. Viglianti, A. MarshakRothstein, I.R. Rifkin, Requirement for DNA CpG content in TLR9-dependent dendritic cell activation induced by DNAcontaining immune complexes, J. Immunol. 183 (2009) 3109–3117. T. Lovgren, M.L. Eloranta, U. Bave, G.V. Alm, L. Ronnblom, 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. 50 (2004) 1861–1872. K. Steinbrink, M. Wolfl, H. Jonuleit, J. Knop, A.H. Enk, Induction of tolerance by IL-10-treated dendritic cells, J. Immunol. 159 (1997) 4772–4780. R.M. Steinman, D. Hawiger, M.C. Nussenzweig, Tolerogenic dendritic cells, Annu. Rev. Immunol. 21 (2003) 685–711.
Pierre Duffau Patrick Blanco⁎ CNRS UMR 5164, 146 rue Léo Saignat, 33076 Bordeaux, France IFR-66, 146 rue Léo Saignat, 33076 Bordeaux, France Université Victor Segalen Bordeaux2, 146 rue Léo Saignat, 33076 Bordeaux, France Centre Hospitalier Universitaire de Bordeaux, Place Amélie Raba Léon, 33076 Bordeaux cedex, France ⁎Corresponding author. Fax: +33 05 56 79 56 45. E-mail address: [email protected].
Clinical Immunology www.elsevier.com/locate/yclim
EDITORIAL
Can dendritic cells still be tamed in systemic lupus erythematosus? Dendritic cells (DC) are professional antigen-presenting cells (APC) which have the unique ability to induce and sustain immune responses. DC constitute a complex and plastic system of cells, which comprise several subsets that are at different stages of maturation. Immature, antigen-capturing DC in peripheral tissues sense pathogens, tissue necrosis, and local inflammation. These “danger” signals induce DC to undergo a maturation process while migrating into T cell areas of draining lymph nodes. There, they present processed antigens to T cells resulting in T cell proliferation and activation [1]. There is now evidence that immature DC during steady state conditions capture self-antigens and present them to T cells that lead to inactivate potentially self-reactive T cells (anergy) and/or to promote the development of regulatory T cells [2]. This process has been shown as a key event of the so called peripheral tolerance. In contrast, if antigen-loaded DC undergo maturation, they induce antigen-specific immunity [3]. Thus unabated DC activation may skew self-antigen presentation from tolerance to autoimmunity [4]. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multiorgan involvement characterised by an immune response against nuclear components that may induce tissue damages. The pathogenesis of this disease remains largely unknown even if environmental triggers as well as immunological factors in the context of susceptibility genes might play an important role [5]. Following the assumption that an ill-regulated DC maturation process would lead to the activation of T cells in the presence of self antigens, the phenotype and function of SLE-derived DC have been the focus of several studies. In this issue, Crispin et al., add to the accumulating evidence indicating that alterations in DC homeostasis are a key feature of SLE pathogenesis [6]. Blood DC contain two DC subsets, a CD11c− one and a CD11c + one. The CD11c− subset called plasmacytoid DC (pDC), comes from an independent, possibly lymphoid-related differentiation pathway. The CD11c+ subset follows a myeloid differentiation pathway and is called myeloid DC (mDC) where monocytes serve as the reservoir of precursors [7]. Notwithstanding, several studies have analysed DC phenotype in patients with lupus, but not surprisingly, their results are conflicting.
1521-6616/$ - see front matter © 2012 Published by Elsevier Inc. doi:10.1016/j.clim.2012.01.006
Earlier reports stated that mDC from patients with SLE display normal or even low levels of co-stimulatory molecules and are poor to normal stimulators in allogenic mixed lymphocyte reactions [8,9]. However, recent studies have reported an overstimulated phenotype and function of SLE monocytes and DC. Ding et al. reported that monocytes from SLE patients undergo an accelerated differentiation process into mDCs and express abnormally high levels of co-stimulatory molecules [10]. In addition, Blanco et al. showed that monocytes in SLE patients were acting as dendritic cells [11]. It also appeared that some of the DC defects were associated with clinical features. For example, increased levels of CD86 correlated with disease activity as well as with nephritis [10]. Accordingly, Decker et al. reported that monocyte-derived DC from SLE patients are characterised by an abnormally high expression of CD86 and produce increased levels of IL-6 upon stimulation [12]. In this study, Crispin et al. examine circulating mDC phenotype in SLE patients [6]. The authors found that patients with SLE had a tendency to have more DC than normal subjects and had significantly more monocytes which are mDC precursors. They looked at the activation status of DC and found that peripheral blood DC bear increased levels of CD80 and CD86 in patients with SLE compared to healthy controls suggesting that SLE DC are characterised ex vivo by an overstimulated phenotype which is in accordance with some previous reports. They did not observe any correlation to disease activity as well as direct link with the underlying immunosuppressive regimen. Factors present in SLE sera, including IFN-α, CD40L, free nucleosomes and autoantibody-DNA complexes cause differentiation and activation of normal DC and stimulate them to produce inflammatory cytokines including IFN-α [11,13–16]. The ex vivo phenotype differences between SLE DC and control DC could result from intrinsic or extrinsic factors to the monocyte/DC. To this end, Crispin et al. used an interesting in vitro system in which they isolated monocytes from SLE patients and healthy controls and incubated them in the presence of GM-CSF and IL-4. The authors found that DC derived in vitro from SLE monocytes compared to healthy monocytes DCs were normal according to their phenotype assessed by the expression of MHC class II molecules and
Editorial costimulation markers as well the stimulation capacity measured as T cell proliferation. These findings suggest that the inflammatory environment found in patients with lupus play an important role in DC maturation and activation. Activation of DC is driven by a variety of stimuli. When stimulated by microbial products, inflammatory cytokines, or T cell-derived signals, DC undergo maturation and become powerful APC [1]. Recent findings suggest that pathogen-associated-nucleic acids can exacerbate SLE pathology through stimulation of Toll-like receptors (TLRs) [17] and it has been shown that self nucleic acids found in apoptotic cells and necrotic acids can activate DC in a TLR and FcγR dependent manner [18–20]. Crispin et al. found that the expression of TLR2 and TLR4 downstream of maturation stimuli dropped in DC from normal controls but remained high or even increased in SLE DC suggesting that intrinsic cellular defects may be involved in alterations of DC homeostasis during SLE. During steady state conditions, DC contribute to the preservation of immune tolerance by presenting antigens to T cells in non-inflammatory conditions. It is well known that IL-10 promotes a tolerance-inducing phenotype in DC [21,22]. Crispin et al. in their paper demonstrate that IL-10 treated SLE-derived DC are able to induce unresponsiveness to allogenic antigens when cultured with normal T cells suggesting that their “tolerogenic” capacity is preserved. Therefore, targeting immature DC might represent a worth testing therapeutic approach in SLE.
Conflict of interest statement
5
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
The authors declare that there are no conflicts of interest.
References [1] J. Banchereau, F. Briere, C. Caux, J. Davoust, S. Lebecque, Y.J. Liu, B. Pulendran, K. Palucka, Immunobiology of dendritic cells, Annu. Rev. Immunol. 18 (2000) 767–811. [2] R.M. Steinman, D. Hawiger, K. Liu, L. Bonifaz, D. Bonnyay, K. Mahnke, T. Iyoda, J. Ravetch, M. Dhodapkar, K. Inaba, M. Nussenzweig, Dendritic cell function in vivo during the steady state: a role in peripheral tolerance, Ann. N. Y. Acad. Sci. 987 (2003) 15–25. [3] R.M. Steinman, Decisions About Dendritic Cells: Past, Present, and Future. Annu Rev Immunol. [4] P. Blanco, A.K. Palucka, V. Pascual, J. Banchereau, Dendritic cells and cytokines in human inflammatory and autoimmune diseases, Cytokine Growth Factor Rev. 19 (2008) 41–52. [5] G.C. Tsokos, Systemic lupus erythematosus. N Engl J Med 365 2110-21. [6] J.C. Crispin, M.I. Vargas-Rojas, A. Monsivais-Urenda, J. Alcocer-Varela, Phenotype and function of dendritic cells of patients with systemic lupus erythematosus, Clin. Immunol. 143 (2012) 45–50. [7] V. Pascual, J. Banchereau, A.K. Palucka, The central role of dendritic cells and interferon-alpha in SLE, Curr. Opin. Rheumatol. 15 (2003) 548–556. [8] C. Scheinecker, B. Zwolfer, M. Koller, G. Manner, J.S. Smolen, Alterations of dendritic cells in systemic lupus erythematosus: phenotypic and functional deficiencies, Arthritis Rheum. 44 (2001) 856–865. [9] M. Koller, B. Zwolfer, G. Steiner, J.S. Smolen, C. Scheinecker, Phenotypic and functional deficiencies of monocyte-derived
[19]
[20]
[21]
[22]
dendritic cells in systemic lupus erythematosus (SLE) patients, Int. Immunol. 16 (2004) 1595–1604. D. Ding, H. Mehta, W.J. McCune, M.J. Kaplan, Aberrant phenotype and function of myeloid dendritic cells in systemic lupus erythematosus, J. Immunol. 177 (2006) 5878–5889. P. Blanco, A.K. Palucka, M. Gill, V. Pascual, J. Banchereau, Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus, Science 294 (2001) 1540–1543. P. Decker, I. Kotter, R. Klein, B. Berner, H.G. Rammensee, Monocyte-derived dendritic cells over-express CD86 in patients with systemic lupus erythematosus, Rheumatology (Oxford) 45 (2006) 1087–1095. P. Duffau, J. Seneschal, C. Nicco, C. Richez, E. Lazaro, I. Douchet, C. Bordes, J.F. Viallard, C. Goulvestre, J.L. Pellegrin, B. Weil, J.F. Moreau, F. Batteux, and P. Blanco, Platelet CD154 potentiates interferon-alpha secretion by plasmacytoid dendritic cells in systemic lupus erythematosus. Sci Transl Med 2 47ra63. P. Decker, H. Singh-Jasuja, S. Haager, I. Kotter, H.G. Rammensee, Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation, J. Immunol. 174 (2005) 3326–3334. M.W. Boule, C. Broughton, F. Mackay, S. Akira, A. Marshak-Rothstein, I.R. Rifkin, Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatinimmunoglobulin G complexes, J. Exp. Med. 199 (2004) 1631–1640. T.K. Means, E. Latz, F. Hayashi, M.R. Murali, D.T. Golenbock, A.D. Luster, Human lupus autoantibody–DNA complexes activate DCs through cooperation of CD32 and TLR9, J. Clin. Invest. 115 (2005) 407–417. H.J. Anders, D. Zecher, R.D. Pawar, P.S. Patole, Molecular mechanisms of autoimmunity triggered by microbial infection, Arthritis Res. Ther. 7 (2005) 215–224. F.J. Barrat, T. Meeker, J. Gregorio, J.H. Chan, S. Uematsu, S. Akira, B. Chang, O. Duramad, R.L. Coffman, Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus, J. Exp. Med. 202 (2005) 1131–1139. K. Yasuda, C. Richez, M.B. Uccellini, R.J. Richards, R.G. Bonegio, S. Akira, M. Monestier, R.B. Corley, G.A. Viglianti, A. MarshakRothstein, I.R. Rifkin, Requirement for DNA CpG content in TLR9-dependent dendritic cell activation induced by DNAcontaining immune complexes, J. Immunol. 183 (2009) 3109–3117. T. Lovgren, M.L. Eloranta, U. Bave, G.V. Alm, L. Ronnblom, 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. 50 (2004) 1861–1872. K. Steinbrink, M. Wolfl, H. Jonuleit, J. Knop, A.H. Enk, Induction of tolerance by IL-10-treated dendritic cells, J. Immunol. 159 (1997) 4772–4780. R.M. Steinman, D. Hawiger, M.C. Nussenzweig, Tolerogenic dendritic cells, Annu. Rev. Immunol. 21 (2003) 685–711.
Pierre Duffau Patrick Blanco⁎ CNRS UMR 5164, 146 rue Léo Saignat, 33076 Bordeaux, France IFR-66, 146 rue Léo Saignat, 33076 Bordeaux, France Université Victor Segalen Bordeaux2, 146 rue Léo Saignat, 33076 Bordeaux, France Centre Hospitalier Universitaire de Bordeaux, Place Amélie Raba Léon, 33076 Bordeaux cedex, France ⁎Corresponding author. Fax: +33 05 56 79 56 45. E-mail address: [email protected].