Clinical Immunology (2007) 122, 125 — 134

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Autoimmunity versus tolerance: Can dying cells tip the balance?                                                           ...
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Autoimmunity versus tolerance: Can dying cells tip the balance?                                                           ...
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Autoimmunity versus tolerance: Can dying cells tip the balance?                                                           ...
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Autoimmunity versus tolerance: Can dying cells tip the balance?                                                           ...
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Autoimmunity versus tolerance: Can dying cells tip the balance?


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Autoimmunity versus tolerance: Can dying cells tip the balance?

  1. 1. Clinical Immunology (2007) 122, 125 — 134 available at SHORT ANALYTICAL REVIEW Autoimmunity versus tolerance: Can dying cells tip the balance? Irene C.B. Viorritto a,b, Nikolay P. Nikolov c, Richard M. Siegel b,c,* a Cell Signaling Section, Genetic Disease Research Branch NHGRI, NIH, Building 49, Room 4A38, Bethesda, MD 20892, USA b Immunology Graduate Group, University of Pennsylvania School of Medicine, USA c Immunoregulation Unit, Autoimmunity Branch, NIAMS, NIH, Building 10, Room 9N238, Bethesda, MD 20892, USA Received 17 July 2006; accepted with revision 19 July 2006 Available online 5 October 2006 KEYWORDS Abstract Apoptosis is a physiological process of self-destruction for cells that are damaged Apoptosis; or programmed to die. Apoptosis occurs through a series of regulated events that allow Autoimmunity; cellular debris to be contained and efficiently phagocytosed without initiating a proinflam- Phagocytosis; matory immune response. Recent data have linked physiological apoptosis and the uptake of Dentritic cell; apoptotic cells by macrophages and some subsets of dendritic cells to the maintenance of Toll-like receptor peripheral immune tolerance. However, when cells die through necrosis, spilling their intracellular contents, or are infected with various pathogens, activation of antigen- presenting cells and induction of an immune response can occur. Receptors for extrinsic pathogen-associated structures, such as membrane bound Toll-like receptors (TLRs) or intracellular Nod-like receptors (NLRs) can also respond to cross-reactive host molecules from dying cells and may focus autoimmune responses onto these antigens. Several autoimmune disorders have been linked to defects in the apoptotic process. Defective apoptosis of immune cells leads to autoimmunity, as in autoimmune lymphoproliferative syndrome (ALPS) associated with mutations in the death receptor Fas. Defective clearance of apoptotic cell debris can also lead to autoantibody production. We will discuss how cell death and apoptotic cell clearance may affect the finely tuned balance between peripheral immune tolerance and autoimmunity. Published by Elsevier Inc. Overview Apoptosis, or programmed cell death, is a physiological * Corresponding author. Bldg 10 Rm 9N238, Bethesda MD 20892 process occurring in cells that are damaged or no longer 301-496-3761, USA. Fax: +1 301 480 3880. useful, including embryogenesis and tissue homeostasis. E-mail address: (R.M. Siegel). During apoptosis the cell is degraded by a series of regulated 1521-6616/$ — see front matter. Published by Elsevier Inc. doi:10.1016/j.clim.2006.07.012
  2. 2. 126 I.C.B. Vioritto et al. steps that allow rapid uptake and removal of cellular debris which primes the apoptosome, a cytoplasmic protein com- by phagocytes without causing inflammation. By contrast, plex of caspase-9 and the upstream activator APAF-1 to cells that die by necrosis spill their cellular contents including cleave caspase-9 into its active form. Caspase-9 cleaves molecules that stimulate inflammation and dendritic cell caspases-3 and -7, which in turn cleave specific substrates, activation that can prime adaptive immune responses against activating a defined cellular program of plasma membrane self-antigens. Apoptotic cell clearance has an important role blebbing, cytoplasmic and organelle contraction and shrink- in embryonic development, tissue homeostasis, and the age, nuclear chromatin condensation, DNA and RNA degra- maintenance of self-tolerance. Signals from the dying cell dation by specific nucleases, and cytoskeletal reorganization such as the exposure of phosphatidylserine on the exterior (reviewed in [1,2]). One of the earliest changes at the plasma surface of the plasma membrane, are recognized by multiple membrane is the display of phosphatidylserine (PS), a receptors on the surface of phagocytic cells, providing a swift membrane lipid that is usually restricted to the inner plasma and efficient disposal system for dying cells. Defects in membrane leaflet, on the external face of the plasma cell apoptosis or the uptake of dying cells by macrophages and membrane. PS provides a platform for recruiting phagocytic dendritic cells have been shown to play a role in several cells to vicinity of dying cells, and the resulting apoptotic pathological conditions, including cancer, neurodegenerative bodies are rapidly ingested by neighboring cells and resident diseases, and autoimmunity. We will discuss recent data on tissue macrophages and dendritic cells (DCs), via receptor- the role of macrophages and dendritic cells in apoptotic cell mediated mechanisms (reviewed in [3]). Although the clearance, and describe how the mode of cell death and dead dflippingT of membrane lipids to allow PS exposure is cell uptake may influence the finely tuned balance between caspase-dependent, PS can become accessible in any cell maintaining immune tolerance and initiation of an potentially losing membrane integrity and is thus not a signal that only pathogenic autoimmune or autoinflammatory response. marks apoptotic cells. Necrosis occurs when cell death is daccidentalT rather Cell death: general mechanisms than programmed. Necrosis is often associated with me- chanical tissue damage, or certain infectious agents. It is Apoptosis, also referred to as programmed cell death, is a characterized by cell swelling, total cellular breakdown, morphologically identifiable form of cell death characterized early loss of plasma membrane integrity, and release of by a complex series of processes that adhere to a strict intracellular contents. Whether active signaling pathways timeline (Fig. 1). The initiating signals for cell death are play a role in necrosis or if it is simply a passive response to integrated by a number of mechanisms, including interac- external catastrophe is not clear at this time. The early tions between pro and anti-apoptotic members of the bcl-2 breakdown of the plasma membrane in necrosis facilitates protein family. If a critical threshold is reached, the spilling of intracellular contents, which can contain immu- mitochondrial outer membrane becomes permeable to large nostimulatory molecules such as heat shock proteins [4]. molecules (MOMP). Mitochondria release cytochrome c, Undegraded mammalian DNA and RNA may also be immu- Figure 1 Steps in apoptosis and apoptotic cell uptake. Critical stages are shown for the apoptotic cell at bottom, with the phosphatidylserine externalized on the plasma membrane early in apoptosis serving as the main signal for apoptotic cell uptake by a macrophage at top.
  3. 3. Autoimmunity versus tolerance: Can dying cells tip the balance? 127 Table 1 Comparing cellular modifications in apoptotic and necrotic death Apoptosis Necrosis Cellular role Active Passive Distribution Dispersed Contiguous Morphology Decreased cell volume Increased cell volume Cellular membrane Preserved Loss of integrity Induction Slow (hours) Rapid (seconds—minutes) Cell removal Rapid Slow Tissue inflammation Absent Present nostimulatory through cross-reactive interactions with cel- whereby organelles or long-lived proteins are digested in lular receptors for pathogen-derived nucleic acids. A double-membrane enclosed lysosome-like structures. In comparison of some of the features of apoptosis and necrosis other cells, a necrosis-like phenotype with rapid cell lysis is shown in Table 1. is observed [5,6]. A distinct mechanism of cell death termed danoikisT has also been described following detach- ment of adherent cells from extracellular matrix substrates Alternative cell death pathways: autophagic cell [7]. death, anoikis It has recently become clear that there are other mechan- Engulfment of dying cells and presentation of isms of programmed cell death distinct from caspase- self-antigens mediated apoptosis. In certain circumstances, stimulation of cells in the presence of caspase blockade with agents In order for activation of the adaptive immune response by that would normally induced apoptosis or other cellular antigens derived from dying cells, efficient presentation responses results in cell death that has biochemical and and costimulation by antigen-presenting cells is necessary morphological features resembling autophagy, a process (Fig. 2). Macrophages and particular subsets of dendritic Figure 2 Influence of apoptotic and other cellular stimuli on activation of antigen-presenting cells. The mode of cell death, kinetics of uptake and presence of other activation signals determine the cell type that clears dying cells and the immunological outcome.
  4. 4. 128 I.C.B. Vioritto et al. cells are responsible for clearance of dying cells in the peripheral tolerance via by presentation of self-antigen tissues. Once engulfed, antigens derived from the dead cells (Fig. 2) [15,16]. Additionally, dendritic cell maturation is are processed and presented at the cell surface associated required for the efficient formation of MHC class II-peptide with the major histocompatibility complex (MHC). Classical- complexes and trafficking of these complexes to the cell ly, MHC class II molecules, known to associate with peptides surface in dendritic cells [17]. Nevertheless, peripheral derived from exogenous antigens, present antigens derived non-mature dendritic cells have been shown to be effective from engulfed apoptotic cells (reviewed in [8]). However, at inducing clonal deletion and anergy in autoreactive CD8+ exogenous antigens can also enter the MHC class I presenta- T cells [18,19]. tion pathway for presentation to CD8+ T cells, a process For skin-derived antigens the situation may be different, called bcross-presentationQ, at which dendritic cells are in that epidermal Langerhans cells were recently shown to particularly adept [9]. Both classical exogenous antigen present a self-antigen derived peptide and activate naRve presentation by MHC class II and MHC class I restricted antigen-specific T cells and induce a chronic skin disease antigen cross-presentation are closely linked to the matura- without any apparent exogenous stimuli [20]. This work tion of dendritic cells, which requires additional signals suggests that, unlike other DCs, Langerhans cells may beyond phagocytosis of apoptotic cells. spontaneously mature and initiate immunogenic responses, Dendritic cell maturation involves changes in cellular and that additional mechanisms must control autoreactiv- morphology and trafficking of antigens that transform ity to skin-derived self-antigens. Physiologically, tissue these cells from phagocytes to efficient antigen-presenting macrophages are likely to be the cell type that phagocy- cells. Immature dendritic cells are present in the circula- tose most apoptotic cells in vivo. After apoptotic cell tion and a number of organs, and have been shown to be uptake, macrophages produce cytokines such as TGF-B, over five-fold more efficient than mature DCs at phago- PGE2, and PAF that dampen activation of adaptive immune cytosing apoptotic cells [10]. Maturation signal(s) repro- cells. Thus, macrophages may actively suppress immune gram dendritic cells to become highly efficient antigen- responses rather than present antigen in a tolerogenic presenting cells, a differentiation step that involves manner [21]. changes in the structure of secretory organelles and Two theories were initially proposed as to how innate antigen trafficking to increase antigen presentation, immune cells are activated. The first, proposed by the late upregulation of surface molecules including CD40, CD80, Charles Janeway in 1989 [22], suggested the existence of and CD86, as well as MHC class II. Maturation signals also an innate pattern recognition system for common struc- trigger dendritic cell migration to draining lymph nodes, tures of antigens from bstrangersQ (e.g., bacterial compo- where antigen presentation to T cells takes place [10—12]. nents). In 1997 the discovery of Toll-like receptors Mature dendritic cells are uniquely efficient at activating validated Janeway’s theory [23]. At least 13 Toll-like naRve T cells, making them ideal cells to initiate immune receptors (TLRs) that recognize extracellular bforeignQ responses to foreign antigens, but also able to activate antigens, such as bacterial cell walls, bacterial DNA motifs, self-reactive T cells present in the periphery that have and viral DNA and RNA, have been identified in mammals. escaped negative selection in the thymus. However, as we Examples of this are the activation of DCs via TLR5 in will discuss, consensus has emerged that antigens from response to bacterial flagellum proteins or TLR3 in response dying cells are presented in a tolerogenic fashion unless to virally infected cells [24,25]. Importantly, it has been other signals are provided that cause maturation of found that TLRs can, in some cases, be triggered by cross- antigen-presenting cells or synthesis of cytokines that reacting host molecules, such as in the case of TLR9- prime the adaptive immune system. mediated B cell costimulation which can apparently be triggered by mammalian chromosomal DNA released from dying cells [26]. A more specific demonstration of the Immunogenicity versus tolerance to antigens involvement of TLR9 in autoantibody production was made from dying cells by crossing TLR9À/À mice to a lupus-prone MRL/MRlpr/lpr background. In the absence of TLR9, but not TLR3, anti- Since apoptosis occurs physiologically in many tissues, one dsDNA and anti-chromatin antibody production was com- proposed model for inducing peripheral tolerance is that pletely ablated. However, other lupus-associated autoanti- immature DCs constantly survey their immunological milieu bodies, such as anti-Smith antigen (anti-Sm), were through endocytosis and phagocytosis mediated by scaven- maintained or even increased in TLR9À/À mice. Surprisingly, ger receptors and uptake of apoptotic cell debris. Whether these mice still developed immune complex nephritis, or not a particular subset of dendritic cells is specialized for suggesting that although anti-dsDNA autoantibodies may the uptake of apoptotic cells is controversial: in the mouse, predict nephritis in SLE, they are not the exclusive the CD8+ dlymphoidT subset of dendritic cells has been most pathogenic specificity [27]. TLR7 (or TLR8 in humans), often implicated [13,14]. Normal recirculation of dendritic which binds ssRNA may regulate production of autoantibo- cells to the lymph node would then allow antigens to be dies against RNA, which may compensate for the lack of presented in a tolerogenic fashion. Local tissue antigen dsDNA antibodies in these mice. Another possibility is that uptake and trafficking by DCs to lymph nodes to present the anti-chromatin antibodies present in TLR9 sufficient tissue-specific self-antigen under non-immunostimulatory mice may actually be protective by mediating clearance of conditions without inducing active autoimmunity or full T immune complexes under conditions of high antigenic cell deletion has been demonstrated in a number of animal burden [28,29]. model systems. This suggests that continual transport of There may also be TLR-independent mechanisms by apoptotic bselfQ cells to the lymph nodes may relate to which cells can respond to foreign and cross-reactive
  5. 5. Autoimmunity versus tolerance: Can dying cells tip the balance? 129 autoantigens. Three groups recently reported a myeloid cell myocarditis, both CD40, a T-cell-derived activation signal, activation pathway stimulated by mammalian DNA that is and TLR signals were required [37]. independent of the TLR adapter molecules MyD88 and TRIF, but dependent on the adaptor protein IPS-1/VISA/MAVS. Mechanisms of apoptotic cell recognition and This innate inflammatory response is characterized by interferon (IFN)-beta induction, as well as TNFA and several uptake chemokines, and a pattern of gene upregulation unique to A better understanding of how antigens from dying cells may this novel sensing mechanism [30—32]. Whether TLR-inde- or may not trigger autoimmunity will come from elucidating pendent sensing of chromatin also plays a role in the the molecular pathways by which phagocytes sense and take pathogenesis of autoimmunity is not known. up these cells, and how these processes impact the Matzinger’s group has suggested an alternative concept maturation and antigen-presenting capability of these cells. of dendritic cell activation in which endogenous ddangerT There has been significant recent progress in identifying the signals from stressed or dying cells may activate host innate molecules involved in apoptotic cell recognition and uptake. immune cells in addition to exogenous dstrangerT signals. Most of these systems involve indirect recognition of the PS Several groups have demonstrated that necrotic cells or on the extracellular surface of the plasma membrane on the their supernatants can trigger maturation of immunostimu- dying cell through various dbridgeT molecules (Fig. 3). latory DCs, whereas apoptotic cells did not [10,33]. Opsonization via the classical and lectin complement path- However, simply pipetting DCs to dissociate cell interac- ways has also been demonstrated to play a role in the tions or transferring the resting dendritic cells to fresh phagocytosis of apoptotic cells as well as its established role plates was found to activate dendritic cells, which demon- in clearing many viruses, bacteria and fungi. Strikingly, strates the difficulties in studying this phenomenon in vitro impairment of many of these pathways in both and genetic [33]. This suggests that there may be several different human diseases strongly predisposes towards systemic pathways of triggering the activation of immunostimulatory autoimmunity. dendritic cells. The molecular identity of endogenous Mer, Tyro3 and Axl are members of a family of receptor bdangerQ signals has been elusive, because it is often tyrosine kinases that have recently been demonstrated to unclear whether, for example, a virally infected cell play roles in the regulation of macrophage and NKT cell secreting an inflammatory cytokine, IFNA is doing so in responses and cytokine production [38,39]. These receptors response to cellular stress/damage, or because the viral have also been shown to mediate recognition and initiate RNA has triggered an interferon response through TLRs or phagocytosis of apoptotic cells. Mer mRNA was found to be other receptors [34]. expressed in innate immune cells (macrophages, DCs, NKs, Some of the molecules that mediate the bdangerQ signals and NKT cells), but not in B or T cells [39]. Philip Cohen and may in fact be known triggers of inflammation in other colleagues have demonstrated that Mer is required for settings. In searching for the identity of factors in necrotic apoptotic cell engulfment in vitro by macrophages, but not cells that stimulated dendritic cell activation and cross- by dendritic cells. Tyro3 and Axl are not yet as well presentation to CD8+ T cells, Ken Rock’s group made the understood. Together, these three kinases, along with their surprising observation that uric acid, a byproduct of nucleic ligands, growth-arrest-specific gene 6 (GAS 6) and protein S, acid metabolism, can induce dendritic cell maturation. both of which have been shown to associate with PS, Uric acid significantly increased cytotoxic CD8+ T cell constitute one system of recognition of apoptotic cells. responses when co-injected with antigen in vivo at CD36 is a scavenger receptor that has been shown to concentrations high enough to form uric acid crystals, associate with phosphatidylserine (PS) via thrombospondin-1 [35]. Long known as a proinflammatory molecule when (TSP-1), which acts as a bridge molecule between PS on the crystallized in the joints in gout, uric acid was also apoptotic cell and CD36 on the macrophage. This receptor recently shown to stimulate the intracellular NLR protein has been suggested to work synergistically with the vitro- cias1 to activate the dinflammasomeT, a protein complex in nectin receptor, a avh3 integrin, on the surface of macro- which caspase-1 processes the inflammatory cytokine IL1-h phages to mediate the uptake of apoptotic cells [40—42]. into the mature active form [36]. If a bdangerQ signal was The vitronectin receptor may mediate phagocytosis primar- all that was necessary to break immune tolerance, one ily in unactivated macrophages whereas CD36 may the major might expect patients with gout, or those with activating mediator of uptake in activated macrophages. The vitro- cias1 mutations (associated with a number of familial nectin receptor may also be important in recognition of autoinflammatory syndromes) to suffer from autoimmunity. apoptotic cells through MFG-E8 (see below). However, in both these cases the disease remains strictly Milk fat globule-epidermal growth factor (EGF)-factor confined to symptoms resulting from innate immune 8 (MFG-E8) is another bridge molecule that links PS on the system activation. In addition, patients with genetic apoptotic cell to the vitronectin receptor. MFG-E8 is a gly- autoinflammatory diseases in which the inflammasome is coprotein secreted by activated macrophages, especially in hyperactivated through genetic mutations rarely develop germinal centers of the spleen and lymph nodes, as well as by autoantibody or lymphocyte-mediated pathology. This immature dendritic cells. MFG-E8 specifically binds to suggests that while TLR-mediated or other innate signals phosphatidylserine on apoptotic cells, facilitating their may provide dfuel for the fireT of systemic autoimmunity by engulfment, and plays a critical role in facilitating the focusing adaptive autoimmune responses on particular clearance of apoptotic B cells in germinal centers [43,44]. antigens, but they seem unlikely to initiate autoimmune C1q and C4 are important early components of the disease alone. In support of this idea, it was found that to classical pathway of complement and are two of the activate dendritic cells sufficiently to trigger autoimmune strongest disease susceptibility genes for the development
  6. 6. 130 I.C.B. Vioritto et al. Figure 3 Ligands and receptors involved in apoptotic cell recognition and uptake. The major recognition systems for surface proteins on dying cells are shown. MBP: Maltose binding protein, MFG-E8: milk fat globule protein E8, PSR: putative phosphatidylserine receptor. of systemic lupus erythematosus (SLE) known in humans. sequence analysis suggests that the proposed PSR could in Cell clearance is reported to be dependent on C1q both fact be a transcription factor that promotes upregulation of through direct recognition of apoptotic cells and activation genes required for phagocytosis of PS+ cells, perhaps of the classical complement pathway. C4 has also been explaining the original transfection experiments that iden- suggested as a mediator of apoptotic cell uptake, possibly tified this molecule. through a different mechanism. Studies suggest that cellular uptake can be mediated by complement receptors on macrophages [45,46]. One proposed mechanism of uptake When uptake goes wrong via C1q is through interaction with CD91 on the phago- cyte. Receptors mediating C4-dependent uptake by pha- Under normal circumstances, apoptotic cells are rapidly gocytes have remained elusive [47]. Mannose-binding cleared by phagocytes [53]. However, if uptake is impaired, lectin and soluble IgM, which can bind C1q and activate or cell death enhanced, apoptotic material may build up to a compliment have also been implicated in apoptotic cell point that overwhelms the uptake systems discussed above. clearance, suggesting the involvement of both the classi- In these circumstances, it has been suggested that self- cal and mannose-binding lectin branches of the comple- tolerance breaks down due to the priming of autoreactive ment pathway. lymphocytes by more efficient antigen-presenting cells that would then take up apoptotic material. If uptake of apoptotic cells is delayed, secondary necrosis may ensue, Phosphatidylserine receptor (PSR) resulting in the exposure of proinflammatory intracellular molecules. Mice deficient in a number of the molecules PSR was discovered in a screen for genes that conferred PS- necessary for apoptotic cell recognition and uptake manifest specific binding and uptake of apoptotic cells [48]. It was similar autoimmune phenotypes (Table 2). proposed to directly recognize PS on apoptotic cells. Triple knockout mice for the related Tyro3/Axl/Mer However, from gene knockout studies in mice it has become receptors have profound defects in apoptotic cell clearance, clear that PSR may act more indirectly. PSRÀ/À mice have blindness (due to failure of retinal epithelial cells to clear defects in mammalian organogenesis, erythropoiesis and T shed outer segment layers resulting in the death of lymphopoiesis, and some groups reported impaired clear- photoreceptor cells), and neurological abnormalities. Addi- ance of apoptotic cells in embryonic liver and thymus. tionally, these mice develop splenomegaly and spontaneous However, this did not induce the upregulation of inflamma- antibodies against nuclear antigens, swollen joints with tory cytokines [49—51]. Rather than being a cell surface lymphocyte infiltration, as well as IgG deposits in the kidney receptor, PSR appears to be a nuclear protein, and may not leading to glomerulonephritis, a common complication of have a bona fide transmembrane domain [52]. Further SLE [54]. Macrophages from merÀ/À mice were reported to
  7. 7. Autoimmunity versus tolerance: Can dying cells tip the balance? 131 Table 2 Phenotypes of mice deficient in apoptotic cell uptake Molecule Phenotype of knockout mouse C1q/C4 Systemic autoimmunity with autoantibodies and glomerulonephritis Increased numbers of apoptotic cells in glomeruli (C1q only) Delayed clearance of apoptotic cells from the peritoneal cavity IgM Autoimmunity to nuclear Ags; renal IgG and complement deposition Mer/Tyro3/Axl and Mer (single KO) Autoimmunity to nuclear Ags; renal IgG and complement deposition Defect in clearance of apoptotic cells in the thymus and spleen MFG-E8 Glomerulonephritis, splenomegaly, autoantibodies, Numerous germinal centers with increased apoptotic B cells PSR (phosphatidylserine receptor) Abnormal development and neonatal lethality Accumulation of apoptotic cells in brain and lungs DNaseI Autoimmunity to chromatin; renal IgG and complement deposition Glomerulonephritis be ~90% less efficient in phagocytosis of apoptotic cells suggesting that CYP1B1 may have an unexpected role in compared to macrophages from wild-type mice [55] and also macrophage phagocytic function that is important for develop elevated levels of antinuclear. However, the genesis maintenance of immunological self-tolerance [57]. Macro- of autoimmunity in these mice may also be linked to phages from patients with systemic lupus erythematosus excessive dendritic cell activation by Toll-like receptors, have also been found to have phagocytic defects [58—60], as MerÀ/À macrophages have increased expression of although in these human studies, it is difficult to determine costimulatory surface molecules and increased production if this is a cause or consequence of the disease. of proinflammatory cytokines such as TNFA in response to Another important mouse model for systemic lupus LPS. erythematosus (SLE) is the C1q-deficient mouse. Homozy- MFG-E8À/À mice develop splenomegaly with the forma- gous deficiency in C1q is associated with severe SLE in tion of numerous germinal centers, and suffer from humans. C1q-deficient mice have a defect in phagocytic glomerulonephritis due to autoantibody production. Macro- uptake of apoptotic cells by activated macrophages as well phages from the MFG-E8-deficient mouse demonstrated a as resident peritoneal macrophages. C1q-deficient mice four-fold decrease in their efficiency of apoptotic cell develop glomerulonephritis with an excess of glomerular uptake compared to wild-type macrophages. However, apoptotic bodies. Mice deficient in C4, another member of engulfment of microspheres was not affected in the the classical complement pathway, show a less severe MFG-E8À/À mice. This mouse model suggests that MFG-E8 disease phenotype than C1qÀ/À mice, and no impairment has a critical role in clearing apoptotic B cells from of resident peritoneal macrophage phagocytic uptake. C3- germinal centers and failure to remove these cells can deficient mice do not develop autoimmunity, suggesting a lead to autoimmunity. Notably, it was found that MFG-E8 hierarchical role for classical compliment proteins in is expressed in immature DCs such as Langerhans cells but apoptotic cell clearance [45]. Similarly, patients with C4 not in thymic macrophages and thus not involved in deficiencies generally have less severe SLE, and those with clearance of apoptotic thymocytes, suggesting that differ- C3 and C2 deficiencies are often non-symptomatic. Addi- ent tissues may use different recognition systems for the tionally, low levels of mannose-binding lectin (which plays uptake of apoptotic cells [44]. This group has also shown the same role as C1q in the lectin pathway) have also been that MFG-E8 carrying a mutation in the second EGF associated with SLE. In conjunction with these findings, domain, designated D89E, inhibited the phagocytosis of deficiencies in molecules that can bind C1q and activate the apoptotic cells both in vitro and in vivo by a variety of classical pathway, such as soluble IgM, have also been linked phagocytes. This mutation masks PS on apoptotic cells. to increased incidence of autoimmunity in humans and Injection of mutated MFG-E8 into mice induced autoanti- mouse models [61]. body production. This effect was exacerbated by co- Supporting the hypothesis that ordered degradation of injecting apoptotic thymocytes. The authors suggest that DNA reduces its immunogenicity, mice deficient in DNAse I the perturbation of apoptotic cell clearance and the also develop systemic autoimmunity. Additionally, data consistent presentation of self-antigens may be enough implicating apoptotic cell debris as immunogens in SLE have to disrupt peripheral immune tolerance [56]. come from DNAse I-deficient mice. DNAse IÀ/À mice develop Mice deficient in even seemingly unrelated molecules can anti-chromatin antibodies similar to those in human SLE develop autoimmunity if apoptotic cell uptake is impaired. patients, as well as glomerulonephritis due to the deposition For example, cytochrome P450 1B1 (CYP1B1) enzyme- of immune complexes in glomeruli [62]. Two human SLE deficient mice were found to have evidence of systemic patients were also reported to have heterozygous nonsense autoimmunity, manifested by antinuclear and anti-DNA mutations in exon 2 of the gene encoding DNAse I [63]. antibodies as well as immune complex deposition in the DNAse I acts together with C1q to efficiently degrade kidney and glomerulonephritis. CYP1B1 is highly expressed necrotic cell-derived chromatin [64]. A significant reduction in the mononuclear phagocyte lineage. Peritoneal macro- of DNAse I activity in sera from SLE patients and patients phages from CYP1B1-deficient mice were impaired in the with rheumatoid arthritis (RA) compared with sera from phagocytosis of apoptotic, necrotic and opsonized cells, healthy donors has been observed. However, only SLE sera
  8. 8. 132 I.C.B. Vioritto et al. showed a strongly reduced capacity to degrade necrotic tolerance to autoimmunity so much as how the dying cell is cell-derived chromatin [65]. Administration of DNAse has perceived; through beat meQ signals from the state of the been studied as a therapeutic modality in patients with SLE, dying cell, the signals and debris it releases, and how long it and was well tolerated, but did not produce clinical persists before phagocytosis occurs. improvement in a small phase I study [66]. Unlike other models mentioned above, macrophages from DNAse I- References deficient mice are not defective in apoptotic cell clearance. Instead, these data support the idea that non-degraded DNA [1] T. Aigner, Apoptosis, necrosis, or whatever: how to find out can lead to enhanced immunogenicity. Whether TLR or other what really happens? J. Pathol. 198 (2002) 1 – 4. innate immune sensors contribute to autoimmunity in [2] M.O. Hengartner, The biochemistry of apoptosis, Nature 407 DNAse-deficient mice is not known. (2000) 770 – 776. Unlike cell death in non-immune cells, which may fuel [3] A. Roos, W. Xu, G. Castellano, A.J. Nauta, P. Garred, M.R. autoimmunity, death of immune cells is generally a negative Daha, C. van Kooten, Mini-review: a pivotal role for innate signal for immune responses to pathogens as well as self- immunity in the clearance of apoptotic cells, Eur. J. Immunol. antigens. A large amount of cell death occurs in peripheral T 34 (2004) 921 – 929. and B cells after antigenic activation, and it has been [4] M.H. Manjili, J. Park, J.G. Facciponte, J.R. Subjeck, HSP110 induces bdanger signalsQ upon interaction with antigen pre- estimated that approximately 90% of antigen-specific lym- senting cells and mouse mammary carcinoma, Immunobiology phocytes die after initial activation. Some of this cell death 210 (2005) 295 – 303. is under the control of the BH3-family protein Bim, which [5] G. Denecker, D. Vercammen, M. Steemans, T. Vanden Berghe, initiates mitochondrial-dependent apoptosis. In addition to G. Brouckaert, G. Van Loo, B. Zhivotovsky, W. Fiers, J. Grooten, accumulation of peripheral T and B cells, Bim-deficient mice W. Declercq, P. Vandenabeele, Death receptor-induced apop- develop systemic autoimmunity on some genetic back- totic and necrotic cell death: differential role of caspases and grounds [67]. In humans with the autoimmune lymphopro- mitochondria, Cell Death Differ. 8 (2001) 829 – 840. liferation syndrome (ALPS) due to mutations in the death [6] L. Yu, A. Alva, H. Su, P. Dutt, E. Freundt, S. Welsh, E.H. receptor Fas/CD95, or lpr/lpr mice homozygous for loss of Baehrecke, M.J. Lenardo, Regulation of an ATG7-beclin 1 function mutations in Fas, multiple immune cell types are program of autophagic cell death by caspase-8, Science 304 (2004) 1500 – 1502. resistant to apoptosis induced through ligation of this [7] M. Zhan, H. Zhao, Z.C. Han, Signalling mechanisms of anoikis, receptor by Fas ligand, which occurs particularly in Histol. Histopathol. 19 (2004) 973 – 983. chronically restimulated T and B cells [68]. Unlike sporadic [8] K.L. Rock, I.A. York, T. Saric, A.L. Goldberg, Protein degrada- SLE, Fas deficiency also produces the accumulation of an tion and the generation of MHC class I-presented peptides, Adv. unusual subset of CD3/CD4 ddouble negativeT T cells, which Immunol. 80 (2002) 1 – 70. can be useful for diagnostic purposes. Autoantibody pro- [9] M.L. Albert, B. Sauter, N. Bhardwaj, Dendritic cells acquire duction is common in ALPS and lpr mice but nephritis is rare antigen from apoptotic cells and induce class I-restricted CTLs, except on susceptible genetic backgrounds. Additionally, a Nature 392 (1998) 86 – 89. recent report suggests that the death of terminally [10] B. Sauter, M.L. Albert, L. Francisco, M. Larsson, S. Somersan, differentiated DCs may also contribute to immune toler- N. Bhardwaj, Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, ance. Mice engineered to express the baculovirus caspase induces the maturation of immunostimulatory dendritic cells, inhibitor p35 in dendritic cells developed late onset sys- J. Exp. Med. 191 (2000) 423 – 434. temic autoimmunity with nephritis on susceptible genetic [11] R.M. Steinman, S. Turley, I. Mellman, K. Inaba, The induction of backgrounds [69]. tolerance by dendritic cells that have captured apoptotic cells, J. Exp. Med. 191 (2000) 411 – 416. [12] L. Delamarre, H. Holcombe, I. Mellman, Presentation of Conclusion exogenous antigens on major histocompatibility complex (MHC) class I and MHC class II molecules is differentially Defects in apoptosis and the clearance of apoptotic cells regulated during dendritic cell maturation, J. Exp. Med. 198 have been linked to several autoimmune diseases, especially (2003) 111 – 122. [13] T.A. Ferguson, J. Herndon, B. Elzey, T.S. Griffith, S. Schoenberger, SLE. Many mouse disease models implicate apoptotic cell D.R. Green, Uptake of apoptotic antigen-coupled cells by uptake mediators such as Mer/Tyro3 and MFG-E8 as having lymphoid dendritic cells and cross-priming of CD8(+) T cells critical roles in protecting against autoimmunity by effi- produce active immune unresponsiveness, J. Immunol. 168 (2002) ciently clearing self-antigens associated with apoptotic 5589 – 5595. cells. As discussed here, the uptake of apoptotic cells by [14] O. Schulz, C. Reis e Sousa, Cross-presentation of cell-associ- immature dendritic cells has been shown to promote ated antigens by CD8alpha+ dendritic cells is attributable to tolerance, whereas cell debris in combination with matura- their ability to internalize dead cells, Immunology 107 (2002) tion triggers such as danger/stranger signals will elicit an 183 – 189. inflammatory immune response. This can result in cytotoxic [15] C. Scheinecker, R. McHugh, E.M. Shevach, R.N. Germain, Constitutive presentation of a natural tissue autoantigen T cell activation via cross-presentation of exogenous self exclusively by dendritic cells in the draining lymph node, antigens in the context of MHC class I, but additional signals J. Exp. Med. 196 (2002) 1079 – 1090. are probably necessary to initiate and maintain systemic [16] F.P. Huang, N. Platt, M. Wykes, J.R. Major, T.J. Powell, C.D. autoimmunity. Macrophages are also involved in the main- Jenkins, G.G. MacPherson, A discrete subpopulation of den- tenance of tolerance by silently phagocytosing apoptotic dritic cells transports apoptotic intestinal epithelial cells to T cells and producing anti-inflammatory cytokines. Thus, it cell areas of mesenteric lymph nodes, J. Exp. Med. 191 (2000) may not be the dying cell itself that tips the balance from 435 – 444.
  9. 9. Autoimmunity versus tolerance: Can dying cells tip the balance? 133 [17] K. Inaba, S. Turley, T. Iyoda, F. Yamaide, S. Shimoyama, C. [35] Y. Shi, J.E. Evans, K.L. Rock, Molecular identification of a Reis e Sousa, R.N. Germain, I. Mellman, R.M. Steinman, The danger signal that alerts the immune system to dying cells, formation of immunogenic major histocompatibility complex Nature 425 (2003) 516 – 521 (Electronic publication 2003 Sep class II-peptide ligands in lysosomal compartments of den- 2007). dritic cells is regulated by inflammatory stimuli, J. Exp. Med. [36] F. Martinon, V. Petrilli, A. Mayor, A. Tardivel, J. Tschopp, Gout- 191 (2000) 927 – 936. associated uric acid crystals activate the NALP3 inflamma- [18] G.M. Davey, C. Kurts, J.F. Miller, P. Bouillet, A. Strasser, A.G. some, Nature 440 (2006) 237 – 241. Brooks, F.R. Carbone, W.R. Heath, Peripheral deletion of [37] U. Eriksson, R. Ricci, L. Hunziker, M.O. Kurrer, G.Y. Oudit, T.H. autoreactive CD8 T cells by cross presentation of self-antigen Watts, I. Sonderegger, K. Bachmaier, M. Kopf, J.M. Penninger, occurs by a Bcl-2-inhibitable pathway mediated by Bim, J. Exp. Dendritic cell-induced autoimmune heart failure requires Med. 196 (2002) 947 – 955. cooperation between adaptive and innate immunity, Nat. [19] F. Lambolez, K. Jooss, F. Vasseur, A. Sarukhan, Tolerance Med. 9 (2003) 1484 – 1490. induction to self antigens by peripheral dendritic cells, Eur. [38] C. Heiring, B. Dahlback, Y.A. Muller, Ligand recognition J. Immunol. 32 (2002) 2588 – 2597. and homophilic interactions in Tyro3: structural insights [20] D. Mayerova, E.A. Parke, L.S. Bursch, O.A. Odumade, K.A. into the Axl/Tyro3 receptor tyrosine kinase family, J. Biol. Hogquist, Langerhans cells activate naive self-antigen-specific Chem. 279 (2004) 6952 – 6958 (Electronic publication 2003 CD8 T cells in the steady state, Immunity 21 (2004) 391 – 400. Nov 6917). [21] V.A. Fadok, D.L. Bratton, A. Konowal, P.W. Freed, J.Y. [39] E.M. Behrens, P. Gadue, S.Y. Gong, S. Garrett, P.L. Stein, P.L. Westcott, P.M. Henson, Macrophages that have ingested Cohen, The mer receptor tyrosine kinase: expression and apoptotic cells in vitro inhibit proinflammatory cytokine function suggest a role in innate immunity, Eur. J. Immunol. production through autocrine/paracrine mechanisms involving 33 (2003) 2160 – 2167. TGF-beta, PGE2, and PAF, J. Clin. Invest. 101 (1998) 890 – 898. [40] V.A. Fadok, M.L. Warner, D.L. Bratton, P.M. Henson, CD36 is [22] C.A. Janeway Jr., Approaching the asymptote? Evolution and required for phagocytosis of apoptotic cells by human macro- revolution in immunology, Cold Spring Harbor Symp. Quant. phages that use either a phosphatidylserine receptor or the Biol. 54 (1989) 1 – 13. vitronectin receptor (alpha v beta 3), J. Immunol. 161 (1998) [23] R. Medzhitov, P. Preston-Hurlburt, C.A. Janeway Jr., A human 6250 – 6257. homologue of the Drosophila Toll protein signals activation of [41] C. Grimsley, K.S. Ravichandran, Cues for apoptotic cell adaptive immunity, Nature 388 (1997) 394 – 397. engulfment: eat-me, don’t eat-me and come-get-me signals, [24] O. Schulz, S.S. Diebold, M. Chen, T.I. Naslund, M.A. Nolte, L. Trends Cell. Biol. 13 (2003) 648 – 656. Alexopoulou, Y.T. Azuma, R.A. Flavell, P. Liljestrom, C. Reis e [42] J. Savill, N. Hogg, Y. Ren, C. Haslett, Thrombospondin Sousa, Toll-like receptor 3 promotes cross-priming to virus- cooperates with CD36 and the vitronectin receptor in macro- infected cells, Nature 433 (2005) 887 – 892. phage recognition of neutrophils undergoing apoptosis, J. Clin. [25] R. Sporri, C. Reis e Sousa, Inflammatory mediators are Invest. 90 (1992) 1513 – 1522. insufficient for full dendritic cell activation and promote [43] R. Hanayama, M. Tanaka, K. Miwa, A. Shinohara, A. Iwamatsu, expansion of CD4+ T cell populations lacking helper function, S. Nagata, Identification of a factor that links apoptotic cells to Nat. Immunol. 6 (2005) 163 – 170 (Electronic publication 2005 phagocytes, Nature 417 (2002) 182 – 187. Jan 2016). [44] R. Hanayama, M. Tanaka, K. Miyasaka, K. Aozasa, M. Koike, Y. [26] E.A. Leadbetter, I.R. Rifkin, A.M. Hohlbaum, B.C. Beaudette, Uchiyama, S. Nagata, Autoimmune disease and impaired M.J. Shlomchik, A. Marshak-Rothstein, Chromatin-IgG com- uptake of apoptotic cells in MFG-E8-deficient mice, Science plexes activate B cells by dual engagement of IgM and Toll-like 304 (2004) 1147 – 1150. receptors, Nature 416 (2002) 603 – 607. [45] P.R. Taylor, A. Carugati, V.A. Fadok, H.T. Cook, M. Andrews, [27] S.R. Christensen, M. Kashgarian, L. Alexopoulou, R.A. Flavell, M.C. Carroll, J.S. Savill, P.M. Henson, M. Botto, M.J. Walport, A S. Akira, M.J. Shlomchik, Toll-like receptor 9 controls anti-DNA hierarchical role for classical pathway complement proteins in autoantibody production in murine lupus, J. Exp. Med. 202 the clearance of apoptotic cells in vivo, J. Exp. Med. 192 (2005) 321 – 331. (2000) 359 – 366. [28] A.B. Clarkson Jr., G.H. Mellow, Rheumatoid factor-like immu- [46] M. Botto, C. Dell’Agnola, A.E. Bygrave, E.M. Thompson, H.T. noglobulin M protects previously uninfected rat pups and dams Cook, F. Petry, M. Loos, P.P. Pandolfi, M.J. Walport, Homozy- from Trypanosoma lewisi, Science 214 (1981) 186 – 188. gous C1q deficiency causes glomerulonephritis associated with [29] P. Coulie, J. Van Snick, Rheumatoid factors and secondary multiple apoptotic bodies, Nat. Genet. 19 (1998) 56 – 59. immune responses in the mouse: II. Incidence, kinetics and [47] A.P. Manderson, M. Botto, M.J. Walport, The role of comple- induction mechanisms, Eur. J. Immunol. 13 (1983) 895 – 899. ment in the development of systemic lupus erythematosus, [30] K.J. Ishii, C. Coban, H. Kato, K. Takahashi, Y. Torii, F. Annu. Rev. Immunol. 22 (2004) 431 – 456. Takeshita, H. Ludwig, G. Sutter, K. Suzuki, H. Hemmi, S. Sato, [48] V.A. Fadok, D.L. Bratton, D.M. Rose, A. Pearson, R.A. M. Yamamoto, S. Uematsu, T. Kawai, O. Takeuchi, S. Akira, A Ezekewitz, P.M. Henson, A receptor for phosphatidylserine- Toll-like receptor-independent antiviral response induced by specific clearance of apoptotic cells, Nature 405 (2000) 85 – 90. double-stranded B-form DNA, Nat. Immunol. 7 (2006) 40 – 48. [49] Y. Kunisaki, S. Masuko, M. Noda, A. Inayoshi, T. Sanui, M. [31] Y. Okabe, K. Kawane, S. Akira, T. Taniguchi, S. Nagata, Toll-like Harada, T. Sasazuki, Y. Fukui, Defective fetal liver erythropoi- receptor-independent gene induction program activated by esis and T lymphopoiesis in mice lacking the phosphatidylserine mammalian DNA escaped from apoptotic DNA degradation, receptor, Blood 103 (2004) 3362 – 3364 (Electronic publication J. Exp. Med. 202 (2005) 1333 – 1339. 2004 Jan 3308). [32] D.B. Stetson, R. Medzhitov, Recognition of cytosolic DNA [50] M.O. Li, M.R. Sarkisian, W.Z. Mehal, P. Rakic, R.A. Flavell, activates an IRF3-dependent innate immune response, Immu- Phosphatidylserine receptor is required for clearance of nity 24 (2006) 93 – 103. apoptotic cells, Science 302 (2003) 1560 – 1563. [33] S. Gallucci, M. Lolkema, P. Matzinger, Natural adjuvants: [51] J. Bose, A.D. Gruber, L. Helming, S. Schiebe, I. Wegener, M. endogenous activators of dendritic cells, Nat. Med. 5 (1999) Hafner, M. Beales, F. Kontgen, A. Lengeling, The phosphati- 1249 – 1255. dylserine receptor has essential functions during embryo- [34] W.R. Heath, F.R. Carbone, Immunology: dangerous liaisons, genesis but not in apoptotic cell removal, J. Biol. 3 (2004) 15, Nature 425 (2003) 460 – 461. (Electronic publication 2004 Aug 2023).
  10. 10. 134 I.C.B. Vioritto et al. [52] P. Cui, B. Qin, N. Liu, G. Pan, D. Pei, Nuclear localization of explanation for the induction of autoantibodies in SLE, Lupus 6 the phosphatidylserine receptor protein via multiple nuclear (1997) 326 – 327. localization signals, Exp. Cell Res. 293 (2004) 154 – 163. [61] J.J. Manson, C. Mauri, M.R. Ehrenstein, Natural serum IgM [53] A.E. van Nieuwenhuijze, T. van Lopik, R.J. Smeenk, L.A. maintains immunological homeostasis and prevents autoimmu- Aarden, Time between onset of apoptosis and release of nity, Springer Semin. Immunopathol. 26 (2005) 425 – 432. nucleosomes from apoptotic cells: putative implications for [62] M. Napirei, H. Karsunky, B. Zevnik, H. Stephan, H.G. Mannherz, systemic lupus erythematosus, Ann. Rheum. Dis. 62 (2003) T. Moroy, Features of systemic lupus erythematosus in Dnase1- 10 – 14. deficient mice, Nat. Genet. 25 (2000) 177 – 181. [54] Q. Lu, G. Lemke, Homeostatic regulation of the immune system [63] S. Tsukumo, K. Yasutomo, DNAseI in pathogenesis of systemic by receptor tyrosine kinases of the Tyro 3 family, Science 293 lupus erythematosus, Clin. Immunol. 113 (2004) 14 – 18. (2001) 306 – 311. [64] U.S. Gaipl, T.D. Beyer, P. Heyder, S. Kuenkele, A. Bottcher, R.E. [55] R.S. Scott, E.J. McMahon, S.M. Pop, E.A. Reap, R. Caricchio, Voll, J.R. Kalden, M. Herrmann, Cooperation between C1q and P.L. Cohen, H.S. Earp, G.K. Matsushima, Phagocytosis and DNAse I in the clearance of necrotic cell-derived chromatin, clearance of apoptotic cells is mediated by MER, Nature 411 Arthritis Rheum. 50 (2004) 640 – 649. (2001) 207 – 211. [65] L.E. Munoz, U.S. Gaipl, S. Franz, A. Sheriff, R.E. Voll, J.R. [56] K. Asano, M. Miwa, K. Miwa, R. Hanayama, H. Nagase, S. Kalden, M. Herrmann, SLE—a disease of clearance deficiency? Nagata, M. Tanaka, Masking of phosphatidylserine inhibits Rheumatology (Oxford) 44 (2005) 1101 – 1107. apoptotic cell engulfment and induces autoantibody produc- [66] J.C. Davis Jr., S. Manzi, C. Yarboro, J. Rairie, I. McInnes, D. tion in mice, J. Exp. Med. 200 (2004) 459 – 467. Averthelyi, D. Sinicropi, V.G. Hale, J. Balow, H. Austin, D.T. [57] J.M. Ward, N.P. Nikolov, J.R. Tschetter, J.B. Kopp, F.J. Boumpas, J.H. Klippel, Recombinant human DNAse I Gonzalez, S. Kimura, R.M. Siegel, Progressive glomerulone- (rhDNAse) in patients with lupus nephritis, Lupus 8 (1999) phritis and histiocytic sarcoma associated with macrophage 68 – 76. functional defects in CYP1B1-deficient mice, Toxicol. Pathol. [67] P. Bouillet, D. Metcalf, D.C. Huang, D.M. Tarlinton, T.W. Kay, F. 32 (2004) 710 – 718. Kontgen, J.M. Adams, A. Strasser, Proapoptotic Bcl-2 relative [58] I. Baumann, W. Kolowos, R.E. Voll, B. Manger, U. Gaipl, W.L. Bim required for certain apoptotic responses, leukocyte Neuhuber, T. Kirchner, J.R. Kalden, M. Herrmann, Impaired homeostasis, and to preclude autoimmunity, Science 286 uptake of apoptotic cells into tingible body macrophages in (1999) 1735 – 1738. germinal centers of patients with systemic lupus erythema- [68] G.H. Fisher, F.J. Rosenberg, S.E. Straus, J.K. Dale, L.A. tosus, Arthritis Rheum. 46 (2002) 191 – 201. Middleton, A.Y. Lin, W. Strober, M.J. Lenardo, J.M. Puck, [59] M. Herrmann, R.E. Voll, O.M. Zoller, M. Hagenhofer, B.B. Dominant interfering Fas gene mutations impair apoptosis in a Ponner, J.R. Kalden, Impaired phagocytosis of apoptotic cell human autoimmune lymphoproliferative syndrome, Cell 81 material by monocyte-derived macrophages from patients with (1995) 935 – 946. systemic lupus erythematosus, Arthritis Rheum. 41 (1998) [69] M. Chen, Y.H. Wang, Y. Wang, L. Huang, H. Sandoval, Y.J. Liu, 1241 – 1250. J. Wang, Dendritic cell apoptosis in the maintenance of [60] J.R. Kalden, Defective phagocytosis of apoptotic cells: possible immune tolerance, Science 311 (2006) 1160 – 1164.