SLE—a disease of clearance deficiency?

L. E. Munoz, U. S. Gaipl, S. Franz, A. Sheriff, R. E. Voll1, J. R. Kalden and Martin Herrmann

Institute for Clinical Immunology, Department of Medicine III, Friedrich-Alexander University of Erlangen-Nuremberg and 1 IZKF Research Group N2, Nikolaus-Fiebiger Center of Molecular Medicine, Erlangen, Germany.

Correspondence to: M. Herrmann, Institute for Clinical Immunology, Friedrich-Alexander University of Erlangen-Nuremberg, Glückstrasse 4a, 91054 Erlangen, Germany. E-mail: martin.herrmann{at}med3.imed.uni-erlangen.de


    Abstract
 Top
 Abstract
 Introduction
 Clearance of dying cells
 Clearance deficiency in SLE
 References
 
Systemic lupus erythematosus (SLE) is a multifactorial disease and its pathogenesis and precise aetiology remain unknown. Under physiological conditions, neither apoptotic nor necrotic cell material is easily found in tissues because of its quick removal by a highly efficient scavenger system. Autoantigens are found in apoptotic and necrotic material and they are recognized by autoimmune sera from SLE patients. The clearance of dying cells is finely regulated by a highly redundant system of receptors on phagocytic cells and bridging molecules, which detect molecules specific for dying cells. Changes on apoptotic and necrotic cell surfaces are extremely important for their recognition and further disposal. Some SLE patients seem to have an impaired ability to clear such apoptotic material from tissues, and this could cause the breakdown of central and peripheral mechanisms of tolerance against self-antigens. In this article, we address the cells, receptors and molecules involved in the clearance process and show how deficiencies in this process may contribute to the aetiopathogenesis of SLE.

KEY WORDS: Apoptosis, Necrosis, Phagocytosis, Clearance, Autoimmunity, SLE


    Introduction
 Top
 Abstract
 Introduction
 Clearance of dying cells
 Clearance deficiency in SLE
 References
 
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by a wide array of clinical manifestations, from skin and mucosal lesions to severe injuries in the central nervous system, kidneys and other organs. The presence of high titres of autoantibodies against nuclear components (antinuclear antibodies), elevated circulating immune complexes and complement consumption [1] are the main characteristics of the disease. However, the pathogenesis and precise aetiology still remain unknown. Several genetic and environmental factors have been implicated as important elements of the disease (reviewed in references [2, 3]). Therefore, SLE is thought to be a multifactorial disease.

The humoral immune response in SLE has been used as a marker of disease activity and it is targeted mainly to double-stranded DNA. Although unspecific, anti-DNA antibodies are hallmark autoantibodies of this disease and they show a high affinity binding activity (reviewed in [2]). In contrast to bacterial DNA, which has potent immunological properties that can stimulate the immune system in SLE [4], human DNA is known to be poorly immunogenic and does not bear T cell epitopes which could initiate T-cell help for DNA-recognizing B cells. Nevertheless, DNA–histone complexes, nucleosomes, are released in high amounts into the circulation of SLE patients [5, 6]. These nucleosomes are targets of anti-DNA autoantibodies and of antihistone autoantibodies, as shown by enzyme-linked immunosorbent assays of autoimmune sera and monoclonal antibodies [7, 8]. They are predominantly of the IgG isotype and molecular analysis reveals a high degree of somatic mutation in their VH regions. These are unique features of an antigen-driven immune response [9, 10]. Affinity maturation of B cells takes place in the germinal centres of secondary lymphoid organs and it is dependent on T-cell help. Nucleosomes can be recognized and internalized by DNA-specific B cells, which in turn can process and present DNA-associated proteins, and thereby receive T-cell help [11]. The presence of histone-specific T-cells in SLE patients [12, 13] reinforces the theory that nuclear material derived from apoptotic or necrotic material may serve as an important source of autoantigens.

Cell death is the most likely phenomenon to supply autoantigens. There are two main forms of cell death, namely apoptosis and necrosis. Whether cells die through apoptosis or necrosis is determined by the initial stimulus and the microenvironment.

Apoptosis is an active, programmed and regulated cellular process which appears under both physiological and pathological conditions in all tissues. In states of high-rate tissue turnover like embryogenesis and development, apoptosis plays a critical role in the maintenance of a balance between old and new cells [14, 15]. Apoptosis consists of an enzymatic chain reaction that, once triggered by the appropriate stimuli, leads to the activation of several intracellular proteases and DNases, which finally degrade intracellular material in an orderly way. The membrane of apoptotic cells shows characteristic and important changes in the arrangement of phospholipids and sugars. Moreover, it remains intact during this process, thereby preventing the release of intracellular components. Finally, cell shrinkage and membrane blebbing constitute the latest stages of the apoptotic process [16]. These morphological and biochemical changes of dying cells are extremely important for their clearance from tissues by the scavenger system. Therefore, the recognition, removal and fate of these cells depend highly upon the stage of the apoptotic process [17]. If these cells are not cleared on time, they lose their membrane integrity and become secondarily necrotic, thereby releasing high amounts of modified nuclear and cytoplasmic material (reviewed in [18]). In this case, inflammation and induction of immune responses against newly formed nuclear antigens are possible.

Cell death by necrosis, on the other hand, occurs when external factors strike cells. A violent interruption of their vital functions and finally a disruption of the plasma membrane are the consequences. This phenomenon is often triggered by an infectious agent, heat, ischaemia, low ATP levels or a mechanical injury. Intracellular content is then released without cleavage, favouring inflammation and tissue damage [19].

No matter if cells die through apoptosis or necrosis, they must quickly be eliminated from tissues in order to prevent further damage. Usually, neither apoptotic nor necrotic cell material is easily found in tissues because of its quick removal by a highly efficient scavenger system [macrophages, polymorphonuclear cells (PMN) and immature dendritic cells] [20, 21]. In the case of apoptotic cells, they are cleared in the very early stages, eliciting neither inflammation nor immune responses [22]. Even more, apoptotic cells show immunosuppressive effects [23]. Necrotic cells induce inflammation and favour the initiation of immune responses [24]. There is growing evidence for a clearance deficiency of early apoptotic cells in mouse models of SLE [25, 26] and in humans [27, 28]. Regarding later stages of apoptosis, apoptotic cells also become leaky. They are then called secondary necrotic cells, and can release DNA-containing nucleosomes together with dangerous inflammatory signals towards immune system cells [3, 29]. Furthermore, it has been shown that the high mobility group B1 (HMGB1) protein, which is attached to the chromatin of apoptotic cells, remains immobilized even under conditions of secondary necrosis, while in the case of primary necrotic cells it is released and acts as an inflammatory cytokine [30, 31]. Therefore, even primary and secondary necrotic cells display different inflammatory signals. In this article, we address the cells, receptors and molecules involved in the clearance process and show how deficiencies in this process may contribute to the aetiopathogenesis of SLE.


    Clearance of dying cells
 Top
 Abstract
 Introduction
 Clearance of dying cells
 Clearance deficiency in SLE
 References
 
The vast redundancy of ligands, receptors and bridging molecules between dying cells and phagocytes points up the extreme importance of a solid and efficient recognition and clearance system. Both apoptotic and necrotic cells expose ‘eat me’ signals that flag them for their removal from tissues by phagocytes.

Receptors involved in the clearance process
One of the earliest changes in apoptosis is the exposure of phosphatidylserine (PS) and phosphatidylethanolamine on the outer leaflet of the membrane. Necrotic cells also expose PS in the outer membrane because the ATP-dependent mechanism that maintains membrane asymmetry is disrupted [32]. PS is then recognized by several receptors of phagocytic cells: the vitronectin receptor ({alpha}vß3 integrin) [33], the ß2-glycoprotein-1 receptor [34], scavenger receptors (SR) such as CD36 [35], CD68 [36] and class A scavenger receptors (SR-A) [37], the ATP-binding cassette transporter 1 (ABC1) [38], the lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) [39], the lipopolysaccharide receptor CD14 [40], and the putative PS receptor [41]. This recognition occurs directly between PS and a receptor on phagocytes or indirectly through bridging molecules that act as opsonizing agents (reviewed in [42]).

PS as recognition signal for phagocytes
PS recognition is a sine qua non condition for the future engulfment of apoptotic cells [43]. We have suggested that PS is exposed on apoptotic and necrotic cells in a clustered fashion and therefore these dying cells are taken up, in contrast to viable cells which also expose PS, but at a lower density [44]. Furthermore, PS has also been found on the surface of phagocytes that engulf apoptotic cells [45, 46]. Importantly, PS-mediated phagocytosis of apoptotic cells suppresses inflammatory signals like IFN-{gamma}, TNF-{alpha} and nitric oxide, and also triggers the production of TGF-ß, an anti-inflammatory cytokine [23]. Apoptotic cell uptake can be inhibited by the protein annexin-V (AxV), which binds in the presence of calcium preferentially and with very high affinity to anionic phospholipids like PS [47]. AxV also very efficiently disrupts the PS-dependent recognition of dying tumour cells during clearance and thus enhances the immune response against the tumour cells [48].

During necrosis, high amounts of intracellular constituents, e.g. annexins, are released when the membrane is broken. Little is known about receptors and ligands involved in the uptake process of primary necrotic cells. Our results show that interaction of PS with human monocyte-derived macrophages (HMDM) serves as a recognition signal for the rapid removal of primary necrotic cells. Furthermore, the complement component C1q plays an important role in the clearance process of necrotic cells by HMDM [49].

The role of pentraxins in the clearance process
The secretory phospholipase A2 IIA (sPLA2 IIA) circulates freely in human serum. sPLA2 IIA binds PS and is, because of this attribute, not able to hydrolyse phospholipids at the outer membrane leaflet of vital intact cells. sPLA2 IIA is only able to lyse phospholipids at the outer leaflet of normal cells if they have undergone a flip-flop of PS to the outer leaflet, as in apoptosis or necrosis. After interaction with sPLA2 IIA, cells expose high amounts of lysophospholipids like lysophosphatidylcholine. The latter constitutes binding sites for the pentraxin C-reactive protein (CRP) [50, 51]. The pentraxins are highly conserved glycoproteins composed of 10 identical subunits arranged in two cyclic pentamers and their binding to ligands is calcium-dependent. They are acute-phase reactants and are involved in the regulation of inflammation. Serum amyloid P (SAP) is the major acute-phase reactant in mice while in humans CRP fulfils this duty. Once bound, CRP induces complement activation via the classical pathway. The cells become opsonized and many chemotactic molecules are released. CRP also acts as an opsonin because it interacts with an Fc receptor on phagocytic cells. This enhances the phagocytosis of cells undergoing apoptosis. It has long been known that CRP levels are low in patients with SLE [52]. The low level of CRP may therefore contribute to the impaired phagocytosis of dying cells in SLE. Additionally, CRP is able to bind to membranes and several nuclear constituents of necrotic cells, such as histones and small nuclear ribonucleoproteins. This selective binding of CRP to apoptotic and necrotic cells may represent an example of a very fine differentiation mechanism between apoptotic and necrotic cells [18]. Very recently it was shown that human-derived CRP suppressed inflammation in the kidney of NZB/NZW mice [53]. An immune-modulatory effect of CRP besides the ability to act as opsonin for apoptotic and necrotic cells and cellular debris was proposed (reviewed in [54]).

SAP protein is another member of the pentraxin family and is constitutively present in serum at a concentration of 40 µg/ml. During inflammation levels can reach 50 times the normal level in mice. SAP binds to extracellular matrix components, to C1q and to C4 binding protein, and it also shows specific binding activity to DNA, nuclear chromatin and nucleic compounds released during necrosis. Furthermore, interaction of SAP with nuclei leads to the solubilization of nuclear chromatin [55]. The exact target of SAP on apoptotic cells is not yet clear. SAP binds to phosphatidylethanolamine, which is found in both early and late apoptotic cells [56]. However, SAP binding has been found relevant only in late apoptotic cells [57]. Like the other pentraxins, it binds to the Fc{gamma} receptors (CD16, CD32 and CD64) on phagocytic cells and seems to function as an opsonin that enhances phagocytosis of bound material [58]. Studies carried out in SAP –/– mice show retardation in the degradation of chromatin exposed by dead cells and an enhanced anti-DNA response when mice are immunized with extrinsic chromatin [59]. This favours the role of SAP in the clearance of chromatin and chromatin-related debris when they are not properly cleared from tissues in early phases of cell death [60].

The long pentraxin PTX3 is another acute-phase reactant of the pentraxin family. It is released by endothelial cells and mononuclear cells after primary proinflammatory signals like lipopolysaccharide, IL-1ß, IL-6 and TNF-{alpha}. These signals also promote the maturation of dendritic cells (DC) even before CRP expression starts in the liver. It has been shown that PTX3 binds better to apoptotic cells than to necrotic ones in vitro, although the specific binding partner is unknown. Human DC failed to internalize dying cells in the presence of PTX3 but still macropinocytosed other substrates. These results suggest that PTX3 sequesters cell remnants from antigen-presenting cells, possibly to prevent the onset of autoimmune reactions in inflamed tissues [61].

Complement and DNase I contribute to an efficient clearance of dying cells
It is well known that dying cells activate the complement system through several mechanisms, and the complement components C1q, C3 and C4 have been implicated in the clearance process of these cells [25, 62]. We observed that complement binding is an early event in necrosis and a rather late event in the case of apoptosis. Therefore we think that such complement components act as a backup mechanism to clear apoptotic cells before they enter the dangerous stage of secondary necrosis [63]. Recently, it has been suggested that previous deposition of IgM on apoptotic cells is required for complement activation through the classical pathway and for the further opsonization of these cells by the C3 component [64]. The hereditary C1q deficiency shows many typical characteristics of human SLE disease and it is the strongest proof of the importance of this complement protein in the pathogenesis of autoimmunity against nuclear structures [65]. C1q knockout mice also show apoptotic material in renal tissues together with glomerulonephritis [66]. However, only mild forms of SLE-like syndromes are observed in these mice. We have also found that C1q is necessary for efficient uptake of necrotic cell-derived degraded chromatin by monocytes and HMDM. Furthermore, serum DNase I is responsible for the degradation of nuclear material, which is, for example, accidentally released by secondary necrotic cells. In humans, DNase I acts together with C1q to efficiently degrade necrotic cell-derived chromatin [49]. We also tested sera of autoimmune patients with regard to their ability to degrade necrotic cell-derived chromatin. A significant activity reduction of DNase I in sera from SLE patients and patients with rheumatoid arthritis (RA) in comparison to sera from normal healthy donors (NHD) was observed. However, only SLE sera showed a strongly reduced degradation capacity of necrotic cell-derived chromatin in comparison with RA sera and NHD sera (own unpublished data). This might be due to the reduced complement activity often found in sera from SLE patients. Finally, some features of SLE like anti-DNA antibodies and glomerulonephritis have also been found in DNase I-deficient mice [67].

Altered carbohydrates as recognition signal for phagocytes
Carbohydrate-binding proteins (lectins) are usually involved in the recognition of characteristic carbohydrate patterns and they are considered as players in the innate immune system [68]. Lectins facilitate microbial removal and also play a role in apoptotic cell clearance. For example, C1q, the mannose-binding lectin and the surfactant proteins A and D are collagen-specific lectins (collectins) that bind efficiently apoptotic and necrotic cells and contribute to their removal [25, 69, 70]. The roles of the pentameric lectins CRP and PTX3 in the clearance of dying cells have already been discussed. Besides of the lectins mentioned, we have found that Narcissus pseudonarcissus lectin, Griffonia simplificolia lectin II and Ulex europaeus agglutinin I lectin have increased binding activity for apoptotic cells in comparison with viable cells. This binding activity was specific for mannose, fucose and N-acetylgalactosamine and was mainly found in the late phases of the apoptotic process when compared with the binding of AxV. Interestingly, these lectins were able to bind with higher intensity to necrotic cells than to apoptotic ones [71]. Therefore, we conclude that the exposure of those special sugar structures is a feature of late apoptotic cells and may represent another redundant mechanism of clearance of dying cells that had escaped earlier mechanisms. It may also represent a major membrane change before secondary necrosis.


    Clearance deficiency in SLE
 Top
 Abstract
 Introduction
 Clearance of dying cells
 Clearance deficiency in SLE
 References
 
In this part we discuss how deficiencies in one or more of the above-mentioned fine tuning mechanisms of the clearance of dying cells might be responsible for the pathological findings in SLE. Evidence of important molecules involved in the clearance process collected from knockout mouse models shows that accumulation of apoptotic cells in tissues together with an immune response against DNA-containing complexes is the common denominator between them [59, 66, 67, 72]. In humans, a deficiency in the phagocytic activity for yeast and bacteria in SLE patients was found [73–75]. We have shown that macrophages from SLE patients are impaired in the phagocytosis of autologous apoptotic material in vitro [27]. The impaired clearance might be the reason for the accumulation of apoptotic cells in tissues of a subgroup of SLE patients. We found that the number of tingible body macrophages, which usually ingest apoptotic material in the germinal centres of lymph nodes, was strongly reduced in some SLE patients. In contrast to all controls, apoptotic material was observed associated with the surfaces of follicular dendritic cells (FDC) [28].

Phagocytosis by PMN was found to be deeply depressed in SLE patients a long time ago [76]. Furthermore, phagocytosis by PMN under inflammatory conditions is impaired in the autoimmune mouse strain MRL/lpr [77]. We are currently investigating the phagocytic function of PMN from healthy donors, from RA patients and from SLE patients under non-inflammatory conditions. We found a heterogeneous phagocytosis defect in some SLE patients. Most of the PMN from SLE patients showed impaired phagocytosis of albumin-coated beads and about 30% had impaired ability to phagocytose polyglobulin-coated beads. Phagocytosis of necrotic cells and degraded chromatin by PMN was also reduced in some SLE patients [78].

Immune responses are initiated in secondary lymphoid organs, where antigen-presenting cells (mature DC) present self and foreign antigens to naive T cells and deliver appropriate signals for proliferation or death. Every autoreactive naive T cell that escapes negative selection in the thymus during its development should die or be transformed to a regulatory T cell during this encounter [21]. However, autoreactive T cells have been isolated from patients with SLE and they are able to induce the production of anti-DNA autoantibodies in vitro [12, 79, 80]. During apoptosis, some nuclear proteins are enzymatically modified [81] and this reveals novel autoantigens that are recognized by autoimmune sera [82]. These modifications may also render cryptic epitopes into T cell-dependent dominant autoantigens [83]. High availability of such T-cell-dependent autoantigens in tissues, as in a clearance deficiency scenario, may break the peripheral tolerance mechanisms. For example, late apoptotic cells and blebs derived from apoptotic cells can activate complement without contact with a specific antibody, becoming coated with the C3d component of complement [62, 84]. FDC in lymphoid tissues are able to bind C3d-opsonized particles via the CD21 receptor and present modified autoantigens to autoreactive B cells [85, 86]. These positively selected B cells can now migrate to T-cell-rich zones, where they can receive appropriate survival signals from T-helper cells, proliferate, and differentiate into memory or plasma cells. Thereby, the retention of autoantigens on the surface of FDC may override the highly important mechanism of B- and T-cell tolerance in SLE patients. Figure 1 summarizes these observations, which suggest that an intrinsic ineffective scavenger system is responsible for many of the pathological alterations found in SLE patients.



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FIG. 1. The fate of apoptotic cells in NHD and SLE patients. In peripheral tissues of NHD, apoptotic cells are cleared very early by tissue macrophages, which produce anti-inflammatory cytokines and down-regulate the antigen presentation function of dendritic cells. In lymphoid tissues apoptotic cells are cleared by tingible body macrophages, which sequester nuclear autoantigens away from FDC. The consequence is no inflammation and the induction of T- and B-cell tolerance. In peripheral and lymphoid tissues of SLE patients apoptotic cells accumulate and enter the stage of secondary necrosis. These cells become accessible to tissue dendritic cells, which are able to produce inflammatory cytokines and present these autoantigens with costimulatory signals to autoreactive T cells. In lymphoid tissues, FDC may serve as autoantigen repositories. This observation is in accordance with the extremely low phagocytic activity of FDC. The nuclear material on the surfaces of FDC is then accessible to autoreactive B cells.

 
In order to further address this problem, we investigated the proliferation and differentiation capabilities of CD34-positive haematopoietic stem cells obtained from peripheral blood of SLE patients and healthy donors. We found similar proliferation rates of the stem cells in patients and controls. However, differentiation into macrophages was diminished in some SLE stem cell cultures. These macrophages of SLE patients were also smaller, died earlier, showed reduced adherence, and had lower phagocytic activity [78].

We can conclude that there is growing evidence in favour of a clearance deficiency as the core mechanism in the pathogenesis of SLE. However, the precise alteration in SLE patients of the delicate and extremely finely tuned clearance process still remains obscure.


    Acknowledgments
 
This work was supported by the Interdisciplinary Center for Clinical Research (IZKF) (projects A4 and N2) at the University Hospital of the University of Erlangen-Nuremberg, by Deutsche Forschungsgemeinschaft SFB 643 (project B5), the research training grant GRK 592 from the German Research Society (DFG) to S.F., Programme Alban, the European Union Programme of High Level Scholarships for Latin America, scholarship E04D047956VE to L.M., and the European Commission [EU (QLK3-CT-2002–02017_APOCLEAR)].

The authors have declared no conflicts of interest.


    References
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 Clearance of dying cells
 Clearance deficiency in SLE
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Submitted 8 March 2005; revised version accepted 26 April 2005.



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