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Published online before print January 10, 2008
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Review Article |
From the Departments of Pathology*and Biochemistry,Institute of Medical Biology, Medical Faculty, University of Tromsø, Tromsø; and the Departments of Rheumatologyand Pathology,University Hospital of Northern Norway, Tromsø, Norway
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune syndrome characterized by autoantibodies to nuclear constituents. Some of these antibodies are diagnostically important, whereas others act as disease-modifying factors. One clinically important factor is autoantibodies against dsDNA and nucleosomes, which have overlapping diagnostic and nephritogenic impact in SLE. Although a scientific focus for 5 decades, the molecular and cellular origin of these antibodies, and why they are associated with lupus nephritis, is still not fully understood. A consensus has, however, evolved that antibodies to dsDNA and nucleosomes are central pathogenic factors in the development of lupus nephritis. In contrast, no agreement has been reached as to which glomerular structures are bound by nephritogenic anti-nucleosome antibodies in vivo. Mutually contradictory paradigms and models have evolved simply because we still lack precise and conclusive data to provide definitive insight into how autoantibodies induce lupus nephritis and which specificity is critical in the nephritic process(es). In this review, data demonstrating the central role of nucleosomes in inducing and binding potentially nephritogenic antibodies to DNA and nucleosomes are presented and discussed. These autoimmune-inducing processes are discussed in the context of Matzinger’s danger model (Matzinger P: Friendly and dangerous signals: is the tissue in control? Nat Immunol 2007, 8:11–13; Matzinger P: The danger model: a renewed sense of self. Science 2002, 296:301–305; Matzinger P: Tolerance, danger, and the extended family. Annu Rev Immunol 1994, 12:991–1045) and Medzhitov’s and Janeway’s (Medzhitov R, Janeway CA Jr: Decoding the patterns of self and nonself by the innate immune system. Science 2002, 296:298–300; Medzhitov R, Janeway CA Jr: How does the immune system distinguish self from nonself? Semin Immunol 2000, 12:185–188; Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002, 20:197–216) distinction of noninfectious self (NIS) and infectious nonself (INS). The mechanisms leading to production of potentially nephritogenic anti-nucleosome antibodies and to overt lupus nephritis are interpreted in the context of these paradigms.
SLE is a prototype of an autoimmune syndrome that is characterized by various clusters of organ manifestations, and most organs in the body may be involved. SLE is classified according to 11 American College of Rheumatology criteria.1 These involve organ manifestations and hematological and immunological parameters. Any combination of 4 of these 11 criteria is sufficient to classify SLE.1 SLE is further characterized by a wide variety of organ-specific and organ-nonspecific autoantibodies. Of these, some are diagnostically important, whereas others may act as disease-modifying factors.2-4 One clinically important factor is autoimmunity to double-stranded (ds)DNA and nucleosomes, which has overlapping diagnostic and pathogenic impact. In situ binding of anti-dsDNA antibodies is associated with lupus nephritis,3,5 cerebral lupus,6 and lupus dermatitis.2,7 It is therefore important to understand the cellular and molecular origin of anti-dsDNA antibodies, and why they are associated with organ affections in SLE.
Lupus nephritis is one of the most serious manifestations of SLE. This organ manifestation has traditionally been characterized by the World Health Organization classification criteria, which focuses on histological parameters. This classification system of lupus nephritis has recently been revised under the auspices of International Society of Nephrology and Renal Pathology Society.8,9 The organ disease is separated into six different classes from subclinical (class I, mild proteinuria) to end-stage disease (class VI). A central classification criterion is detection of immune complexes in glomerular basement membranes and in the mesangial matrix. This demonstrates that autoimmunity plays a major role in the pathogenesis of lupus nephritis. Whether glomerular-bound antibodies are part of immune complex deposits or directly bound to inherent renal structures has been an unsolved issue and is not mentioned in the World Health Organization classification system or in the revised classification criteria.
Lupus Nephritis and the Role of Antibodies to DNA and Nucleosomes
Shortly after their detection in 1957,10-12 antibodies to dsDNA were associated with renal manifestation of SLE, and anti-dsDNA antibodies have been eluted from affected glomeruli.13-17 At the time when the nephritogenic potential of antibodies to dsDNA was revealed, their binding in glomeruli was logically claimed to depend on extracellular DNA. This DNA was thought to be bound in situ in glomeruli where it was targeted by the antibodies. This assumption derived from two facts: DNA bound glomerular collagen18,19 and the antibodies were specific for DNA.13,20
This model has, however, been difficult to validate by experimental results and is today critically challenged by alternative models implying that antibodies bind to cross-reacting glomerular antigens such as 
-actinin, laminin, or cell surface structures.17,21-29
Thus, data from different types of experiments and analytical strategies have resulted in different models explaining how anti-DNA antibodies induce nephritis. However, although the models are attractive, none have been validated beyond any doubt, although the dominant specificity of nephritogenic antibodies for dsDNA may point at the most obvious target structures in nephritic kidneys—nucleosomes released from dead cells.
One problem with the cited literature is that most of the current models are explained relative to the way the experiments were performed. Generally, dual specificity of a given antibody does not reveal the real target molecule(s) in a pathophysiological context. For example, the fact that anti-dsDNA antibodies eluted from kidneys cross-react with non-DNA/nucleosome glomerular structures, such as laminin14,30
or -actinin,17,21
does not at all inform about the nature of the de facto target structures in vivo.
Thus, there is currently no definitive, firm, and objective distinction that separates nonpathogenic from pathogenic antibodies.3,4,31,32 One experimental result illustrates this: an antibody against nucleosomes may bind glomeruli when in complex with nucleosomes, whereas noncomplexed antibodies do not bind.33 This may be one example of glomerular antibody binding because the homologous antigen is made available, not because of a unique property of the antibody (see below). Thus, there must exist cellular processes and/or available molecular structures that determine anti-dsDNA antibody binding in the kidney and, thereby, their nephritogenic potential. Basically, irrespective of which parameters are important, release or exposure of relevant antigens recognized by nephritogenic anti-dsDNA antibodies must be crucial events making target molecules available for the antibodies,3 if the central antigens are not naturally available as, eg, glomerular basement membrane structures. To solve these problems, we must consider the cellular and structural origin of the immune response to dsDNA and nucleosomes and trace the biochemical nature and origin of target structures for such induced, potentially nephritogenic antibodies.
In this review, antibodies to dsDNA and nucleosomes are discussed in the context of their origin, fine molecular specificity, and nature of their glomerular target structures. The surprising perception of these lines of experiments, observations, and considerations is that there exist no principal nephritogenic subpopulations among affinity-maturated antibodies to dsDNA and nucleosomes. Their nephritogenic potential is determined by release and subsequent in situ binding of nucleosomes or chromatin fragments in glomerular vascular membranes and in the mesangial matrix or by forming complexes in circulation. Only in such situations will antibodies bind in glomeruli and exert their pathogenic activity.33
Origin of Nephritogenic Anti-Nucleosome Antibodies—Specificity of B Cells
Although antibodies to dsDNA were discovered 50 years ago,10-12 the processes responsible for their induction in vivo are still poorly understood. Because DNA and nucleosomes have been regarded as weak immunogens,34 a dogma evolved that such antibodies are induced by cross-reactive antigens rather than by DNA or by nucleosomes (see below).35,36 The observed manifold cross-reactions of monoclonal anti-dsDNA antibodies supports this notion.36-38
This is further evident from the elegant study of Wellmann and colleagues.39 They used site-directed mutagenesis to systematically revert the somatic mutations of monoclonal anti-dsDNA antibodies from SLE patients and determined the changes in antigen-binding pattern.39 The data demonstrated that high-affinity antibody binding to nucleosomes and to surface structures of apoptotic cells were acquired by the same somatic mutations that generated high-affinity dsDNA binding. Fully reverted antibodies with germ-line heavy chain variable (VH) regions did not bind DNA but phospholipids, such as phosphatidylserine.39 A similar study by Li and colleagues40 demonstrated a comparable transformation in antibody specificity. By substituting a key arginine residue with glycine in the variable region of an anti-DNA transgene, they observed reduced affinity for dsDNA, and complete reversion of this antibody to germline configuration enhanced affinity for phosphatidylserine. Many anti-DNA antibodies show cross-reactions with phospholipids,36 and some can bind to apoptotic cells,41,42 most likely through an interaction with phosphatidylserine that is exposed on the surface of apoptotic cells.43,44 Whether phosphatidylserine is able to induce antibodies that may somatically mutate toward dsDNA without participation of DNA in secondary immune responses is still unproven.
On the other hand, numerous reports have demonstrated that antibodies to dsDNA can be induced by experimental immunization with dsDNA, provided it is in complex with an immunogenic carrier protein.4,45-50 Consistent with this model is the demonstration of nucleosome- and histone-specific T cells in both murine and human SLE, with the potential to provide cognate help for DNA-specific B cells.51-55
It is clear from such observations that immunogenicity of DNA depends on complex formation with immunogenic peptides. This creates a complex able to stimulate DNA-specific B cells and peptide-specific T cells in analogy to a hapten-carrier model for induction of anti-hapten antibodies. This has been experimentally demonstrated by immunizing mice with mammalian dsDNA in complex with the Trypanosoma cruzii-derived DNA-binding peptide Fus 145,46 or with the DNA-binding polyomavirus encoded large T antigen (T-ag).49,50,56 Immunization of normal mice with bacterial DNA in complex with methylated bovine serum albumin resulted in anti-dsDNA antibodies with a dominant specificity for the bacterial DNA used as immunogen, whereas binding to mammalian dsDNA was less pronounced.48,57 In all these experimental systems, the immunization regime resulted in lupus-like nephritis with proteinuria and glomerular IgG deposits.45,48,58 Thus, for a long time DNA was erroneously regarded as a poor immunogen, and experimental immunization did not result in anti-DNA antibodies similar to those spontaneously produced in murine and human SLE.34,59-63 This paradigm changed with the results cited above.
Given that stimulation of the immune system by immunogenic DNA is sustained, the IgG antibodies affinity maturate and gain higher clinical impact. This process is principally outlined in Figure 1
. These considerations relate to the ability of B cells to respond to dsDNA. The crucial point in this advanced insight was that responsiveness to dsDNA was primarily controlled by T cells with specificity for certain proteins associated with DNA.45,49,50,54,64-66
These may be either infectious-derived, like the Fus 1 peptide or T-ag (see above), or purely autologous, like nucleosomal proteins.51,53-55
This distinction needs further clarification.
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B cells may have a lower capacity to develop tolerance to nucleosomes than T cells, as is evident from the fact that it is relatively easy to induce high-affinity anti-dsDNA antibodies by immunizing normal mice with DNA-carrier protein complexes.45,49,50,67,68 Such autoimmune B cells may bind autologous nucleosomal DNA and present peptides from, eg, nucleosome-bound viral proteins, to T cells committed to respond to such peptides. The result of cognate interaction between autoimmune B cells and viral peptide-specific T cells may in fact be production of somatically mutated autoantibodies similar to those seen in SLE. Thus, in this situation, true SLE-related autoantibodies may be produced on a nonautoimmune background.
However, humoral autoimmunity to components of nucleosomes may not be the only outcome of this self (dsDNA)-nonself (viral protein) model for stimulation of autoimmune B cells. B cells that recognize the DNA component of viral protein-nucleosome complexes will process the complex and present peptides derived from both autologous proteins (like histones) and viral proteins. In this situation, T cells committed to respond to viral peptides will recognize peptide-HLA II complexes. Provided sufficient co-stimulatory signals, this will result in mutual stimulation of nucleosome-specific B cells and viral peptide-specific T cells. The former may proceed into plasma cells producing antibodies to nucleosomes, whereas the latter may transform into effector T cells and secrete interleukins (ILs), particularly IL-2 in this context.54,55 This establishes a scenario that might influence tolerance of autoimmune T cells with specificity for autologous nucleosome-derived peptides. Activation of autoimmune T cells by linked presentation of self and nonself molecules have been documented in several experimental systems.54,55,69-73
The most likely explanation for this is that IL-2, produced by, eg, responder viral DNA-bound peptide-specific T cells, by itself terminates histone-specific T-cell anergy by inducing proliferation of the anergic T cells.74,75
This process is outlined in Figure 2
.54-56
In this situation T cells may further expand in response to the presented histone peptide-HLA class II complexes.
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Functional T cells specific for histones or for nucleosomes have been characterized in both murine and human SLE,51,53,77 demonstrating that autoimmune T cells undergo antigen-specific activation in vivo. Although formal requirements for activation of autoimmune nucleosome-specific T cells have been determined, the basis for termination of T-cell tolerance in vivo in SLE has not been established. In one situation autoimmune T cells may be activated when nonself and self molecules are processed and presented in the context of HLA class II molecules by the same antigen-presenting cells. On the other hand, autoimmune nucleosome-specific T cells may be directly activated by exposed necrotic chromatin in vivo. This pathway is still unproven but may be explained by Matzinger’s danger model (see below).78-80
Necrotic Nucleosomes—Potential Inducer and Target Structures for Nephritogenic Autoantibodies
Although formal cellular and molecular requirements for anti-DNA antibody production have been revealed (see above),53,56,76 we still lack relevant insight into the requirements for these processes in vivo in the context of spontaneous SLE. However, in recent years, ideas78-83 and results84-88 have provided new perspectives to understand the basis for such autoimmune processes in vivo.
Basically, we should consider two apparently incompatible paradigms: Matzinger’s78-80 danger model, leaving the distinction between self versus nonself irrelevant, and Janeway’s and Medzhitov’s81-83 distinction between INS and NIS. A relevant example to approach this discussion is the biological consequence of transformation of apoptotic to secondary necrotic cells and release of (necrotic) chromatin by disrupting apoptotic blebs.
Clearance of apoptotic cells is reduced in SLE.5,86,87 This defect transforms the silent, noninflammatory removal of apoptotic cells into release of chromatin structures meant to be hidden within blebs until taken up by phagocytic cells. Because chromatin particles generated in the context of apoptosis are normally encapsulated within blebs presenting eat me (friendly as opposed to danger) signals, this ensures that they are cleared in a fast and discreet way. Retained and exposed tissue-distributed chromatin may break this silence and become a problem for the immune system by initiating inflammation,85,86 because they, according to Matzinger’s danger model,78-80 may provide signals (by eg, CpG motifs) that may initiate dendritic cell maturation and exposure of co-stimulatory signals (when CpG binds Toll like receptor 9). In addition, apoptosis-induced changes in chromatin may enhance immunogenicity and pathogenicity of chromatin in vivo.89 Thus, danger signals and secondary structural alterations linked to apoptosis and necrosis may contribute to inflammation and activation of dendritic cells. The dendritic cells may in other words become armed and effective antigen-presenting cells with the potential to activate relevant nucleosome-specific T cells provided they are not deleted in the thymus. However, Andreassen and colleagues54,55 have clearly demonstrated that even immunologically normal individuals harbor autoimmune nucleosome-specific T cells in their circulation and that they are easily activated to be functional T-helper cells. Is there really a need for a nonself, nucleosome-bound component to activate such autoimmune T cells?
In Matzinger’s79 context, the immune system may be more concerned with structures that provide danger signals, than with those that are foreign. In that sense, NIS molecules may be as harmful as INS structures. Thus, purely autologous, secondary necrotic structures provide danger signals (like Toll-like receptor engagement, up-regulation of co-stimulatory molecules, and engagement of appropriate autoimmune T cells). This scenario may result in dendritic cell maturation and presentation of, eg, nucleosome-derived peptides for relevant T cells. These may be fully activated and provide cognate help for DNA-specific B cells.78,79,84,86 This is consistent with the fact that Toll-like receptors bind autologous structures like the CpG motif, present in all mammalian DNA, and, eg, HSP60 and HSP70 (see Matzinger79 for discussion).
Thus, there is no obvious need for a self-nonself hapten-carrier model to initiate and maintain humoral and cellular autoimmunity to nucleosomes, at least not in SLE. That model may, however, explain the appearance of anti-nucleosome antibodies in healthy individuals who process apoptotic cells appropriately. This response is, however, transient in nature and will die out on termination of the infection.
The Danger Model—Predicting Pathogenic Autoimmunity
In the viral infection-dependent self-nonself (hapten-carrier) model, the discrimination between INS and NIS is set aside, as B cells recognize the self component, while processing and presenting the nonself component to nontolerant T cells (see Figure 2
). This intermolecular cognate interaction provides a basis for initiation and affinity maturation of humoral autoimmunity. This model is operational49,54,66,73,90
and provides an exception from Medzhitov’s and Janeway’s81-83
distinction between INS and NIS to control autoimmunity, in which indeed INS is the factor that renders NIS immunogenic. We therefore predict that autoimmunity induced by complexes of INS and NIS is nonpathogenic simply because the structures initiating the autoimmune response are not available for antibody binding in peripheral tissue because of their normal processing and removal. The autoimmune response is transient because the complex formation of INS and NIS is terminated when the infection is healed. Thus, this model does not relate to impaired clearance of dead cells. That defect confers to the danger model.
The probability that autoimmunity induced in context of Matzinger’s78-80 danger model is pathogenic is higher just because of the nature of the model. The immunogenic (necrotic) chromatin is retained in tissue, provides danger signals, arms the innate immune system, and subsequently induces affinity-maturated IgG antibodies to (the necrotic) nucleosomes. Retained necrotic chromatin in peripheral tissue (like in glomeruli) represents the partner that renders such induced IgG autoantibodies pathogenic because they are available in vivo for antibody binding. Thus, we see the Janus face of secondary necrotic chromatin, which activates the innate and, in the next round, the adaptive immune system and represents the available target structures for the induced autoantibodies, as was also previously discussed.5,87,91 In consequence, secondary necrotic chromatin induces and binds the antibodies and is therefore the central partner in the evolution of the pathogenic process. Lupus nephritis may well be an organ disorder that fits with this paradigm.
Pathogenic Antibodies to dsDNA and Nucleosomes—What Do They Recognize in Vivo
There is compelling evidence for a central role of anti-dsDNA antibodies in the pathogenesis of lupus nephritis. However, until now no consensus has been reached whether only a subpopulation of these antibodies is really nephritogenic. For this reason the structural basis for the pathogenic function of both murine and human anti-dsDNA antibodies has yet to be determined. If nucleosomes indeed drive the immune response against nucleosomes and DNA, then one may assume that 1) nucleosomes are exposed in vivo at a level that is not reached in normal physiology, 2) nucleosomes by themselves are immunogenic for both B cells and T cells, and 3) exposed nucleosomes are targeted in situ (in eg, glomeruli) or in circulation by the same antibodies they induce. If this is correct, lupus nephritis is induced by antibodies that recognize and bind nucleosomes in affected glomeruli (ie, homologous recognition). In fact, recent theoretical considerations, experimental data, and clinical analyses are all consistent with this recognition principal and inconsistent with the idea that nephritogenic antibodies recognize cross-reacting glomerular antigens.
Lupus Nephritis—A Nucleosome-Mediated Disease
As a disease process, lupus nephritis may be fully explained by the danger model of Matzinger.78-80
Until recently, our understanding of how antibodies to dsDNA were involved in lupus nephritis was inconsistent and incoherent. Because it has been difficult to agree on the mode of glomerular antibody binding, several models have been described. One model implies glomerular antibody binding to exposed chromatin structures (Figure 3, A–D)
in which chromatin in capillary membranes is visualized as electron-dense structures (EDSs, Figure 3A
). As seen in Figure 3, B–D
, antibodies bound to glomerular membrane-associated chromatin are visible by transmission electron microscopy as EDSs.15,92,93
The other model suggests that antibodies bind through cross-reactions with different inherent renal nonchromatin constituents (not shown because this model lacks firm evidence).14,17,21,23,25,27,94
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).
Data obtained by the newly developed co-localization TUNEL IEM assay, in which extracellular DNA was traced by TdT-mediated introduction of biotinylated nucleotides and glomerular in vivo-bound autoantibodies simultaneously by IEM, demonstrated that TUNEL-positive DNA co-localized with autoantibodies in glomerular membrane-associated EDSs in both murine95
and human94
nephritic kidneys. This confirms earlier results from the co-localization IEM assay, in which in vivo-bound glomerular autoantibodies co-localized perfectly with binding of experimental antibodies to dsDNA, histones, or transcription factors constitutively bound to nucleosomes. Both in vivo-bound and experimental antibodies bound exclusively in EDSs (Figure 3)
,92,93
and they did not co-localize with, eg, anti-laminin antibodies.92
These results generally demonstrate two properties of extracellular nucleosomes. First, in situations in which nucleosomes are not cleared, they may be modified, unmasked from apoptotic blebs, and then gain immunogenic power by providing danger signals. Thereby, they become able to activate autoimmune nucleosome-specific T cells and to induce antibodies reactive with nucleosomes and individual components of nucleosomes, such as dsDNA, histones, and nonhistone proteins.5,87,96 Second, they associate with glomerular membranes in complex with nephritogenic antibodies.15,92,93 Thus, apoptotic, but retained secondary necrotic nucleosomes may represent both inducer and target structures for nephritogenic autoantibodies in SLE.
The Critical Role of Nucleosomes in Lupus Nephritis
While analyzing specificity and strength of the antibodies eluted from diseased kidneys, data demonstrated that they generally bound DNA and nucleosomes similar to or much better than they bound, eg, -actinin, laminin, or collagen.15,14,17
This harmonizes nicely with the fact that in vivo-bound antibodies co-localize with experimental antibodies against chromatin constituents and with TUNEL-positive DNA in capillary membranes and mesangial matrix, the central loci for immune complex deposits.92,93
Exposure and accessibility of chromatin in situ according to such observations is consistent with nucleosomes as target structures for in vivo-bound antibodies.
If nucleosomes indeed represent the glomerular structures binding nephritogenic antibodies in vivo, then why are the nucleosomes localized to capillary membranes and mesangial matrix? Recently, we analyzed if nucleosomes and DNA possessed affinity for glomerular laminin, collagen IV, and the mesangial matrix heparan sulfate proteoglycan perlecan by surface plasmon resonance. Kinetic analyses demonstrated that nucleosomes bound collagen IV and laminin at high affinity, but they did not bind perlecan.95 Collectively, these results provide firm evidence that dominant target structures for nephritogenic autoantibodies are constituted by TUNEL-positive chromatin associated with glomerular capillary membranes and the mesangial matrix at high affinity. These data demonstrate that antibodies reactive with nucleosomes exert their pathogenic effect only in the context of exposure of their homologous target structures, ie, nucleosomes.
Central Unsolved Problems
The data and considerations discussed here open for new, hypothesis-directed studies that may provide information regarding how to approach the rational for causal therapy as, eg, to avoid nucleosome or antibody-nucleosome complex binding in glomeruli. Central questions include why chromatin is released at all and why it is preferentially deposited in glomerular membranes and mesangial matrix. Where do the chromatin fragments come from—through circulation or are they released within the kidney? Is lupus nephritis an isolated organ disease or part of a systemic disorder? We are currently approaching these questions by morphological, genetic, and biological studies on tissue from autoimmune, lupus-prone mice and from human SLE patients.
Concluding Remarks
The considerations given here link the danger model of Matzinger78-80 to persistent nephritogenic autoimmunity and the NIS-INS model of Medzhitov and Janeway81-83 to transient nonpathogenic autoimmunity (in the situation in which NIS is in complex with INS). Autoimmunity induced by the former process, but not the latter, is by nature persistent attributable to a sustained clearance deficiency in SLE patients. In both situations, however, dendritic cells may be activated by the complexes (NIS-INS complex or necrotic chromatin), establish germinal centers, and provide the scenario for antibody production. However, only in individuals with reduced clearance of, eg, apoptotic cells does secondary necrotic chromatin accumulate in tissue where it serves as in situ target structures for such antibodies. Autoantibodies to dsDNA or to nucleosomes become pathogenic only in that situation. Without exposed chromatin, they remain nonpathogenic.
Footnotes
Address reprint requests to Elin S. Mortensen, Department of Pathology, Institute of Medical Biology, The Medical Faculty, University of Tromsø, N-9037 Tromsø, Norway. E-mail: elin.mortensen{at}fagmed.uit.no
Supported by The Health and Rehabilitation Organization Norway, The Northern Norway Regional Health Authority Medical Research Program (grants SFP-100-04, SFP-101-04), and the University of Tromsø (milieu support given to O.P.R.).
Accepted for publication November 21, 2007.
References
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