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Rheumatology 2001; 40: 1405-1412
© 2001 British Society for Rheumatology
Original Papers |
An analysis of clinical disease activity and nephritis-associated serum autoantibody profiles in patients with systemic lupus erythematosus: a cross-sectional study
Centre for Rheumatology, Bloomsbury Rheumatology Unit, Department of Medicine, University College London, London W1T 4NJ, UK
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Abstract |
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Objective. To establish the correlation between lupus nephritis-associated autoantibody levels and the presence/activity of lupus nephritis and global disease activity using cross-sectional data in patients with systemic lupus erythematosus (SLE).
Methods. Disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) index. Antibody levels against single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), histones, nucleosomes and heparan sulphate (HS) were analysed by ELISA in SLE patients with (n=11) and without (n=22) nephritis and in normal controls (n=21). Antibody subclasses were also analysed.
Results. Higher levels of anti-dsDNA and anti-HS antibodies were found in patients with lupus nephritis, the level of anti-HS antibodies correlating with the BILAG renal score. Predominant subclasses were IgG1 and IgG3 for dsDNA antibodies, IgG2 for anti-nucleosome antibodies, and IgG2 and IgG3 for anti-HS antibodies.
Conclusion. Correlation was demonstrated between antibodies to dsDNA, ssDNA, histones, nucleosomes and HS. There is a strong correlation between the level of anti-HS antibodies and disease activity in patients with lupus nephritis as measured by BILAG.
KEY WORDS: Systemic lupus erythematosus, Serum autoantibodies, Nephritis.
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Introduction |
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Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by the production of a variety of autoantibodies against nuclear, cytoplasmic and cell surface antigens. Nephritis is the most important feature of lupus as kidney damage is a major threat to long-term survival [1].
The cellular and molecular mechanisms that are responsible for the production of anti-nuclear antibodies in this disease and the way in which these antibodies participate in tissue destruction remain highly controversial. Studies of IgG class-switching and somatic mutations in the VH regions of anti-DNA antibodies have suggested that potentially pathogenic anti-DNA antibodies are the products of T-cell-dependent, autoantigen-driven immune responses [2–4]. The primary autoantigen is believed to be DNA bound to protein (e.g. nucleosomes) rather than naked DNA [5–8].
The specificity of the antibody required and the mechanisms involved in the induction of renal damage in SLE remain controversial. It is also not clear whether the DNA binding specificity of antibodies alone is sufficient for glomerulonephritis to occur [9]. The lack of correlation between the anti-DNA response and renal disease in some patients with SLE has led to the search for other autoantibodies, e.g. autoantibodies directed against histones, nucleosomes and laminin, which may contribute to nephritis [10–16].
However, the prevailing wisdom regarding lupus nephritis is that anti-DNA antibodies mediate this disorder, either by the deposition of immune complexes (ICs) (presumed to be DNA-anti-DNA ICs) or by DNA antibodies in the circulation binding to antigens [e.g. DNA or DNA and histones or heparan sulphate (HS)] in the glomerular basement membrane (GBM). HS in the GBM has been implicated as a target antigen or bridging molecule for the binding of autoantibodies or immune complexes to renal tissue [1, 17, 18]. As histones have a very high affinity for HS, the cross-reactive polyclonal anti-DNA antibodies that bind to histones might play a role in the pathogenesis of nephritis in SLE [19]. It has also been suggested that HS is important for the glomerular deposition of nucleosomes precomplexed to anti-nucleosome antibodies [20].
Anti-nuclear antibodies with the ability to fix complement are primarily immunoglobulin (Ig) G1 and IgG3, and these subclasses correlate with the presence of lupus nephritis and levels of anti-DNA antibodies [21]. Studies of the extractable nuclear antigen response suggest that anti-Ro, La and U1-ribonucleoprotein antibodies are primarily IgG1, whereas anti-Sm BB' antibody contains equal amounts of IgG1 and IgG2. To date there is no clear report on the subclass distribution of anti-dsDNA, anti-HS and anti-nucleosome activity in relation to disease activity in SLE patients. The contribution of antibody binding to DNA, as opposed to histone/DNA (i.e. nucleosomes) or histones alone, to the immunopathology in patients with SLE remains uncertain.
We have previously assessed the value of measuring antibodies to dsDNA and extractable nuclear antigens in serial bleeds from 14 Afro-Caribbean patients with SLE [22]. In the present study we explored the relationship between disease activity and serum antibody levels against five antigens (ss-DNA, dsDNA, histones, HS and nucleosomes) in a cohort of Caucasian patients. We also assessed the IgG subclass response to these antigens. We analysed the relationship between antibodies of these specificities and we discuss their activity in patients with active and inactive SLE. Unlike most previous authors, we did not use a global disease activity index, but rather the British Isles Lupus Assessment Group (BILAG) index [23], which distinguishes disease activity in eight organs and systems.
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Patients and methods |
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Patients and controls
Serum samples were obtained from 33 randomly selected Caucasian patients with a clinical diagnosis of SLE who attended the lupus clinic at the Bloomsbury Rheumatology Unit between 1990 and 1997. All patients met four or more of the 1982 revised American College of Rheumatology (ACR) criteria for the classification of SLE [24]. Thirty female patients and three male patients were selected, their ages ranging from 16 to 61 years (mean 30 yr). Eleven of these patients had lupus nephritis, diagnosed histologically. Sera from 21 healthy blood donors (13 women, eight men) were used as normal controls.
Data on clinical disease activity corresponding to the patients’ samples were available from the BILAG index records [23]. The BILAG index (now computerized for easy use) measures clinical disease activity according to the principle of the physician's intention to treat. The index assesses separately eight organs or systems: general, mucocutaneous, central nervous system, musculoskeletal, cardiovascular/respiratory, vascular, renal and haematological. Each system is allocated alphabetic scores (A–E) according to the presence or absence of a variety of clinical features (mostly) in each organ/system: A=disease that requires urgent disease-modifying therapy; B=disease that demands close attention and perhaps modification of minor therapy, e.g. antimalarial or non-steroidal anti-inflammatory drugs, or prednisolone <20 mg/day; C=stable mild disease; D=system previously affected but currently inactive; E=system never involved. Global disease activity was calculated for each assessment, using the system A=9, B=3, C=1, D=0 and E=0.
Study design
In this cross-sectional study, individual sera from each of the patients and controls were analysed using enzyme-linked immunosorbent assays (ELISA) specific for anti-dsDNA, anti-ssDNA, anti-nucleosome, anti-histone and anti-HS antibodies. ELISAs were also performed to identify the subclasses of the anti-dsDNA, anti-nucleosome and anti-HS antibodies.
Anti-dsDNA and anti-ssDNA ELISAs
ELISAs were used to detect ssDNA and dsDNA antibodies as described elsewhere, with minor modification [25]. Duplicate serum samples (100 µl/well) of a 1:200 dilution in phosphate-buffered saline containing 0.05% Tween (PBS-T) were used. Each plate contained a known positive and negative serum. Plates were washed four times in PBS-T and 100 µl of a 1:1000 dilution (in PBS-T) of alkaline phosphatase-conjugated goat anti-human IgG (anti-
chain-specific) (Sigma) was added per well and incubated for 1 h at 37°C to determine the bound antibodies. Plates were then washed. Freshly prepared substrate solution (phosphatase substrate tablets; Sigma, catalogue number 104; Sigma St Louis, MO) was added to each well and incubation was performed at 37°C. After 30 min the optical density (OD) at 405 nm was read using a spectrometer (MR4000; Dynatech).
The uncoated (antigen-free) halves of the plates were used to determine background activity, which was subtracted from values obtained for the coated sides. The mean of the duplicates was taken as the final result. The mean OD value +2 S.D. of the 21 healthy control samples was taken as the cut-off point for positive results.
Anti-histone, anti-nucleosome and anti-HS ELISAs
Antibodies to histones, nucleosome and HS were detected using a procedure [17, 26] similar to that used in the anti-DNA ELISA. Immunolon I plates (Dynatech Laboratories) were used for the anti-nucleosome assays, and Maxisorb (Nunc, Denmark) plates were used for the detection of histones and HS antibodies. Plates were precoated with 150 µl/well of protamine chloride (Sigma, Poole, UK) (0.5 mg/ml in bicarbonate buffer) prior to the addition of HS and incubated for 1 h at 37 °C. Total histones (5 µg/ml) (from calf thymus; Boehringer, Mannheim, Germany), 10 µg/ml of nucleosomes (a gift from Dr David Stollar, Boston, MA, USA) and 50 µg/ml HS (bovine kidney; Sigma) were used as antigens for the respective assays. Human monoclonal antibodies [9, 27] and serum samples from SLE patients were used as positive controls where appropriate.
IgG subclass detection
To determine the IgG subclass distribution of autoantibodies against dsDNA, nucleosomes and HS, ELISAs were carried out using conjugates specific for each subclass. Conjugates of IgG1, IgG2, IgG3 and IgG4 with alkaline phosphatase (Binding Site, Cambridge, UK) were used at dilutions of 1:250, 1:250, 1:500 and 1:100 respectively in PBS-T. The specificities of these conjugates were confirmed and the dilutions were determined on the basis of the reactivity of the conjugates against different concentrations of myelin basic proteins specific for subclasses 1, 2, 3 and 4 (Sigma, UK) with a separate ELISA (method as described above). Human monoclonal antibodies [9, 27] and serum samples from SLE patients, specific for different IgG subclasses, available at Bloomsbury Rheumatology Unit, were used as positive controls in each assay. Results were expressed as OD at 450 nm.
Statistical analysis
As the levels were not normally distributed, non-parametric tests were carried out. The Mann–Whitney test, Spearman's rank correlation and the Wilcoxon rank test were used with the Statistical Package for Social Sciences, Inc. (SPSS; Chicago, IL, USA) program.
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Results |
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Patients
Out of the 33 patients with SLE in the cross-sectional study, 14 had clinically active lupus (i.e. global score >6). Eleven patients had nephritis, including four patients who, in the BILAG renal section, scored B and seven who were in the C category. Table 1
summarizes some of the collective results (e.g. treatment, disease manifestations, clinical activity etc.) for the patients.
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Antibody levels
The normal values for the controls were taken as the mean+2 S.D. of the OD values for each of the assays. In every case, the mean antibody levels were higher in the SLE group than in the controls (P<0.001 for each of antibodies) (data not shown).
dsDNA antibodies
Seventy-three per cent of the patients with SLE were positive for anti-dsDNA antibodies and 82% of the patients with lupus nephritis exhibited these autoantibodies (Table 2). The mean anti-dsDNA antibody concentrations in patients with lupus nephritis were significantly greater than those in patients without lupus nephritis (P=0.018) (groups B and C were compared with groups D and E of the BILAG system) (Fig. 1). Anti-dsDNA antibody levels of patients with clinically active disease (global score >6) were compared with those of patients with inactive disease (global score <6), and the differences were not significant (P=0.239) either in patients with SLE as a whole or in the subgroup of patients with nephritis (Table 3).
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(n=11) and patients without lupus nephritis 
(n=22), determined by ELISA.The mean value for each antibody is shown as a horizontal line. *P=0.0162–0.0228.
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ssDNA antibodies
Eighty-two per cent of SLE patients were positive for ssDNA antibodies and 91% of the patients with lupus nephritis had a higher titre than non-renal patients. There was no significant difference in the ssDNA antibody levels between the renal and non-renal groups (P=0.061) or between the four individual groups when they were compared with each other. For the 33 patients with SLE, there was no difference in ssDNA antibodies between patients with active and inactive disease.
Histone antibodies
Seventy per cent had a positive titre of anti-histone antibodies, and 91% of the patients with lupus nephritis were positive. However, there was no significant difference in anti-histone antibody titre between the renal and non-renal patients with SLE (P=0.125). Again, there was no significant difference between these autoantibodies in the clinically active and inactive groups (P=0.623) in patients with SLE as a whole, or in the 11 patients with lupus nephritis.
Nucleosome antibodies
Seventy-three per cent of the patients with SLE were positive for anti-nucleosome antibodies, and the percentage increased to 82% in the patients with lupus nephritis. There was no significant difference (P=0.40) in nucleosome antibodies between the patients with and without lupus nephritis. There was a significant difference in anti-nucleosome antibodies between active and inactive disease (P=0.022) for all the patients with SLE.
HS antibodies
Forty-two per cent of the patients had a positive titre of anti-HS antibodies, and the percentage was almost doubled in the lupus nephritis patients (73%) (Table 3
). As with dsDNA, the mean level of anti-HS antibodies in the lupus nephritis patients was significantly greater than in patients without renal involvement (P=0.016). There was no difference in anti-HS level when clinically active patients were compared with inactive SLE patients (P=0.755), but there was a difference between these two groups when the patients with lupus nephritis were analysed (P=0.018). HS antibodies were never found in the absence of anti-dsDNA antibodies.
Using Spearman's rank correlation test, we found several significant correlations between antibody levels (Table 4). The most significant correlations were between antibodies to dsDNA and ssDNA, between antibodies to ssDNA and nucleosomes and between antibodies to HS and dsDNA. Renal activity score showed a significant correlation with anti-HS (r=0.449, P=0.018) (Table 5) but not with anti-dsDNA, anti-ssDNA or anti-nucleosome antibodies. However, the anti-HS antibody levels did not appear to correlate with disease activity in any of the other organs or systems (data not shown). Global score correlated well with both anti-nucleosome and histone antibodies, and with renal score.
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Subclass analysis
Sera from 30 patients (with and without lupus nephritis) were selected and analysed by ELISA to determine the subclass distribution for anti-dsDNA, nucleosome and HS antibodies (Fig. 2). The mean+2 S.D. of the control sera was taken as a cut-off point to select the positive results.
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, patients positive for dsDNA; •, control patients for dsDNA; 
, patients positive for anti-HS antibodies; 
, patients negative for anti-HS antibodies. The mean value for each subclass is shown as a horizontal line (not visible when the mean level is negligible).
dsDNA antibodies
Twenty-one of the serum samples tested positive for dsDNA antibodies and were compared with samples from six control SLE patients, i.e. patients who had negligible or no dsDNA antibodies (Fig. 2). Anti-dsDNA positive sera demonstrated a relatively high incidence of IgG1 and IgG3 antibodies, 57% of the sera being positive for IgG1 or IgG3 antibodies. Twenty-nine per cent were positive for IgG2 and IgG4 antibodies. Thirty-eight per cent of patients were positive for both IgG1 and IgG3. Patients with active SLE had significantly higher levels of IgG3 antibodies (P=0.014) than patients with inactive disease, and a similar result was observed in the subgroup of patients with lupus nephritis (P=0.048). There was no difference in IgG1, IgG2 or IgG4 antibody levels between patients with active and inactive SLE. The only trend to a significant correlation between total anti-dsDNA antibodies and subclasses was for IgG3 (r=0.431, P=0.051). There were no correlations between renal involvement and different IgG subclasses, nor was there any significant difference in the subclass levels between samples from patients with lupus nephritis when compared with non-renal disease patients. IgG1 and IgG3 were both correlated with global score (r=0.502, P=0.020 and r=0.482, P=0.030 respectively).
Nucleosome antibodies
Twenty-four of the serum samples tested positive for anti-nucleosome antibodies, and were compared with samples from six ‘control’ SLE patients with negligible nucleosome antibodies. Anti-nucleosome-positive sera demonstrated a very high incidence of IgG2 and IgG3 antibodies, 88 and 92% of the sera being positive for IgG2 and IgG3 respectively. Seventy-one per cent of the sera were positive for IgG1 but only 13% of sera had IgG4. There was no difference in the distribution among the patients with and without lupus nephritis. There were no statistically significant differences in subclass levels between samples from patients with and without nephritis, and no difference between the patients with active disease and those with inactive disease. The total anti-nucleosome antibody levels were correlated with IgG2 (r=0.471, P=0.020). No subclass was seen to correlate with global score and there were no correlations between renal involvement and subclass distribution.
HS antibodies
Eleven of the serum samples tested positive for anti-HS antibodies, and were compared with samples from five ‘control’ SLE patients. As can be seen from Fig. 2, HS antibodies are made up of primarily IgG2 or IgG3 subclasses (but not both, i.e. if there were high levels of IgG2 there were negligible IgG3 antibodies and vice versa). None of the HS samples was positive for IgG1, but 55% were positive for IgG2. Thirty-six per cent of the samples were positive for IgG3 and/or IgG4. The only significant difference between the patients with and without lupus nephritis was between IgG1 and IgG3 (P<0.028) (IgG3>IgG1). There were no significant differences in subclass levels between the patients with active SLE and those with inactive SLE. None of the subclasses appeared to correlate with the HS antibodies. As with the other nucleosome and dsDNA antibodies, there appeared to be no correlation with renal involvement in any of the subclasses.
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Discussion |
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Glomerulonephritis is a major determinant of the course and prognosis of SLE, glomerular injury resulting from either the deposition (or in situ formation) of ICs in the renal glomeruli or from the direct cytotoxicity of a subset of pathogenic autoantibodies for glomerular cells [28]. A number of antibodies, including anti-DNA antibodies, have been implicated in the development of lupus nephritis, but it is evident that the immunogen for the induction of autoantibodies in SLE is unlikely to be DNA itself. However, DNA complexed to histones or nucleosomes may well be involved in both the induction and the pathophysiology of SLE [20].
In this study we classified disease activity with the BILAG system, which has been shown to be both valid and reliable [23]. When converted into a global score system, it has also been shown to correlate with the SLEDAI (Systemic Lupus Disease Activity Index) and the SLAM (Systemic Lupus Activity Measure) global score indices [29].
This study shows that levels of all five autoantibodies were significantly greater in the patients with SLE than in the healthy controls (P<0.001). Eighty-two per cent of SLE patients with lupus nephritis had anti-dsDNA antibodies. These levels are within the 40–92% range reported by Harley and Gaither [30]. Patients with lupus nephritis had significantly higher levels of anti-dsDNA antibodies than patients without renal disease (P=0.018) (Fig. 1), as reported by others [17]. When the levels in each individual BILAG group were studied, we found a significant difference in antibody levels in patients in groups A and B compared with group E (P=0.034). There was no significant difference in dsDNA antibody levels between patients with active or inactive SLE using a global BILAG score of 6 as the cut-off level.
There was a significant difference in HS reactivity between patients with lupus nephritis compared with patients without renal disease, as was also found by Fillit and Lahits [31]. Also, patients with active disease and lupus nephritis had significantly higher levels of anti-nucleosome antibodies than patients with inactive disease and nephritis. Measuring anti-ssDNA, anti-histone and anti-nucleosome antibodies added very little to the assessment of renal disease activity.
Global score was seen to correlate with both anti-nucleosome and anti-histone antibodies (r=0.44 for both antibodies). Massa et al. [32] also found anti-nucleosome reactivity to correlate with disease severity. The presence of renal disease correlated with antibodies to dsDNA and HS, but only the latter showed a significant correlation with disease activity in the kidney. Like Kramers et al. [17], we never found anti-HS reactivity in the absence of DNA antibodies, and, together with their correlations with each other and with renal disease, this observation suggests that anti-HS reactivity is mediated by anti-DNA (or anti-chromatin) antibodies, and that there are no autoantibodies in SLE which specifically and directly bind to HS, as suggested by others [33]. Hylkema et al. [34] similarly observed a correlation between anti-HS reactivity/anti-DNA levels and HS reactivity/nephritis in lupus patients. Thus, they concluded that the anti-HS reactivity is a direct reflection of anti-DNA reactivity. In contrast, Termaat et al. [35] found that the anti-HS titre was not merely a reflection of the reactivity measured in the Farr assay, and they concluded that only a subpopulation of anti-DNA molecules can bind to HS. None of the studies, including ours, measured HS reactivity after absorbing out the reactivity against other autoantigens. As it is difficult in practice to absorb out the entire spectrum of autoantigen reactivity without inactivating the autoantibodies in the sera, one could consider the HS reactivity of the crude sera to be a surrogate marker for what may be a broad antibody specificity.
Although the number of patients in this cross-sectional analysis was modest, the patients were studied in detail. It was perhaps unfortunate that we did not have a selection of patients with renal grade A.
The IgG subclass analysis showed that the predominant subclasses of anti-dsDNA antibodies were IgG1 and IgG3. This was also found by Kay et al. [36] and is compatible with an antigen-driven, T-cell-dependent antibody response. Patients most frequently had both IgG1 and IgG3 subclasses. IgG3 levels were significantly greater than IgG1 and IgG4 levels (P=0.013 and 0.003 respectively). IgG3 was the only subclass seen to correlate with total dsDNA antibody levels. As reported by Devey et al. [37], who showed a correlation of IgG1 and IgG3 with disease activity in general and renal involvement in particular, we found the same correlation with disease activity in general (but not for renal disease alone). There were no such correlations found in the nucleosome and HS subclasses. There were also no differences in the subclass levels (dsDNA, nucleosome and HS antibodies) when we compared patients with nephritis with patients without nephritis, but patients with active SLE had increased levels of anti-dsDNA IgG3, as did the patients with lupus nephritis with active SLE.
The predominant subclass of anti-nucleosome antibodies was IgG2, possibly implying a role for T-cell-independent antibody production against nucleosomes. Similarly, Loizou et al. [38] found a subgroup of eight autoimmune subjects with a predominant elevation of IgG2 anti-cardiolipin antibodies. The majority of patients had very low levels of IgG1 and IgG3, and levels IgG2 were significantly higher than those of the other subclasses. IgG2 was the only subclass to correlate with total anti-nucleosome antibody levels. Unlike the dsDNA subclasses, patients with active SLE did not have significantly increased levels of any subclass against nucleosomes.
Overall, the results for the anti-HS subclass ELISAs showed very low antibody levels. Five out of the eleven patients tested positive for the IgG2 subclass and the remaining patients had very low levels of IgG3 instead. IgG3 levels were significantly higher than IgG1 levels, but there were no other significant differences. Patients either had IgG2 or IgG3 antibodies, never both. The predominance of IgG2-like anti-nucleosome antibodies suggests a role for T-cell-independent antibody production—antibodies induced against carbohydrate and carbohydrate-like substances often belong to the IgG2 subclass. It may be that the in vivo HS reactivity observed is a result of ICs joined to the GBM via HS (rather than a specific anti-HS antibody) and therefore the subclass distributions obtained in the HS subclass ELISA could be the result of anti-dsDNA and nucleosome antibodies binding indirectly to the HS. It is interesting to note that the two predominant subclasses in the HS ELISA are IgG2 and IgG3, the dominant subclasses of anti-nucleosome and anti-dsDNA antibodies.
The study of autoantibodies, their production and their role in the immunopathology of SLE and lupus nephritis is complex. Insight into these issues is not only of theoretical interest but may also lead to new approaches to diagnostic testing and more preventative or specific therapies.
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Acknowledgments |
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This work was supported by grants from the Arthritis Research Campaign.
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Notes |
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Correspondence to: C. T. Ravirajan, Bloomsbury Rheumatology Unit, Centre for Rheumatology, University College London, Arthur Stanley House, 40–50 Tottenham Street, London W1T 4NJ, UK.
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