Serial studies of the IgG subclass and functional affinity of DNA antibodies in systemic lupus erythematosus

doi:10.1016/0896-8411(88)90069-8

Journal of Autoimmunity

Volume 1, Issue 5, October 1988, Pages 483-494

https://doi.org/10.1016/0896-8411(88)90069-8 Get rights and content

Abstract

T3he functional affinity and IgG subclass of antibodies to ss and dsDNA were measured by ELISA in five serial samples from 41 patients with systemic lupus erythematosus (SLE) who were divided into relatively homogeneous disease subgroups. Anti-dsDNA antibodies were restricted to IgG1 and IgG3 in renal disease and levels increased with disease severity. Functional affinity of IgG1 and IgG3 anti-dsDNA fell in patients with severe renal disease, suggesting that the high affinity antibody population lost from the serum was localizing in the kidneys. IgG2 anti-dsDNA were found in patients with joint and skin disease alone and in the thrombotic/spontaneous abortion subgroup. IgG2 antibody levels did not correlate with disease severity but did correlate with the presence of antibodies to Klebsiella K30 and may have represented a cross-reactive antibody population.

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Cited by (36)

De-sialylated and sialylated IgG anti-dsDNA antibodies respectively worsen and mitigate experimental mouse lupus proteinuria and possible mechanisms
2022, International Immunopharmacology
Citation Excerpt :
Hence, low RAS activity associated with the three subclones of IgG anti-dsDNA antibodies induced low SIA/anti-dsDNA ratios through different gene expressions, either upregulated or downregulated. In patients with SLE, serum anti-dsDNA levels and IgG subclass anti-dsDNA antibodies have been utilized as disease activity markers and/or to reflect the severity of nephritis; however, contradictory reports, as well as clinical observations, have been documented in a significant population of patients with SLE [1,3–5]. Given the contradictory role of anti-dsDNA antibodies in the pathogenesis of lupus nephritis, our current findings further illustrated this issue.
The role of sialylated and de-sialylated (de-SIA) IgG anti-dsDNA antibodies in experimental mouse lupus remains unclear.
To examine how sialylated and de-SIA IgG anti-dsDNA antibodies affect lupus mouse proteinuria and possible mechanisms.
Blood was serially obtained from pristane-induced female BALB/c lupus mice to assess correlations between alpha-2,6-sialic cid (SIA) ratios of serum IgG anti-dsDNA and proteinuria. Kidney C3 staining was correlated with blood IgG anti-dsDNA. Sialylated IgG anti-dsDNA with its de-SIA form was administered to determine the effect on lupus proteinuria and in vitro consequences.
We observed that the SIA contents of IgG anti-dsDNA were lower in Week 16/1+ (Week 16 with 1 + proteinuria) and W24/2 + mice than those in W16 (no proteinuria) and W24/1 + mice, respectively (P < 0.005 for both). C3 staining densities in the kidney correlated inversely with the α-2,6-SIA content of plasma IgG anti-dsDNA (r = -0.660). Highly sialylated A52L1 IgG anti-dsDNA injection mitigated lupus proteinuria significantly from PBS injection; however, its de-SIA form worsened proteinuria (aggravation of proteinuria: the latter vs. the former [sialylated A52L1 IgG anti-dsDNA] with an infinite odds ratio). Highly sialylated A52L1 IgG anti-dsDNA resulted in higher interleukin (IL)-10/IL-12 ratios, higher transforming growth factor-β1 levels, and lower tumor necrosis factor-α levels in sera than its de-SIA from.
We concluded that a low SIA/serum IgG anti-dsDNA ratio indicated a high severity of nephritis in pristane-induced lupus mice. Highly sialylated IgG anti-dsDNA, in contrast to the de-SIA form, alleviated the severity of lupus proteinuria.
Lupus Nephritis
2019, Chronic Renal Disease
Lupus nephritis (LN) is clinically evident in 50–75% of lupus patients and is a significant cause of end-stage renal disease. Although LN is a paradigm of immune complex–mediated renal injury, its pathogenesis is complex, involving abnormalities in multiple components of the immune system including B and T cells, the complement cascade (especially the alternative pathway), and tissue enzymes that clear denatured DNA. The diagnosis of LN still hinges on the renal biopsy, with glomerular changes being the predominant feature in the classification of LN. The prognostic role of interstitial inflammation has recently been demonstrated. Treatment regimens for severe proliferative LN consist of combination therapy using corticosteroids with cyclophosphamide or antimetabolites (mycophenolate). After remission is achieved, maintenance therapy with a tapering dose of corticosteroids is combined with an antimetabolite (mycophenolate or azathioprine). LN may be refractory to standard regimens in up to 50% of patients and B-cell therapies, calcineurin inhibitors, immunomodulators, and complement inhibitors have been used in this setting with varying success.
DNA repair and systemic lupus erythematosus
2017, DNA Repair
Citation Excerpt :
Interestingly, disease in SLE patients and lupus-prone mice is associated with increased isotype switching of autoreactive IgMs resulting in high titers of autoreactive IgGs and the deposition of immunocomplexes within the kidneys. Together, this leads to renal disease, which is one of the major clinical manifestations of SLE [43–47]. Class-switched antibodies to IgG confer transport into extravascular spaces, activation of the complement system, and binding to Fc receptors, providing the optimal potential for autoreactive antibodies to elicit proinflammatory and pathogenic responses [48].
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with no known cure that affects at least five million people worldwide. Monozygotic twin concordance and familial aggregation studies strongly suggest that lupus results from genetic predisposition along with environmental exposures including UV light. The majority of the common risk alleles associated with genetic predisposition to SLE map to genes associated with the immune system. However, evidence is emerging that implicates a role for aberrant DNA repair in the development of lupus. Here we summarize our current knowledge of the potential association of lupus with mutations in DNA repair genes. We also discuss how defective or aberrant DNA repair could lead to the development of lupus.
Lupus Nephritis
2015, Chronic Renal Disease
Lupus nephritis (LN) is clinically evident in 50 to 75% of patients with systemic lupus erythematosus and is a significant cause of ESRD. Although LN is a paradigmatic example of immune complex-mediated renal injury, the pathogenesis is complex, involving abnormalities in multiple components of the immune system, including B and T cells, the complement cascade (especially the alternative pathway), and tissue enzymes that clear denatured DNA. The diagnosis of LN still hinges on the renal biopsy, with glomerular changes being the predominant feature in the classification of LN. The prognostic role of interstitial inflammation in LN has recently been demonstrated. Treatment regimens for severe proliferative LN consist of combination therapy using corticosteroids with cyclophosphamide or antimetabolites (mycophenolate). After remission is obtained, maintenance therapy with a tapering dose of corticosteroids is combined with an antimetabolite (mycophenolate or azathioprine). LN may be refractory to standard regimens in up to 50% of patients. B-cell therapies, calcineurin inhibitors, immunomodulators and complement inhibitors have been used in this setting with varying success.
Increased mesangial cell hyaluronan expression in lupus nephritis is mediated by anti-DNA antibody-induced IL-1β
2006, Kidney International
Citation Excerpt :
As identical concentrations of anti-DNA antibodies were used in these experiments, the data highlight the functional heterogeneity of anti-DNA antibodies at different phases of disease, and imply that anti-DNA antibodies still detectable during clinical remission might be ‘less pathogenic’. The results on IgG isotypes confirmed the predominance of IgG1 in anti-DNA antibody preparations.40, 41 Some investigators have suggested an association between IgG1 and IgG3 anti-DNA antibodies with renal disease, whereas others have observed an association between IgG2 anti-DNA antibodies and nephritic flare.40, 41
The mechanism by which anti-DNA antibodies contribute to the pathogenesis of lupus nephritis (LN) remains to be fully elucidated. Hyaluronan (HA) is an important extracellular matrix constituent that accumulates during tissue injury, and participates in lymphocyte recruitment to sites of inflammation. The role of HA in the pathogenesis of LN has not been defined. We investigated the expression of HA in renal biopsies and circulating HA levels in patients with diffuse proliferative LN, and the effect of human anti-DNA antibodies on HA synthesis in cultured human mesangial cells (HMC). HA expression was increased in the mesangium, and in the periglomerular and tubular distribution in LN kidney biopsies. LN patients showed increased levels of circulating HA, especially during active disease, which correlated with anti-DNA antibody titers (r=0.35, P=0.0234). Anti-DNA antibodies isolated during active LN but not remission increased de novo synthesis of ³H-labeled HA, which was accompanied by induction of HA synthase (HAS) II transcription, and enhanced IL-1β, IL-6, and tumor necrosis factor-α secretion in HMC (P<0.001 for all). Only anti-DNA antibody induction of IL-1β enhanced HA synthesis, which was abrogated by inhibitors of de novo mRNA or protein synthesis. Our findings demonstrate that HA expression is significantly increased within the mesangium in diffuse proliferative LN mediated through anti-DNA antibody-induced IL-1β. Given that HA plays a pivotal role during inflammatory responses, influences cellular behavior and assists in the recruitment of lymphocytes to sites of injury, it is likely that HA contributes to the pathogenesis of LN.
Origin and anti-tumor effects of anti-dsDNA autoantibodies in cancer patients and tumor-bearing mice
2005, Immunology Letters
In the present investigation, we detected anti-dsDNA autoantibodies in cancer patients and modeled the production of anti-dsDNA autoantibodies by inoculating tumors in BALB/c mice. Moreover, induction of anti-dsDNA autoantibodies by immunization with inactivated tumor cells and their DNA indicated that DNA of tumor cells was probably the primary antigen, which was supported by the significantly increasing levels of sera free DNA in cancer patients and tumor-bearing mice. cELISA and indirect immunofluorescence assay showed that the anti-dsDNA autoantibodies could bind to the surface components of tumor cells. In vitro assay showed that immunosera at week 6 from immunized mice displayed significant cytotoxicity to tumor cells compared to that of negative control, but no cytotoxicity mediated by immunosera at week 22 was observed. In addition, by flow cytometry and electrophoresis of fragmented DNA, the cytotoxicity might probably be mediated by apoptosis. Our data also showed that the ability of the anti-dsDNA autoantibodies to induce apoptosis of SP2/0 and Wehi 164 cells was significantly correlated (r = 0.990, p < 0.01 and r = 0.901, p < 0.05) with their functional affinity. In vivo, the growth of solid tumors was significantly inhibited in the immunized mice inoculated directly with SP2/0 and Wehi 164 cells, or in the naïve mice which were inoculated with SP2/0 cells preincubated with immunosera containing anti-dsDNA autoantibodies. In conclusion, we demonstrated the origin of anti-dsDNA autoantibodies in cancer patients and tumor-bearing mice. And our data also showed that these autoantibodies revealed anti-tumor effect by inducing apoptosis.

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Journal of Autoimmunity

Abstract

References (29)

The origin and significance of anti-DNA antibodies

Immunol. Today

Precipitating antibody to DNA detected by two-stage electroimmunodiffusion

Lancet

Comparison of three methods used for the measurement of the avidity of antibody to DNA

J. Immunol. Methods

Dissociation studies of DNA/anti-DNA complexes in relation to anti-DNA avidity

J. Immunol. Methods

Determination of the functional affinity of IgG1 and IgG4 antibodies to tetanus toxoid by isotype-specific solid-phase assays

J. Immunol. Methods

The biological significance of antibody affinity

Immunol. Today

The biological and pathological significance of antibody affinity

Failure of affinity maturation leads to increased susceptibility to immune complex glomerulonephritis

Immunology

Effect of antibody avidity on the induction of renal injury in anti-glomerular basement membrane nephritis

Br. J. Exp. Pathol.

In vitro demonstration of a particular affinity of glomerular basement membrane and collagen for DNA

J. Exp. Med.

Role of low avidity antibody to native DNA in human and murine lupus syndrome

J. Rheumatol.

Qualitative characteristics of anti-DNA antibodies in lupus nephritis

Arthritis Rheum.

Avidity of anti-DNA antibodies in serum and IgG glomerular eluates from patients with systemic lupus erythematosus

J. Clin. Invest.

A longitudinal study of high and low avidity antibodies to double-stranded DNA in systemic lupus erythematosus

Athritis Rheum.

Cited by (36)

De-sialylated and sialylated IgG anti-dsDNA antibodies respectively worsen and mitigate experimental mouse lupus proteinuria and possible mechanisms

Lupus Nephritis

DNA repair and systemic lupus erythematosus

Lupus Nephritis

Increased mesangial cell hyaluronan expression in lupus nephritis is mediated by anti-DNA antibody-induced IL-1β

Origin and anti-tumor effects of anti-dsDNA autoantibodies in cancer patients and tumor-bearing mice