Cross-reactivity of monoclonal anti-DNA antibodies with heparan sulfate is mediated via bound DNA/histone complexes

Termaat, R. M.; Brinkman, Kees; Gompel, F Van; Heuvel, L.P.W.J. van den; Veerkamp, J.H.; Smeenk, R. J. T.; Berden, Jo H. M.

doi:10.1016/s0896-8411(05)80019-8

Cited by 87 publications

(49 citation statements)

References 35 publications

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“…After reconstitution with the column effluent, the MoAbs regained their binding to HS. In the reconstituting effluent, DNA and histones could be demonstrated [17]. Also in SLE sera we demonstrated a strong decrease in anti-HS reactivity after purification under dissociating condi-tions [18].…”

Section: Introductionmentioning

confidence: 63%

Higher anti-heparan sulphate reactivity during systemic lupus erythematosus (SLE) disease exacerbations with renal manifestations; a long term prospective analysis

Kramers¹,

Termaat²,

Borg³

et al. 1993

Clinical and Experimental Immunology

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SUMMARYCross-reactive antibodies against heparan sulphate (HS) have been suggested to play a role in initiating renal disease in SLE. Recently, we found that HS-reactivity is mediated by anti-DNA antibodies complexed with DNA and histones. To evaluate the clinical significance of anti-HS reactivity, we studied prospectively a cohort of 72 consecutive SLE patients, of whom 22 experienced 40 exacerbations. In 20 of these exacerbations renal symptoms were present. In these 20 exacerbations significantly higher anti-DNA (median 1:160) and anti-HS (median 1:30) titres were detected compared with exacerbations without renal manifestations (median 1:60 for anti-DNA and negative for anti-HS). There were no correlations with other symptoms of SLE. Anti-HS titres showed a significant correlation with anti-DNA antibody titres {r^ = 0-57, P < 0 05). Anti-HS without anti-DNA reactivity was never detected. Some SLE patients showed a high anti-DNA titre without anti-HS reactivity, suggesting that not all anti-DNA antibodies are able to bind to histone/DNA complexes and thus to exhibit anti-HS reactivity. Our findings indicate that anti-HS reactivity is correlated with renal disease in SLE.

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Section: Introductionmentioning

confidence: 63%

Higher anti-heparan sulphate reactivity during systemic lupus erythematosus (SLE) disease exacerbations with renal manifestations; a long term prospective analysis

Kramers¹,

Termaat²,

Borg³

et al. 1993

Clinical and Experimental Immunology

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“…It has been proposed that the binding of anti-DNA antibodies to glomerular structures can occur through two mechanisms: the direct binding of these antibodies to crossreactive epitopes or indirect binding via intercalating DNA and/or chromatin material (11,13,15,38 -41). It has been previously reported that indirect binding was mediated by heparan sulfate or other cell surface molecules through interactions with DNA, histones, and nucleosomes (12,13,38). On the other hand, direct crossreactivity has been associated with pathogenicity (39,40,42).…”

Section: Discussionmentioning

confidence: 99%

Mesangial Cell-Binding Anti-DNA Antibodies in Patients with Systemic Lupus Erythematosus

Chan¹,

Leung²,

Ho³

et al. 2002

Journal of the American Society of Nephrology

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ABSTRACT. The mechanisms by which anti-DNA antibodies contribute to the pathogenesis of lupus nephritis (LN) remain to be elucidated. This study investigates the binding of polyclonal anti-DNA immunoglobulins from patients with systemic lupus erythematosus (SLE) to human mesangial cells (HMC) in vitro. Testing of cross-sectional serum samples from 280 LN patients (108 during active disease; 172 during remission), 35 SLE patients without renal involvement, 72 patients with non-lupus primary glomerular diseases, and 37 healthy subjects with a cellular enzyme-linked immunosorbent assay showed significant IgG mesangial cell-binding activity in patients with SLE, particularly those with active LN (P < 0.0001). Significant HMC-binding activity was demonstrated in 83.9%, 42.8%, and 47.1% of patients with active LN, inactive LN, and non-renal SLE, respectively. This was predominantly attributed to binding by anti-DNA antibodies, and immune complex binding accounted for 4.6%, 3.5%, and 2.8% of seropositive samples in the respective groups. Longitudinal studies in 27 LN patients demonstrated correlation between serial levels of anti-DNA antibodies, serum HMC-binding activity, and disease activity in 18 patients (66.7%). Affinity-purified polyclonal IgG anti-DNA antibodies from sera with HMC-binding activity showed significant binding to cultured HMC, and to a lesser extent glomerular and proximal tubular epithelial cells and human umbilical vein endothelial cells, but not tumor cell lines, peritoneal mesothelial cells, bronchial epithelial cells, or fibroblasts. The binding of anti-DNA antibodies to HMC was increased 1.47-fold (P = 0.0059) after the removal of Ig-associated DNA by DNase treatment, but it was unaffected by DNase treatment of HMC membrane. Controlled trypsinization of membrane proteins in HMC resulted in a 1.26-fold (P = 0.0025) increase in their binding by anti-DNA antibodies. In conclusion, subsets of anti-DNA antibodies from patients with SLE are capable of binding to HMC. The association of such binding with renal involvement and disease activity and its modulation by DNA concentration suggest that Ig binding to HMC can be a potential marker for disease activity in selected patients and that the binding of anti-DNA antibodies to HMC may be a pathogenetic mechanism in LN.

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“…One of the major problems with the anti-DNA mAbs is that these IgG may be complexed with nucleosomes (DNA complexed with histones) released from dead cells in the culture supernatant of hybridomas and may give false positive results in assays of cross-reactive binding to several Ags (7,30,31). To assess the purity of the mouse mAbs used, we estimated the possible extent of nucleosome contamination.…”

Section: Purity Of Monoclonal Anti-dna Absmentioning

confidence: 99%

Calreticulin, a Potential Cell Surface Receptor Involved in Cell Penetration of Anti-DNA Antibodies

Seddiki

Nato

Lafaye

et al. 2001

The Journal of Immunology

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A 50-kDa protein was purified as a potential receptor, using an affinity matrix containing biotinylated F14.6 or H9.3 anti-DNA mAbs derived from autoimmune (New Zealand Black × New Zealand White)F1 mouse and membrane extracts from cells. This protein was identified as calreticulin (CRT) by microsequencing. Confocal microscopy and FACS analysis showed that CRT was present on the surface of various cells. CRT protein was recognized by a panel of anti-DNA mAbs in ELISA. The binding of F14.6 to lymphocytes and Chinese hamster ovary cells was inhibited by soluble CRT or SPA-600. Thus, the anti-DNA mAbs used in this study bound to CRT, suggesting that CRT may mediate their penetration into the cells and play an important role in lupus pathogenesis.

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Cross-reactivity of monoclonal anti-DNA antibodies with heparan sulfate is mediated via bound DNA/histone complexes

Cited by 87 publications

References 35 publications

Higher anti-heparan sulphate reactivity during systemic lupus erythematosus (SLE) disease exacerbations with renal manifestations; a long term prospective analysis

Higher anti-heparan sulphate reactivity during systemic lupus erythematosus (SLE) disease exacerbations with renal manifestations; a long term prospective analysis

Mesangial Cell-Binding Anti-DNA Antibodies in Patients with Systemic Lupus Erythematosus

Calreticulin, a Potential Cell Surface Receptor Involved in Cell Penetration of Anti-DNA Antibodies

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