Early anti-nucleosome autoantibodies from a single MRL +/+ mouse: fine specificity, V gene structure and pathogenicity

Jovelin, Fabien; Mostoslavsky, Gustavo; Amoura, Zahir; Chabre, Henri; Gilbert, Danièle; Eilat, Dan; Bach, Jean‐François; Koutouzov, Sophie

doi:10.1002/(sici)1521-4141(199811)28:11<3411::aid-immu3411>3.0.co;2-g

Cited by 26 publications

(16 citation statements)

References 45 publications

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“…Eilat and coworkers (5,22) were able to use this model for assessing tissue damage produced by anti-DNA autoantibodies. RAG-1 Ϫ/Ϫ mice do not produce B and T cells due to a targeted mutation in a gene that is essential for recombination of Ig and TCR genes (17).…”

Section: Discussionmentioning

confidence: 99%

Treatment with a Laminin-Derived Peptide Suppresses Lupus Nephritis

Amital

Heilweil

Ulmansky

et al. 2005

The Journal of Immunology

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The role of DNA as the target for pathogenic lupus autoantibodies in systemic lupus erythematosus is equivocal and renal damage may be due to cross-reactivity of lupus Abs with glomerular components. We have previously shown that lupus autoantibodies bind to the laminin component of the extracellular matrix. In the present work, we have analyzed the fine specificity of the interaction of pathogenic murine lupus autoantibodies with this molecule and the effect of inhibiting their binding to laminin during the course of the disease. We have found that pathogenic murine lupus autoantibodies react with a 21-mer peptide located in the globular part of the α-chain of laminin. Immunization of young lupus-prone mice with this peptide accelerated renal disease. Analysis of transgenic, congenic, and RAG-1−/− mice confirmed the importance of this epitope in the pathogenesis of lupus renal disease. We have synthesized a panel of peptides that cross-react with the anti-laminin Abs and have found that the binding of lupus autoantibodies to the extracellular matrix could be inhibited in vitro by some of these competitive peptides. Treatment of MRL/lpr/lpr mice with these peptides prevented Ab deposition in the kidneys, ameliorated renal disease, and prolonged survival of the peptide-treated mice. We suggest that laminin components can serve as the target for lupus Abs. The interaction with these Ags can explain both the tissue distribution and the immunopathological findings in lupus. Moreover, inhibition of autoantibody binding to the extracellular matrix can lead to suppression of disease.

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Section: Discussionmentioning

confidence: 99%

Treatment with a Laminin-Derived Peptide Suppresses Lupus Nephritis

Amital

Heilweil

Ulmansky

et al. 2005

The Journal of Immunology

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“…Anti-ssDNA and anti-dsDNA Abs. Serum autoantibody levels were assessed by ELISA, as previously described (30). Briefly, ELISA plates pretreated with poly(L-lysine) (100 g/ml) were coated with phage dsDNA (5 g/ml in PBS, pH 7.2) (Roche Diagnostics).…”

Section: Elisasmentioning

confidence: 99%

IFN-α Induces Early Lethal Lupus in Preautoimmune (New Zealand Black × New Zealand White)F1 but Not in BALB/c Mice

Mathian

Weinberg

Gallegos

et al. 2005

The Journal of Immunology

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Recent studies indicate that IFN-α is involved in pathogenesis of systemic lupus erythematosus. However, direct proof that IFN-α is not only necessary, but also sufficient to induce lupus pathogenicity is lacking. In this study, we show that in vivo adenovector-mediated delivery of murine IFN-α results in preautoimmune (New Zealand Black (NZB) × New Zealand White (NZW))F1, but not in normal, mice, in a rapid and severe disease with all characteristics of systemic lupus erythematosus. Anti-dsDNA Abs appeared as soon as day 10 after initiation of IFN-α treatment. Proteinuria and death caused by glomerulonephritis occurred in all treated mice within, respectively, ∼9 and ∼18 wk, at a time when all untreated (NZB × NZW)F1 did not show any sign of disease. IFN-α in vivo induced an overexpression of B lymphocyte stimulator in circulation at similar levels in both the preautoimmune and the normal mouse strains. All effects elicited by IFN-α were dose dependent. (NZB × NZW)F1 infused with purified murine IFN-α also showed acceleration of lupus. Thus, prolonged expression of IFN-α in vivo induces early lethal lupus in susceptible animals.

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“…SLE autoantibodies that bind exclusively to a supramolecular complex have already been described: restricted anti-nucleosome mAb that do not react with histones or DNA were recently identified and demonstrated to occur early during the course of the lupus-like disease developed by MRL mice [19]; certain anti-CL mAb are considered to react with epitopes formed by the association of CL and g 2-GPI [17,22]. However, the particular properties exhibited by our anti-CL mAb, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Since a homogeneous nuclear pattern is usually obtained with autoantibodies directed against double-stranded (ds)DNA, individual or total histones and since 4E10, 1E2, 2E6 and 1G11 did not bind to either antigens, we wondered whether they could react with nucleosomes as it is known that anti-nucleosome antibodies described recently in both human and murine lupus also stain nuclei in a homogeneous pattern [18][19][20]. Fig.…”

Section: Anti-cl Mab Also React With Nucleosomesmentioning

confidence: 99%

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Overlap of the anti-cardiolipin and anti-nucleosome responses of the (NZW X BXSB)F1 mouse strain: a new pattern of cross-reactivity for lupus-related autoantibodies

et al. 2000

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The association of anti‐nuclear antigen (ANA) and anti‐cardiolipin (CL) antibodies is often observed during systemic lupus erythematosus (SLE) or the primary anti‐phospholipid syndrome, thereby raising the possibility of a relationship between these two autoantibody populations. To determine whether ANA and anti‐CL antibodies can overlap, we derived, from a male (NZW × BXSB)F1 mouse, 14 hybridomas selected based on their capacities to react with CL and to label HEp‐2 cell nuclei. Four of these anti‐CL were IgG and bound to CL and phosphatidylserine in a cofactor‐dependent manner and reacted strongly with nucleosomes. Variable region sequence analysis indicated that these four monoclonal antibodies (mAb) were derived from three independent B cell clones that used recurrent heavy and/or light chain immunoglobulin rearrangements, as assessed by comparison with each other and prototypic anti‐CL mAb previously derived from different lupus mouse strains. These results indicate that anti‐CL mAb can have overlapping cross‐reactivities with nucleosomes, thereby defining a new category of SLE‐related autoantibodies characterized by their capacities to recognize distinct supramolecular complexes, formed by the association of an anionic structure and a protein, that exert a strong selective pressure on autoreactive B cell clones.

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Early anti-nucleosome autoantibodies from a single MRL +/+ mouse: fine specificity, V gene structure and pathogenicity

Cited by 26 publications

References 45 publications

Treatment with a Laminin-Derived Peptide Suppresses Lupus Nephritis

Treatment with a Laminin-Derived Peptide Suppresses Lupus Nephritis

IFN-α Induces Early Lethal Lupus in Preautoimmune (New Zealand Black × New Zealand White)F1 but Not in BALB/c Mice

Overlap of the anti-cardiolipin and anti-nucleosome responses of the (NZW X BXSB)F1 mouse strain: a new pattern of cross-reactivity for lupus-related autoantibodies

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