The Role of Anti-DNA Antibodies in the Development of Lupus Nephritis: A Complementary, or Alternative, Viewpoint?

Goilav, Béatrice; Putterman, Chaim

doi:10.1016/j.semnephrol.2015.08.005

Cited by 34 publications

(35 citation statements)

References 66 publications

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“…The issue regarding the relative importance of DNA/anti-DNA and nucleosome/anti-nucleosome ICs in the pathogenesis of LN was once again raised by two recent review papers (12, 13). Pedersen et al (12) reviewed their studies that emphasized the importance of the nucleosome/anti-nucleosome IC in the pathogenesis of LN while Goilav and Putterman (13) were more conciliatory with the conclusion that both IC systems were complementary.…”

Section: Breaking Tolerance To Double Stranded Dna Nucleosome and Omentioning

confidence: 99%

“…Pedersen et al (12) reviewed their studies that emphasized the importance of the nucleosome/anti-nucleosome IC in the pathogenesis of LN while Goilav and Putterman (13) were more conciliatory with the conclusion that both IC systems were complementary. Our 2004 publication in the Journal of Experimental Medicine (14) cited by Goilav and Puttermen (13) is relevant to this issue. The paper has by large been ignored by those who favor the important role of ANA and anti-dsDNA Ab in the pathogenesis of SLE in general and LN in particular.…”

Section: Breaking Tolerance To Double Stranded Dna Nucleosome and Omentioning

confidence: 99%

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Pathogenesis of proliferative lupus nephritis from a historical and personal perspective

Wang

Dai

et al. 2017

Clinical Immunology

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Section: Breaking Tolerance To Double Stranded Dna Nucleosome and Omentioning

confidence: 99%

Section: Breaking Tolerance To Double Stranded Dna Nucleosome and Omentioning

confidence: 99%

Pathogenesis of proliferative lupus nephritis from a historical and personal perspective

Wang

Dai

et al. 2017

Clinical Immunology

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“…A theoretical model of these conflicting hypotheses and data sets is shown in Figure 2. The emerging concepts and models developed from divergent hypotheses are clearly visible in the conflicting interpretations of the pathogenesis, as described by one set of researchers 6,7 versus another set of researchers. 1,2,30 The following discussion has one perspective: to define lupus nephritis pathogenesis and key points for specific, causal therapy strategies.…”

Section: Pathogenesisdbackground and Present Statusmentioning

confidence: 99%

“…There are no unifying concepts available to explain lupus nephritis as it appears in murine models or in humans with SLE. Some recently reviewed concepts 1,7 claim that anti-dsDNA antibodies are pathogenic because they recognize exposed chromatin in the mesangium or in glomerular basement membrane ( Figure 3A). Others indicate that antibodies target cross-reacting antigens that appear as normal constituents in glomeruli 1,15 ( Figure 3B), or that chromatin-IgG complexes derive from circulation.…”

Section: Pathogenesis Of Lupus Nephritisdincommensurable Modelsmentioning

confidence: 99%

Future Perspectives on Pathogenesis of Lupus Nephritis

Rekvig

Thiyagarajan

Pedersen

et al. 2016

The American Journal of Pathology

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Divergent incommensurable models have been developed to explain the pathogenesis of lupus nephritis. Most contemporary models favor a central role for anti-chromatin antibodies. How they exert their pathogenic effect has, however, endorsed conflicts that at least for now preclude insight into definitive pathogenic pathways. The following paradigms are contemporarily in conflict with each other: i) the impact of anti-double-stranded DNA (dsDNA) antibodies that cross-react with inherent renal antigens, ii) the impact of anti-dsDNA antibodies targeting exposed chromatin in glomeruli, and iii) the impact of relative antibody avidity for dsDNA, chromatin fragments, or cross-reacting antigens. Aside from these three themes, the pathogenic role of T cells in lupus nephritis is not clear. These different models should be tested through a collaboration between scientists belonging to the different paradigms. If it turns out that there are different pathogenic pathways in lupus nephritis, the emerging pathogenic mechanism(s) may be encountered with new individual causal therapy modalities. Today, therapy is still unspecific and far from interfering with the cause(s) of the disorder. This review attempts to describe what we know about processes that may cause lupus nephritis and how such basic processes may be affected if we can specifically interrupt them. Secondary inflammatory mechanisms, cytokine signatures, activation of complement, and other contributors to inflammation will not be discussed herein; rather, the events that trigger these factors will be discussed.

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“…Anti-double-stranded (ds) DNA are prototypical autoantibodies in systemic lupus erythematosus (SLE) and form part of the American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC) criteria for the classification of SLE [1,2]. Although anti-dsDNA are used widely as diagnostic and longitudinal biomarkers in routine clinical practice, controversies persist regarding their diagnostic significance in nephritis, correlation with disease activity and prediction of flares in SLE and explanations of their origins and pathogenicity [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Precipitating anti-dsDNA peptide repertoires in lupus

Wang

Colella

Beroukas

et al. 2018

Clinical and Experimental Immunology

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Anti-double-stranded (ds)DNA autoantibodies are prototypical serological markers of systemic lupus erythematosus (SLE), but little is known about their immunoglobulin variable (IgV) region composition at the level of the secreted (serum) proteome. Here, we use a novel proteomic workflow based on de novo mass spectrometric sequencing of anti-dsDNA precipitins to analyse IgV subfamily expression and mutational signatures of high-affinity, precipitating anti-dsDNA responses. Serum anti-dsDNA proteomes were oligoclonal with shared (public) expression of immunoglobulin (Ig)G heavy chain variable region (IGHV) and kappa chain variable region (IGKV) subfamilies. IgV peptide maps from eight subjects showed extensive public and random (private) amino acid replacement mutations with prominent arginine substitutions across heavy (H)- and light (L)-chains. Shared sets of L-chain complementarity determining region 3 (CDR3) peptides specified by arginine substitutions were sequenced from the dominantly expressed IGKV3-20 subfamily, with changes in expression levels of a clonal L-chain CDR3 peptide by quantitative multiple reaction monitoring (MRM) paralleling the rise and fall of anti-dsDNA levels by Farr radioimmunoassays (RIA). The heavily mutated IgV peptide signatures of precipitating anti-dsDNA autoantibody proteomes reflect the strong selective forces that shape humoral anti-dsDNA responses in germinal centres. Direct sequencing of agarose gel precipitins using microlitre volumes of stored sera streamlines the antibody sequencing workflow and is generalizable to other precipitating serum antibodies.

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The Role of Anti-DNA Antibodies in the Development of Lupus Nephritis: A Complementary, or Alternative, Viewpoint?

Cited by 34 publications

References 66 publications

Pathogenesis of proliferative lupus nephritis from a historical and personal perspective

Pathogenesis of proliferative lupus nephritis from a historical and personal perspective

Future Perspectives on Pathogenesis of Lupus Nephritis

Precipitating anti-dsDNA peptide repertoires in lupus

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