The Sensitizing Properties of the Nucleic Acids and Their Derivatives

Winkenwerder, Walter L.; Buell, Mary V.; Howard, John Eager

doi:10.1126/science.90.2337.356

Cited by 22 publications

(9 citation statements)

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“…We know that the DNA purified for the purpose of detecting anti-dsDNA antibodies was in fact dominantly dsDNA also without further active elimination of ssDNA [(19, 20), Rekvig, unpublished observations]. Thus, the dsDNA structure described above turned out to be the target for anti-dsDNA antibodies in SLE, a statement that also may be valid for the early 1938 detection of anti-DNA antibodies in context of infections (21–23), and that complexes between them had the potential to induce inflammation in SLE-related lupus nephritis [for review see e.g., (4) and below].…”

Section: The Dsdna: Structure Autoimmune Inducer and Target—status mentioning

confidence: 99%

The dsDNA, Anti-dsDNA Antibody, and Lupus Nephritis: What We Agree on, What Must Be Done, and What the Best Strategy Forward Could Be

Rekvig

2019

Front. Immunol.

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This study aims to understand what lupus nephritis is, its origin, clinical context, and its pathogenesis. Truly, we encounter many conceptual and immanent tribulations in our attempts to search for the pathogenesis of this disease—and how to explain its assumed link to SLE. Central in the present landscape stay a short history of the early studies that substantiated the structures of isolated or chromatin-assembled mammalian dsDNA, and its assumed, highly controversial role in induction of anti-dsDNA antibodies. Arguments discussed here may provoke the view that anti-dsDNA antibodies are not what we think they are, as they may be antibodies operational in quite different biological contexts, although they bind dsDNA by chance. This may not mean that these antibodies are not pathogenic but they do not inform how they are so. This theoretical study centers the content around the origin and impact of extra-cellular DNA, and if dsDNA has an effect on the adaptive immune system. The pathogenic potential of chromatin-anti-dsDNA antibody interactions is limited to incite lupus nephritis and dermatitis which may be linked in a common pathogenic process. These are major criteria in SLE classification systems but are not shared with other defined manifestations in SLE, which may mean that they are their own disease entities, and not integrated in SLE. Today, the models thought to explain lupus nephritis are divergent and inconsistent. We miss a comprehensive perspective to try the different models against each other. To do this, we need to take all elements of the syndrome SLE into account. This can only be achieved by concentrating on the interactions between autoimmunity, immunopathology, deviant cell death and necrotic chromatin in context of elements of system science. System science provides a framework where data generated by experts can be compared, and tested against each other. This approach open for consensus on central elements making up “lupus nephritis” to separate what we agree on and how to understand the basis for conflicting models. This has not been done yet in a systematic context.

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Section: The Dsdna: Structure Autoimmune Inducer and Target—status mentioning

confidence: 99%

The dsDNA, Anti-dsDNA Antibody, and Lupus Nephritis: What We Agree on, What Must Be Done, and What the Best Strategy Forward Could Be

Rekvig

2019

Front. Immunol.

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“…Serum autoantibodies to native DNA are a specific diagnostic criterion for SLE,2 and a prognostic factor for the development of lupus nephritis (LN) that affects 30%–60% of patients 3. However, the earliest reports of antibody responses to nucleic acids/nucleoproteins were documented in association with clinically apparent bacterial infections 4–6. Yet two decades later autoantibodies to nuclear antigens were recognised to be a common feature of SLE 7–9.…”

Section: Introductionmentioning

confidence: 99%

Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal

Azzouz

Omarbekova

Heguy

et al. 2019

Annals of the Rheumatic Diseases

337

410

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Background/PurposeTo search for a transmissible agent involved in lupus pathogenesis, we investigated the faecal microbiota of patients with systemic lupus erythematosus (SLE) for candidate pathobiont(s) and evaluated them for special relationships with host immunity.MethodsIn a cross-sectional discovery cohort, matched blood and faecal samples from 61 female patients with SLE were obtained. Faecal 16 S rRNA analyses were performed, and sera profiled for antibacterial and autoantibody responses, with findings validated in two independent lupus cohorts.ResultsCompared with controls, the microbiome in patients with SLE showed decreased species richness diversity, with reductions in taxonomic complexity most pronounced in those with high SLE disease activity index (SLEDAI). Notably, patients with SLE had an overall 5-fold greater representation of Ruminococcus gnavus (RG) of the Lachnospiraceae family, and individual communities also displayed reciprocal contractions of a species with putative protective properties. Gut RG abundance correlated with serum antibodies to only 1/8 RG strains tested. Anti-RG antibodies correlated directly with SLEDAI score and antinative DNA levels, but inversely with C3 and C4. These antibodies were primarily against antigen(s) in an RG strain-restricted pool of cell wall lipoglycans. Novel structural features of these purified lipoglycans were characterised by mass spectrometry and NMR. Highest levels of serum anti-RG strain-restricted antibodies were detected in those with active nephritis (including Class III and IV) in the discovery cohort, with findings validated in two independent cohorts.ConclusionThese findings suggest a novel paradigm in which specific strains of a gut commensal may contribute to the immune pathogenesis of lupus nephritis.

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“…During the last 40 years, more than 2,200 articles are published (PubMed search term: anti-dsDNA antibodies). The anti-DNA antibodies were first described in 1938 and 1939 in bacterial infectious contexts ( 67 – 69 ), and further studied and their presence confirmed 15 years later ( 70 ). In 1957, anti-DNA antibodies were described in a strict autoimmune context; in SLE ( 71 – 74 ).…”

Section: Anti-dsdna Antibodies—a Short Historymentioning

confidence: 99%

“…In this discussion, we need to challenge the canonical impact of “The anti-dsDNA antibody” as biomarker for the autoimmune syndrome SLE. “The anti-dsDNA antibody” exists and is described in context of bacterial and viral infections ( 27 , 67 – 69 , 83 – 93 ), different cancer forms ( 94 – 107 ) and in autoimmune syndromes like autoimmune hepatitis ( 108 ), Sjøgren syndrome ( 109 ), SLE ( 33 ), or primary antiphospholipid syndrome ( 110 ) and other disorders. The term “anti-dsDNA antibody” must therefore be changed to “anti-dsDNA antibodies,” also in light of the different DNA structure-specificities that characterize the diverse anti-dsDNA antibodies.…”

Section: Anti-dsdna Antibodies—status Of Their Definition and Clinicamentioning

confidence: 99%

Systemic Lupus Erythematosus: Definitions, Contexts, Conflicts, Enigmas

Rekvig

2018

Front. Immunol.

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Systemic lupus erythematosus (SLE) is an inadequately defined syndrome. Etiology and pathogenesis remain largely unknown. SLE is on the other hand a seminal syndrome that has challenged immunologists, biologists, genetics, and clinicians to solve its nature. The syndrome is characterized by multiple, etiologically unlinked manifestations. Unexpectedly, they seem to occur in different stochastically linked clusters, although single gene defects may promote a smaller spectrum of symptoms/criteria typical for SLE. There is no known inner coherence of parameters (criteria) making up the disease. These parameters are, nevertheless, implemented in The American College of Rheumatology (ACR) and The Systemic Lupus Collaborating Clinics (SLICC) criteria to classify SLE. Still, SLE is an abstraction since the ACR or SLICC criteria allow us to define hundreds of different clinical SLE phenotypes. This is a major point of the present discussion and uses “The anti-dsDNA antibody” as an example related to the problematic search for biomarkers for SLE. The following discussion will show how problematic this is: the disease is defined through non-coherent classification criteria, its complexity is recognized and accepted, its pathogenesis is plural and poorly understood. Therapy is focused on dominant symptoms or organ manifestations, and not on the syndrome itself. From basic scientific evidences, we can add substantial amount of data that are not sufficiently considered in clinical medicine, which may change the paradigms linked to what “The Anti-DNA antibody” is—and is not—in context of the imperfectly defined syndrome SLE.

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The Sensitizing Properties of the Nucleic Acids and Their Derivatives

Cited by 22 publications

References 0 publications

The dsDNA, Anti-dsDNA Antibody, and Lupus Nephritis: What We Agree on, What Must Be Done, and What the Best Strategy Forward Could Be

The dsDNA, Anti-dsDNA Antibody, and Lupus Nephritis: What We Agree on, What Must Be Done, and What the Best Strategy Forward Could Be

Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal

Systemic Lupus Erythematosus: Definitions, Contexts, Conflicts, Enigmas

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