SLE: a cognitive step forward-a synthesis of rethinking theories, causality, and ignored DNA structures.

Systemic lupus erythematosus (SLE) is classified by instinctual classification criteria. A valid proclamation is that these formally accepted SLE classification criteria legitimate the syndrome as being difficult to explain and therefore enigmatic. SLE involves scientific problems linked to etiological factors and criteria.

The greatest contribution to medical science is the transformation from studying symptoms to studying their causes-the unrelenting legacy of Robert Koch and Louis Pasteur-and a causality perspective to approach a definition of SLE.

The basic initiative related to this study is derived from the fact that systemic lupus erythematosus (SLE) is a unique and fertile subject. We are, however, still far from understanding its nature. It may be fair to indicate that we are spending more time and resources on studying the complexity of SLE than studying the validity of classification criteria.

SLE classification criteria: Is "The causality principle" integrated and operative - and do the molecular and genetical network, on which criteria depend on, support the definition of SLE as "a one disease entity" - A theoretical discussion.

Molecular and cellular aspects of the autoimmune pathophysiology in SLE is linked to the "The causality principle". SLE Classification Criteria identify per definition disease measures (here: synonymous with classification criteria), but not diagnostic criteria within a classical framework. These two mostly theoretical criteria collections represent a salient conflict between phenomenology and the causality principle - between disease measures and molecular interactions that promote such measures, in other words their cause(s).

SLE classification criteria: Science-based icons or algorithmic distractions - an intellectually demanding dilemma.

It is, so to say, not a prerogative authority assigned to SLE classification criteria that allow them to declare something definitively important about SLE. This is particularly true as criteria-based classification processes overrule the highly needed evolution of concise diagnostic criteria. It is classification criteria that allocate SLE patients into cohorts intended to describe the nature of their disease.

The Anti-DNA Antibodies: Their Specificities for Unique DNA Structures and Their Unresolved Clinical Impact-A System Criticism and a Hypothesis.

Systemic lupus erythematosus (SLE) is diagnosed and classified by criteria, or by experience, intuition and traditions, and not by scientifically well-defined etiology(ies) or pathogenicity(ies). One central criterion and diagnostic factor is founded on theoretical and analytical approaches based on our imperfect definition of the term "The anti-dsDNA antibody". "The anti-dsDNA antibody" holds an archaic position in SLE as a unique classification criterium and pathogenic factor.

Autoimmunity and SLE: Factual and Semantic Evidence-Based Critical Analyses of Definitions, Etiology, and Pathogenesis.

One cannot discuss anti-dsDNA antibodies and lupus nephritis without discussing the nature of Systemic lupus erythematosus (SLE). SLE is insistently described as a prototype autoimmune syndrome, with anti-dsDNA antibodies as a central biomarker and a pathogenic factor. The two entities, "SLE" and "The Anti-dsDNA Antibody," have been linked in previous and contemporary studies although serious criticism to this mutual linkage have been raised: Anti-dsDNA antibodies were first described in bacterial infections and not in SLE; later SLE, viral and parasitic infections and in malignancies.

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

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.

Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression.

Renal DNase I is lost in advanced stages of lupus nephritis. Here, we determined if loss of renal DNase I reflects a concurrent loss of urinary DNase I, and whether absence of urinary DNase I predicts disease progression. Mouse and human DNase I protein and DNase I endonuclease activity levels were determined by western blot, gel, and radial activity assays at different stages of the murine and human forms of the disease.

Systemic Lupus Erythematosus: Definitions, Contexts, Conflicts, Enigmas.

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.

IL-1β Promotes a New Function of DNase I as a Transcription Factor for the Fas Receptor Gene.

Recently we described that endonuclease inactive DNase I translocated into the nucleus in response to increased endogenous IL-1β expression. Here, we demonstrate impact and function of translocated DNase I in tubular cells. Effect of cytokines on expression level and nuclear localisation of DNase I and corresponding levels of Fas receptor (FasR) and IL-1β were determined by confocal microscopy, qPCR and western blot analyses, in presence or absence of siRNA against IL-1β and DNase I mRNA.

Lupus nephritis progression in FcγRIIB-/-yaa mice is associated with early development of glomerular electron dense deposits and loss of renal DNase I in severe disease.

FcγRIIB-/-yaa mice develop severe lupus glomerulonephritis due to lack of an inhibitory immune cell receptor combined with a Y-chromosome linked autoimmune accelerator mutation. In the present study, we have investigated nephritis development and progression in FcγRIIB-/-yaa mice to find shared features with NZB/NZW F1 lupus prone mice and human disease. We sacrificed 25 male FcγRIIB-/-yaa mice at various disease stages, and grouped them according to activity and chronicity indices for lupus nephritis.

B Cell Tolerance to Deiminated Histones in BALB/c, C57BL/6, and Autoimmune-Prone Mouse Strains.

Deimination, a posttranslational modification of arginine to citrulline carried out by peptidylarginine deiminases, may compromise tolerance of self-antigens. Patients with connective tissue autoimmunity, particularly rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or Felty's syndrome, present with autoantibodies to deiminated histones (dH), which thus form a category of antibodies to citrullinated protein antigens (ACPA). In general, ACPA are a sensitive diagnostic for RA and may form in response to the release of nuclear chromatin (DNA plus dH) from granulocytes, usually referred to as neutrophil extracellular traps.

Lipid degradation promotes prostate cancer cell survival.

Prostate cancer is the most common male cancer and androgen receptor (AR) is the major driver of the disease. Here we show that Enoyl-CoA delta isomerase 2 (ECI2) is a novel AR-target that promotes prostate cancer cell survival. Increased ECI2 expression predicts mortality in prostate cancer patients (p = 0.

A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS).

Objectives: Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE.

Methods: An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting.

Future Perspectives on Pathogenesis of Lupus Nephritis: Facts, Problems, and Potential Causal Therapy Modalities.

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.

Murine and Human Lupus Nephritis: Pathogenic Mechanisms and Theoretical Strategies for Therapy.

Lupus nephritis is one of the most serious manifestations of systemic lupus erythematosus, and represents one of the criteria implemented to classify systemic lupus erythematosus. Although studied for decades, no consensus has been reached related to the basic cellular, molecular, and immunologic mechanism(s) responsible for lupus nephritis. No causal treatments have been developed; therapy is approached mainly with nonspecific immunosuppressive medications.

TNFα Amplifies DNaseI Expression in Renal Tubular Cells while IL-1β Promotes Nuclear DNaseI Translocation in an Endonuclease-Inactive Form.

We have demonstrated that the renal endonuclease DNaseI is up-regulated in mesangial nephritis while down-regulated during progression of the disease. To determine the basis for these reciprocal DNaseI expression profiles we analyse processes accounting for an early increase in renal DNaseI expression. Main hypotheses were that i.

The anti-DNA antibody: origin and impact, dogmas and controversies.

The inclusion of 'the anti-DNA antibody' by the ACR and the Systemic Lupus International Collaborating Clinics (SLICC) as a criterion for systemic lupus erythematosus does not convey the diverse origins of these antibodies, whether their production is transient or persistent (which is heavily influenced by the nature of the inducing antigens), the specificities exerted by these antibodies or their clinical impact-or lack thereof. A substantial amount of data not considered in clinical medicine could be added from basic immunology evidence, which could change the paradigms linked to what 'the anti-DNA antibody' is, in a pathogenic, classification or diagnostic context.

Galectin-3 binding protein links circulating microparticles with electron dense glomerular deposits in lupus nephritis.

Objective: A high level of galectin-3-binding protein (G3BP) appears to distinguish circulating cell-derived microparticles in systemic lupus erythematosus (SLE). The aim of this study is to characterize the population of G3BP-positive microparticles from SLE patients compared to healthy controls, explore putative clinical correlates, and examine if G3BP is present in immune complex deposits in kidney biopsies from patients with lupus nephritis.

Methods: Numbers of annexin V-binding and G3BP-exposing plasma microparticles from 56 SLE patients and 36 healthy controls were determined by flow cytometry.

Clinical phenotype associations with various types of anti-dsDNA antibodies in patients with recent onset of rheumatic symptoms. Results from a multicentre observational study.

Unlabelled: Despite anti-dsDNA antibodies constitute a wide range of specificities, they are considered as the hallmark for systemic lupus erythematosus (SLE).

Objective: To identify clinical phenotypes associated with anti-dsDNA antibodies, independently of any clinical diagnoses.

Methods: Patients with recent onset of any rheumatic symptoms were screened for antinuclear antibodies (ANA).

The pathogenesis and diagnosis of systemic lupus erythematosus: still not resolved.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations affecting different tissues. A characteristic feature of SLE is the presence of autoantibodies against double-stranded (ds)DNA, histones and nucleosomes, and other chromatin components. SLE is a prototype type III hypersensitivity reaction.

Anti-dsDNA antibodies as a classification criterion and a diagnostic marker for systemic lupus erythematosus: critical remarks.

Antibodies to mammalian dsDNA have, for decades, been linked to systemic lupus erythematosus (SLE) and particularly to its most serious complication, lupus nephritis. This canonical view derives from studies on its strong association with disease. The dogma was particularly settled when the antibody was included in the classification criteria for SLE that developed during the 1970s, most prominently in the 1982 American College of Rheumatology (ACR), and recently in The Systemic Lupus International Collaborating Clinics (SLICC) classification criteria.

LMW heparin prevents increased kidney expression of proinflammatory mediators in (NZBxNZW)F1 mice.

We have previously demonstrated that continuous infusion of low molecular weight (LMW) heparin delays autoantibody production and development of lupus nephritis in (NZBxNZW)F1 (B/W) mice. In this study we investigated the effect of LMW heparin on renal cytokine and chemokine expression and on nucleosome-mediated activation of nucleosome-specific splenocytes. Total mRNA extracted from kidneys of heparin-treated or -untreated B/W mice was analysed by qPCR for the expression of several cytokines, chemokines, and Toll-like receptors.

Lupus nephritis: enigmas, conflicting models and an emerging concept.

Autoantibodies to components of chromatin, which include double-stranded DNA (dsDNA), histones and nucleosomes, are central in the pathogenesis of lupus nephritis. How anti-chromatin autoantibodies exert their nephritogenic activity, however, is controversial. One model assumes that autoantibodies initiate inflammation when they cross-react with intrinsic glomerular structures such as components of membranes, matrices or exposed nonchromatin ligands released from cells.