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). Essentially, each criterion evolves from immunogenic and inflammatory signals – some are interconnected, some are not. Disparate signals instigated by disparate causes. These may promote clinically heterogenous SLE cohorts with respect to organ affection, autoimmunity, and disease course. There is today no concise measures or arguments that settle whether SLE cohorts evolve from one decisive etiological factor (homogenous cohorts), or if disparate pathobiological factors promote SLE (heterogenous cohorts). Current SLE cohorts are not ideal substrates to serve as study objects if the research aims are to describe etiology, and molecular interactions that cause - and link - primary and secondary pathophysiological events together - events that account for early and progressive SLE. We have to develop SLE criteria allowing us to identify definable categories of SLE in order to describe etiology, pathophysiology and diagnostic criteria of delimitated SLE versions. In this regard, the causality principle is central to define dominant etiologies of individual SLE categories, and subsequent and consequent down-stream diagnostic disease measures. In this sense, we may whether we like it or not identify different SLE categories like “genuine SLE” and “SLE-like non-SLE” syndromes. Many aspects of this problem are thoroughly discussed in this study

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 in SLE, viral and parasitic infections and in malignancies. An increasing number of studies on classification criteria for SLE have been published in the aftermath of the canonical 1982 American College of Rheumatology SLE classification sets of criteria. Considering these studies, it is surprising to observe a nearby complete absence of fundamental critical/theoretical discussions aimed to explain how and why the classification criteria are linked in context of etiology, pathogenicity, or biology. This study is an attempt to prioritize critical comments on the contemporary definition and classification of SLE and of anti-dsDNA antibodies in context of lupus nephritis. Epidemiology, etiology, pathogenesis, and measures of therapy efficacy are implemented as problems in the present discussion. In order to understand whether or not disparate clinical SLE phenotypes are useful to determine its basic biological processes accounting for the syndrome is problematic. A central problem is discussed on whether the clinical role of anti-dsDNA antibodies from principal reasons can be accepted as a biomarker for SLE without clarifying what we define as an anti-dsDNA antibody, and in which biologic contexts the antibodies appear. In sum, this study is an attempt to bring to the forum critical comments on the contemporary definition and classification of SLE, lupus nephritis and anti-dsDNA antibodies. Four concise hypotheses are suggested for future science at the end of this analytical study

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. Therefore, all major SLE classification criteria since the 1971 preliminary criteria usurp the role of diagnostic criteria. Today´s practice silently accept that the SLE classification process “diagnose” SLE patients despite the fact that classification criteria are not accepted as diagnostic criteria! This is a central paradox in contemporary SLE research strategies. Contemporary SLE cohorts are designed to investigate SLE´s etiological features. However, each cohort that is categorized by classification criteria has one central inherent problem. From theoretical and practical arguments, they embody multiple distinct clinical phenotypes. This raises the critical and principal question if phenotypically heterogenic SLE cohorts are useful to identify basic SLE-specific etiology(ies) and disease process(es). In times to come, we must prioritize development of firm diagnostic criteria for SLE, as the classification criteria have not contributed to reduce the enigmatic character of the syndrome. No radical improvements are visible in the horizon that may lead to concise investigations of SLE in well-defined homogenous SLE cohorts. We must develop new strategies where studies of phenotypically standardized cohorts of SLE must be central elements. Problems related to contemporary SLE classification criteria are contemplated, analyzed, and critically discussed in this study

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. 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

Chromatin as a target antigen in human and murine lupus nephritis

The present review focuses on pathogenic molecular and transcriptional events in patients with lupus nephritis. These factors are renal DNaseI, exposed chromatin fragments and the corresponding chromatin-reactive autoantibodies. Lupus nephritis is the most serious complication in human systemic lupus erythematosus, and is characterised by deposition of chromatin fragment-IgG complexes in the mesangial matrix and glomerular basement membranes. The latter deposition defines end-stage disease. This event is stringently linked to a renal-restricted shutdown of expression of the DNaseI gene, as determined by loss of DNaseI mRNA level and DNaseI enzyme activity. The major aim of the present review is to generate new therapeutic strategies based on new insight into the disease pathogenesis

ホクオウテキ ヘイワ キンコウ : フンソウ コウゾウ ノ ヘンカン ノタメノ アプロｰチ ､ カイケツ シュホウ ト ソノ ゲンリ

PDF/A formatsAccess: via World Wide Web東京外国語大学大学院総合国際学研究科博士 (学術) 論文 (2017年1月)Author's thesis (Ph.D)--Tokyo University of Foreign Studies, 2017博甲第222号Bibliography: p. 208-231Summary in English and Japanese東京外国語大学 (Tokyo University of Foreign Studies)博士 (学術

Flexible Lipid Bilayers in Implicit Solvent

A minimalist simulation model for lipid bilayers is presented. Each lipid is represented by a flexible chain of beads in implicit solvent. The hydrophobic effect is mimicked through an intermolecular pair potential localized at the ``water''/hydrocarbon tail interface. This potential guarantees realistic interfacial tensions for lipids in a bilayer geometry. Lipids self assemble into bilayer structures that display fluidity and elastic properties consistent with experimental model membrane systems. Varying molecular flexibility allows for tuning of elastic moduli and area/molecule over a range of values seen in experimental systems.Comment: 5 pages, 5 figure