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

Ole Petter Rekvig

doi:10.3389/fimmu.2021.808008

Abstract

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. In a wider sense, antibodies to unique transcriptionally active or silent DNA structures and chromatin components may have individual and profound nephritogenic impact although not considered yet – not in theoretical nor in descriptive or experimental contexts. This hypothesis is contemplated here. In this analysis, our state-of-the-art conception of these antibodies is probed and found too deficient with respect to their origin, structural DNA specificities and clinical/pathogenic impact. Discoveries of DNA structures and functions started with Miescher’s Nuclein (1871), via Chargaff, Franklin, Watson and Crick, and continues today. The discoveries have left us with a DNA helix that presents distinct structures expressing unique operations of DNA. All structures are proven immunogenic! Unique autoimmune antibodies are described against e.g. ssDNA, elongated B DNA, bent B DNA, Z DNA, cruciform DNA, or individual components of chromatin. In light of the massive scientific interest in anti-DNA antibodies over decades, it is an unexpected observation that the spectrum of DNA structures has been known for decades without being implemented in clinical immunology. This leads consequently to a critical analysis of historical and contemporary evidence-based data and of ignored and one-dimensional contexts and hypotheses: i.e. “one antibody - one disease”. In this study radical viewpoints on the impact of DNA and chromatin immunity/autoimmunity are considered and discussed in context of the pathogenesis of lupus nephritis.

Highlights

This theoretical study critically analyses immunology of DNA and chromatin
Dong et al induced antibodies to p53 by immunizing non-autoimmune mice with purified p53-T antigen complex [146]. These results demonstrate that infections, commonly encountered in Systemic lupus erythematosus (SLE) [32] and in cancers [77, 78] may be involved in systemic autoimmunity, and explain why anti-dsDNA antibodies principally cannot serve as a unique biomarker for SLE
Any structure-specific anti-dsDNA antibody, detected in any assay using any DNA molecule is valid as a criterium for SLE

Summary

INTRODUCTION

This theoretical study critically analyses immunology of DNA and chromatin. The discussion is basically immunological and unlinked from SLE, but elements of the syndrome is discussed, as chromatin autoimmunity is relevant to understand SLE in both historical and contemporary contexts. In order to probe hypotheses linked to experimental and empirical studies aimed to describe origin of anti-dsDNA antibodies, we need to settle a semantic distinction: AntidsDNA antibodies may be the result of immune responses to DNA-protein complexes in context of 2 principally different mechanisms for termination of tolerance: Autoimmunity versus immunity (see Figure 3A–D, for principle models). Changes in the B DNA structure reflect dynamic conversion of the basic structure into variants like ssDNA, Z DNA, cruciform DNA, bent DNA and others (see Figures 1 and 4) Such activation-related structures have their own, unique ability to induce highly specific immune responses, with relevance to the impact of anti-dsDNA in SLE and lupus nephritis. These observations implicate that IgG anti-dsDNA antibodies exert a stronger pathogenic impact than IgM antibodies with corresponding DNA specificity

CONCLUDING REMARKS

ETHICS STATEMENT

Results