Elsevier

Autoimmunity Reviews

Volume 7, Issue 8, September 2008, Pages 594-597
Autoimmunity Reviews

Predictive value of anti-dsDNA autoantibodies: Importance of the assay

https://doi.org/10.1016/j.autrev.2008.06.003Get rights and content

Abstract

The predictive potential of anti-dsDNA autoantibodies (AAb) lays on their biological activity and their ability to cause the pathological changes typically found in patients with SLE. In this review, we discuss old and recent evidence that supports the idea of AAb against dsDNA may cause directly tissue damage. Tissue deposition, Ab isotype, affinity maturation, and its ability to activate complement and engage Fc receptors are the classical determinants of the pathogenicity of anti-dsDNA AAb. Furthermore, there is strong evidence that suggest that anti-dsDNA AAb of the IgG isotype are able to shuttle nuclei acid fragments through the plasma membrane causing activation and secretion of inflammatory cytokines. Nucleic acid-containing immune complexes may thus serve as a virus-mimeticum.

Introduction

Anti-double stranded DNA (dsDNA) AAb production is one of the main features of human and mouse Systemic Lupus Erythematosus (SLE). A wide variety of antibodies directed against various autologous cytoplasmic and nuclear antigens occur together with anti-dsDNA reactivity in this inflammatory autoimmune disease [1]. Furthermore, anti-dsDNA antibodies are detectable in up to 95% of untreated patients with active disease and their titres are reduced after therapy [2]. The positive correlation of serum AAb levels with disease activity and the finding of DNA–anti-DNA immune complexes in the sites of tissue damage suggest a role of anti-dsDNA AAb in the pathogenesis of SLE [3].

The determination of anti-dsDNA antibodies in serum from patients with SLE has become an important tool in the diagnostic algorithm and in the follow up of the disease. Their potential to predict disease relapses and efficacy of therapeutics has been broadly assessed under different clinical and experimental settings [4], [5]. However, the real importance of their clinical value should be evaluated considering their biological properties and pathological effects on the living organism.

Since in 1957 anti-dsDNA antibodies were identified, many different assays have been developed to measure their appearance in circulation of patients with autoimmune diseases and they have demonstrated its usefulness in the diagnosis and monitoring of the disease. Notably, the Farr assay is one of the most reproducible anti-dsDNA antibodies detection approach. However, it uses radioactivity and may miss low-avidity antibodies. The reactivity of sera against the haemoflagellate Chritidia lucillae is very simple and sensitive, but poorly quantifiable detection system. Nowadays, immobilised dsDNA in a plate with poly-l-lysine serves as a very easy, safe, and rapid quantitative assay (ELISA) to be applied in the clinical practice [6].

The predictive potential of anti-dsDNA AAb lays on their biological activity and their ability to cause the pathological changes typically found in patients with SLE. In this review, here we discuss old and recent evidence that supports the idea of Ab against dsDNA may cause directly tissue damage.

Section snippets

Classical determinants of the pathogenicity of anti-dsDNA AAb

Anti-dsDNA antibodies from patients with SLE are typically of IgG isotype and demonstrate high affinity for dsDNA. Several IgG human monoclonal AAb showed extensive somatic mutations, which are suggestive for an antigen-driven selection in germinal centers [7], [8]. One of these AAb, lost its affinity for dsDNA when the somatic mutations were reverted. This antibody also bound to the surface of apoptotic cells and to nucleosomes; both features also required the same somatic mutations that

Novel mechanisms of pathogenicity of anti-dsDNA AAb

Complement deficiencies are also considered important for the development of SLE, especially of the early components of the system [24]. This has revealed the importance of complement proteins as “opsonisators” of dead and dying cells for their appropriate clearance from tissues [25]. Nevertheless, there is no available data about the clearance status of C1q deficient patients. The C1q knockout mouse develops glomerulonephritis and shows impaired clearance of apoptotic cells [26]. Activation of

Take home messages

  • Antigen affinity, complement activation and Fc-receptor engagement, in a clearance deficiency scenario make anti-dsDNA AAb extremely dangerous for multiple organs.

  • The AAb-mediated inflammatory phagocytosis of apoptotic remnants may account for chronification and development of clinical overt disease.

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