Towards a better understanding of the clinical association of anti-DFS70 autoantibodies

doi:10.1016/j.autrev.2015.11.006

Autoimmunity Reviews

Volume 15, Issue 2, February 2016, Pages 198-201

https://doi.org/10.1016/j.autrev.2015.11.006 Get rights and content

Abstract

Anti-DFS70 antibodies and their clinical associations remain an immunological paradox. Unlike other antinuclear antibodies (ANA), especially when present at high titres, anti-DFS70 antibodies are not prevalent in ANA associated rheumatic diseases. Despite significant interest and progress in understanding the clinical association of anti-DFS70 antibodies, no specific clinical associations have been confirmed. In reality, several studies reporting clinical association of these antibodies (i.e. atopic dermatitis, thrombosis, autoimmune thyroiditis) have added confusion instead of bringing significant insight. In addition, several groups have consistently reported on the occurrence of anti-DFS70 antibodies in a relevant fraction of apparently healthy individuals. This review aims to analyse the current knowledge and to provide future guidance to analyse potential clinical associations of anti-DFS70 antibodies by summarizing and interpreting recent findings.

Section snippets

Take-home messages

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potential clinical associations of anti-DFS70 antibodies remains speculative and future, well defined, studies are required to provide more insights.
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HEp-2 cells can be used to screen for anti-DFS70 antibodies, but their presence should be confirmed using a specific test for anti-DFS70 antibodies (i.e. ELISA, CIA or by immunoadsorption).

Competing interests

M. Mahler is employed at Inova Diagnostics selling autoantibody assays. The other authors received consultant fees from Inova Diagnostics in the past.

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The antinuclear antibody dense fine speckled pattern and possible clinical associations: An indication of a proinflammatory microenvironment
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Citation Excerpt :
There is significant clinical utility in the use of anti-DFS70/LEDGF as a marker of exclusion, but limited information remains regarding the role the autoantibodies play in the pathogenesis of patients' symptoms and whether the autoantibodies are indeed associated with a particular disease or diseases. No specific clinical associations have been confirmed (Mahler et al., 2016), which has translated to confusion, misunderstanding, and diagnostic dilemmas. The purpose of this study was to determine the prevalence of SARD among a group of ANA-DFS positive individuals and to identify the final diagnoses among the non-SARD individuals in order to determine possible clinical associations.
Indirect immunofluorescence (IIF) is the most prevalent screening antinuclear antibody test for systemic autoimmune rheumatic disease (SARD). Certain IIF patterns have known antibody and disease associations, but the dense fine speckled (ANA-DFS) pattern has no confirmed clinical associations. Our objective was to determine the prevalence of SARD among a group of ANA-DFS positive individuals and to identify final diagnoses among non-SARD individuals in order to determine possible clinical associations with the ANA-DFS pattern.
A retrospective study of 425 patients from a university health care system with a positive ANA-DFS pattern consecutively between August 2017 and September 2018. Sera samples underwent ANA testing by IIF on HEp-2 cell substrates (Euroimmun, Germany). Clinical information was retrieved from electronic health records and stored in a de-identified database.
The prevalence of SARD was 24%. Undetermined diagnosis (17%), skin disorders (12.1%), and fibromyalgia/chronic pain syndrome/chronic fatigue syndrome (11.8%) were the most common non-SARD diagnoses. Taking into account past medical history, the most common non-SARD were atopic disorders (21.2%), fibromyalgia/chronic pain syndrome/chronic fatigue syndrome (17.6%), and skin disorders (16.7%).
The ANA-DFS pattern may be indicative of an underlying antigen-antibody interaction that plays a role in either the initiation or propagation of immunologic reactions. DFS70/LEDGF is a transcription factor involved in cell survival and stress protection, and autoantibodies may inhibit its function. It is likely that there are other antibodies producing the ANA-DFS pattern besides anti-DFS70/LEDGF, and more research is necessary to identify additional antibody specificities. The ANA-DFS pattern may be an indicator of a proinflammatory microenvironment given the high frequency of symptomatic patients and disease processes with an immunologic basis (including SARD).
Dense fine speckled (DFS) immunofluorescence pattern and anti-DFS70 antibodies: Cleaning up the current concepts
2020, Clinica Chimica Acta
Clinical value of anti-DFS70 antibodies in a cohort of patients undergoing routine antinuclear antibodies testing
2020, Journal of Immunological Methods
Citation Excerpt :
An additional complicating issue is the coexistence of SARD-associated ANA specificities, which can mask and hide the DFS pattern (Bizzaro et al., 2016). As with any other HEp-2 IFA pattern, the anti-DFS70 reactivity in samples yielding the AC-2 pattern needs to be confirmed in follow-up specific immunoassays (Mahler et al., 2016; Bentow et al., 2016). Recognition of DFS pattern by IIF was initially identified as an atypical ANA pattern in a patient with interstitial cystitis but have since been linked to a much wider array of conditions (Ochs et al., 1994).
It is has been proposed that the presence of anti-DFS70 antibodies could be used to eliminate a SARD diagnosis. However, anti-DFS70 antibodies were also observed at relatively high frequency in patients with SARD. The clinical significance of these antibodies is therefore not yet clear. In this study, we assessed the clinical significance of the presence of anti-DFS70 antibodies.
A total of 3432 sera samples were obtained from patients who underwent routinely requested ANA screening in the clinical laboratory of a University Hospital, between June 2017 and June 2019. Antinuclear antibody testing was performed by indirect immunofluorescence (IIF) on Hep-2 cell substrates (Euroimmun, Germany), and anti-ENA were measured by LIA (Euroimmun, Germany).
Among 3432 serum samples tested for ANA, 57.3% were ANA positive by IIF. Participants had mean age of 46.4 and 74.8% of the participants were female. Only 11.4% of the study population had SARD. The frequency of DFS pattern by IIF was 8.1%. Analysis of the DFS pattern positive samples by LIA revealed the presence of anti-DFS70 autoantibodies in 67.5% of all DFS, AC-2 pattern ANAs. When using the results of the ANA IIF HEp-2 DFS pattern/Anti-DFS70 LIA, likelihood ratio (LR) for SARD was 0.33. When comparing the ANA IIF HEp-2 DFS pattern with anti-DFS70 LIA, the ANA IIF HEp-2 DFS pattern's LR was lower (0.63 vs 0.85).
Although the DFS pattern cannot exclude the presence of SARD, the likelihood is lower than with other patterns. Therefore, anti-DFS70 antibodies represent an important biomarker that can aid in the interpretation of positive ANA patients and, therefore, should be included in test algorithms for ANA testing. The optimal test algorithm might be laboratory specific being dependent on referral patterns for ANA testing.
Antihistone and antispliceosome antibodies
2020, Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects
Autoantibodies are classically important in making an accurate diagnosis and classification of systemic lupus erythematosus (SLE). Antibodies directed against histone (components of the nucleosome) and anti-small nuclear ribonucleoproteins (snRNP; components of the spliceosome) were among the first antinuclear protein responses identified in SLE. Because antihistone antibodies have been described in many diseases, they are generally regarded as a nonspecific biomarker. However, autoantibody reactivity to higher ordered structures that are dependent on histones, such as chromatin or nucleosomes and the snRNPs in the spliceosome (a macromolecular complex important for the mRNA splicing events) have been consistently reported to be highly sensitive and specific biomarkers for SLE and some patients with drug-induced lupus. Anti-snRNPs are primarily directed to Sm and U1RNP and they have the wide diagnostic and clinical use. Anti-Sm is a highly specific marker for SLE, whereas anti-U1RNP often coexists with anti-Sm in SLE, is detected in a variety of other systemic autoimmune rheumatic diseases, and is a key serological criterion for mixed connective tissue disease. The appearance of anti-nucleosome and anti-snRNP antibodies early in the course of SLE is an indicator that the loss of immune tolerance to chromatin and spliceosome components and is a key event in the pathogenesis of SLE.
Dense fine speckled nuclear immunofluorescence: A mildly reassuring antinuclear antibody pattern meriting consideration
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ReviewTowards a better understanding of the clinical association of anti-DFS70 autoantibodies

Abstract

Section snippets

Take-home messages

Competing interests

J Urol

Clin Chim Acta

Clin Immunol

Autoimmun Rev

Autoimmun Rev

Autoimmun Rev

Autoimmun Rev

Autoimmun Rev

Importance of the dense fine speckled pattern on HEp-2 cells and anti-DFS70 antibodies for the diagnosis of systemic autoimmune diseases

Autoimmun Rev

The clinical significance of the dense fine speckled immunofluorescence pattern on HEp-2 cells for the diagnosis of systemic autoimmune diseases

Clin Dev Immunol 2012

Autoimmunity to the nuclear autoantigen DFS70 (LEDGF): what exactly are the autoantibodies trying to tell us?

Arthritis Rheum

Thrombophilia associated with anti-DFS70 autoantibodies

PLoS One

The significance of autoantibodies to DFS70/LEDGFp75 in health and disease: integrating basic science with clinical understanding

Clin Exp Med

Review
Towards a better understanding of the clinical association of anti-DFS70 autoantibodies