Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions

Abstract

The discovery and initial characterization 20 years ago of antinuclear autoantibodies (ANAs) presenting a dense fine speckled (DFS) nuclear pattern with strong staining of mitotic chromosomes, detected by indirect immunofluorescence assay in HEp-2 cells (HEp-2 IIFA test), has transformed our view on ANAs. Traditionally, ANAs have been considered as reporters of abnormal immunological events associated with the onset and progression of systemic autoimmune rheumatic diseases (SARD), also called ANA-associated rheumatic diseases (AARD), as well as clinical biomarkers for the differential diagnosis of these diseases. However, based on our current knowledge, it is not apparent that autoantibodies presenting the DFS IIF pattern fall into these categories. These antibodies invariably target a chromatin-associated protein designated as dense fine speckled protein of 70 kD (DFS70), also known as lens epitheliumderived growth factor protein of 75 kD (LEDGF/p75) and PC4 and SFRS1 Interacting protein 1 (PSIP1). This multi-functional protein, hereafter referred to as DFS70/LEDGF, plays important roles in the formation of transcription complexes in active chromatin, transcriptional activation of specific genes, regulation of mRNA splicing, DNA repair, and cellular survival against stress. Due to its multiple functions, it has emerged as a key protein contributing to several human pathologies, including acquired immunodeficiency syndrome (AIDS), leukemia, cancer, ocular diseases, and Rett syndrome. Unlike other ANAs, "monospecific" anti-DFS70/LEDGF autoantibodies (only detectable ANA in serum) are not associated with SARD and have been detected in healthy individuals and some patients with non-SARD inflammatory conditions. These observations have led to the hypotheses that these antibodies could be considered as negative biomarkers of SARD and might even play a protective or beneficial role. In spite of 20 years of research on this autoantibody-autoantigen system, its biological and clinical significance still remains enigmatic. Here we review the current state of knowledge of this system, focusing on the lessons learned and posing emerging questions that await further scrutiny as we continue our quest to unravel its significance and potential clinical and therapeutic utility.

Anti-DFS70 Antibodies Among Patient and Healthy Population Cohorts in China: Results From a Multicenter Training Program Showing Spontaneous Abortion and Pediatric Systemic Autoimmune Rheumatic Diseases Are Common in Anti-DFS70 Positive Patients

“…In our study, the percentage of monospecific anti-DFS70 patients was much higher in non-SARD (76.8%) than in SARD (15.2%) patients in HEp-2 IFA screening cohort. This to some extent supports that monospecific anti-DFS70 is a reliable biomarker to rule out diagnosis of SARD (35). Moreover, anti-Ro52/TRIM21 and anti-SSA/Ro60 were the most commonly detected autoantibodies accompanying anti-DFS70 antibodies in our LIA ENA profiles, while SLE-specific antibodies including Sm and dsDNA were not observed.…”

Hepatoma-Derived Growth Factor: An Overview and Its Role as a Potential Therapeutic Target Molecule for Digestive Malignancies

“…Subsequently, four new proteins have been also reported as HDGF-related proteins (HRPs), which include well-conserved N-terminal amino acid sequences (homologous to the amino terminus of HDGF; HATH region) [ 6 , 7 , 8 ]. In addition, Lens epithelium-derived growth factor (LEDGF) [ 9 ], a survival factor for the lens epithelium, also includes a HATH region. HDGF and its related proteins include two putative nuclear localization signals (NLSs) ( Figure 1 ).…”

“…( B ) The homology of the HATH regions in the HDGF and its family proteins. High homology was observed [ 6 , 7 , 8 , 9 ]. The red square indicates the basic amino acid-rich regions (KPNKRK or KPNKRR; basic residues underlined) as the presumed first nuclear localization signal (NLS1) in the HATH regions.…”

Anti-DFS70 Antibodies for Differentiating Systemic Autoimmune Rheumatic Disease in Patients with Positive ANA Tests: A Systematic Review and Meta-Analysis

“…The anti-DFS70 antibody targets DFS70 protein and appears as a DFS pattern in an ANA test [6]. The DFS70 protein upregulates the expression of anti-oxidant, stress response and cancer-associated genes in various cell types, and is regarded as a stress activated transcription co-activator [37]. However, the physiological function and importance of DFS70 protein in non-disease conditions remain largely unknown [37].…”

“…The DFS70 protein upregulates the expression of anti-oxidant, stress response and cancer-associated genes in various cell types, and is regarded as a stress activated transcription co-activator [37]. However, the physiological function and importance of DFS70 protein in non-disease conditions remain largely unknown [37]. Despite being found in some inflammatory diseases, such as atopic diseases and eye diseases initially [3], the anti-DFS70 antibody also occurs commonly in sera from patients with non-SARD conditions, and even in healthy subjects (up to 21.6%) [3,4,6].…”