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

Abstract

Antinuclear autoantibodies (ANAs) displaying the nuclear dense fine speckled immunofluorescence (DFS-IIF) pattern in HEp-2 substrates are commonly observed in clinical laboratory referrals. They target the dense fine speckled autoantigen of 70 kD (DFS70), most commonly known as lens epithelium-derived growth factor p75 (LEDGFp75). Interesting features of these ANAs include their low frequency in patients with systemic autoimmune rheumatic diseases (SARD), elevated prevalence in apparently healthy individuals, IgG isotype, strong trend to occur as the only ANA specificity in serum, and occurrence in moderate to high titers. These autoantibodies have also been detected at varied frequencies in patients with diverse non-SARD inflammatory and malignant conditions such as atopic diseases, asthma, eye diseases, and prostate cancer. These observations have recently stimulated vigorous research on their clinical and biological significance. Some studies have suggested that they are natural, protective antibodies that could serve as biomarkers to exclude a SARD diagnosis. Other studies suggest that they might be pathogenic in certain contexts. The emerging role of DFS70/LEDGFp75 as a stress protein relevant to human acquired immunodeficiency syndrome, cancer, and inflammation also points to the possibility that these autoantibodies could be sensors of cellular stress and inflammation associated with environmental factors. In this comprehensive review, we integrate our current knowledge of the biology of DFS70/LEDGFp75 with the clinical understanding of its autoantibodies in the contexts of health and disease.

Recent Approaches To Optimize Laboratory Assessment of Antinuclear Antibodies

“…In this regard, ANA positivity could suggest a predisposition for autoimmunity, with ANA expression preceding overt clinical disease, as described for a number of autoimmune conditions (40). On the other hand, false-positive results for apparently healthy individuals or non-SARD patients may be related to specific binding and/or cross-reactivity with undefined or defined targets such as antibodies to DFS70 (41). The DFS70 pattern is associated with autoantibodies binding to a ubiquitously expressed protein called lens epitheliumderived growth factor (LEDGF) (or p75 or psip1 gene product), which was first described by Ochs and colleagues in 1994 (42) and was subsequently reported for patients with atopic dermatitis and asthma (43).…”

Detection of autoantibodies to DSF70/LEDGFp75 in Mexican Hispanics using multiple complementary assay platforms

“…DFS70/LEDGFp75 is a stress response transcription coactivator that protects mammalian cells against diverse environmental stressors [8]. This autoantigen is also essential for the integration of human immunodeficiency virus 1 (HIV-1) [10].…”

“…In addition, it has been recognized as an oncoprotein whose overexpression in cancer cells promotes tumor aggressive properties such as increased clonogenicity, migration, invasion, chemotherapy resistance, stress survival, angiogenesis and tumor growth (reviewed in Refs. [8, 9]).…”

Report on the second International Consensus on ANA Pattern (ICAP) workshop in Dresden 2015

“…The nuclear dense fine speckled pattern (AC-2) is considered particularly important given its strong association with anti-DFS70/LEDGF antibodies and the fact that many investigators either have not heard of it or do not know the relevance of its negative correlation to systemic autoimmune rheumatic diseases. 8,9 There was some concern over the apparent lack of clinical relevance of Golgi-like pattern (AC-22) [10][11][12] or the rods and rings pattern (AC-23), [13][14][15][16] and yet they represent distinctive and consistent patterns that belong to the competentlevel group. It has been proposed that the competent level and expert level are equivalent to the more simple description of ''basic'' and ''advanced'' levels and should not depend strictly on the clinical relevance of the pattern.…”