Antiribonuclease H2 antibodies are an immune biomarker for systemic lupus erythematosus

Abstract

We previously reported that autoantibodies against the proliferating cell nuclear antigen protein (PCNA)-binding protein chromatin assembly factor-1 (CAF-1) are specifically found in patients with systemic lupus erythematosus (SLE). PCNA and its complex constituents elicit autoimmune responses in patients with SLE, suggesting that autoantibody diversification likely occurs owing to epitope spreading. Therefore, we sought to clarify whether patients with SLE exhibit an autoimmune response to Ribonuclease H2 (RNase H2), another PCNA-binding protein that regulates cell division. As results, RNase H2 autoantibodies were detected in the sera of 33.9% (19/56) of SLE patients, which was significantly higher than that observed in sera from other patients with systemic autoimmune diseases (polymyositis/dermatomyositis, systemic sclerosis, Sjogren's syndrome, mixed connective tissue disease and rheumatoid arthritis) and healthy controls. Regression analysis also showed that serum anti-RNase H2 levels were strongly correlated to that of CAF-1 in SLE patients. Our data support the use of RNase H2 autoantibodies as a serum biomarker for SLE diagnosis. Moreover, the strong correlation observed between RNase H2 and CAF-1 suggests that intermolecular epitope spreading may play a critical role in autoantibody production and diversification in SLE.

Pathophysiological Role of Nucleic Acid-Sensing Pattern Recognition Receptors in Inflammatory Diseases

“…For example, mice deficient in the 3′ repair exonuclease encoded by Trex1 show severe systemic lupus erythematosus (SLE)-like symptoms. Mutations in subunits of the RNaseH2 exonuclease complex ( RNASEH2a, RNASEH2b, RNASEH2c ) result in the accumulation of immune-stimulatory DNA damage, leading to the chronic production of IFNs in some patients with SLE and AGS ( Günther et al., 2015 ; Nozawa et al., 2017 ). SAMHD1 is a deoxynucleotide triphosphate (dNTP) triphosphohydrolase that has been found to be a negative regulator of the dNTP pool.…”

Nucleic Acid Sensors as Therapeutic Targets for Human Disease

“…For example, inactivating mutations in DNASE1L3, which is responsible for degrading plasma DNA, are associated with a monogenic form of SLE (Tsukumo and Yasutomo, 2004;Al-Mayouf et al, 2011), while IFN-mediated autoinflammation has been linked to DNase II deficiency in humans (Rodero et al, 2017). The RNaseH2 exonuclease pathways has also been implicated in SLE pathogenesis, with anti-ribonuclease H2 antibodies identified in SLE patients (Pendergraft and Means, 2015;Nozawa et al, 2017).…”