High Prevalence and Disease Correlation of Autoantibodies Against p40 Encoded by Long Interspersed Nuclear Elements in Systemic Lupus Erythematosus

Abstract

Objective Long interspersed nuclear element 1 (LINE‐1) encodes 2 proteins, the RNA binding protein p40 and endonuclease and reverse transcriptase (open‐reading frame 2p [ORF2p]), which are both required for LINE‐1 to retrotranspose. In cells expressing LINE‐1, these proteins assemble with LINE‐1 RNA and additional RNA binding proteins, some of which are well‐known autoantigens in patients with systemic lupus erythematosus (SLE). This study was undertaken to investigate whether SLE patients also produce autoantibodies against LINE‐1 p40. Methods Highly purified p40 protein was used to quantitate IgG autoantibodies in serum from 172 SLE patients and from disease controls and age‐matched healthy subjects by immunoblotting and enzyme‐linked immunosorbent assay (ELISA). Preparations of p40 that also contained associated proteins were analyzed by immunoblotting with patient sera. Results Antibodies reactive with p40 were detected in the majority of patients and many healthy controls. Their levels were higher in patients with SLE, but not those with systemic sclerosis, compared to healthy subjects (P = 0.01). Anti‐p40 reactivity was higher in patients during a flare than in patients with disease in remission (P = 0.03); correlated with the SLE Disease Activity Index score (P = 0.0002), type I interferon score (P = 0.006), decrease in complement C3 level (P = 0.0001), the presence of anti‐DNA antibodies (P < 0.0001) and anti‐C1q antibodies (P = 0.004), and current or past history of nephritis (P = 0.02 and P = 0.003, respectively); and correlated inversely with age (r = −0.49, P < 0.0001). SLE patient sera also reacted with p40‐associated proteins. Conclusion Autoantibodies reacting with LINE‐1 p40 characterize a population of SLE patients with severe and active disease. These autoantibodies may represent an early immune response against LINE‐1 p40 that does not yet by itself imply clinically significant autoimmunity, but may represent an early, and still reversible, step toward SLE pathogenesis.

Reactivity of IgG With the p40 Protein Encoded by the Long Interspersed Nuclear Element 1 Retroelement: Comment on the Article by Carter et al

“…In systemic lupus erythematosus (SLE), anti-double-stranded DNA (anti-dsDNA) autoantibodies are features of active disease and are particularly associated with lupus nephritis, and the identity of the self or foreign antigens that "break tolerance" (leading to anti-dsDNA and other autoantibody specificities) has been a topic of extensive study. In that context, the study described by Carter et al (1), in which they identified reactivity of sera from SLE patients using the 40-kd protein product of the first open-reading frame (ORF) of the human long interspersed nuclear element 1 (LINE-1) retroelement, is of great interest.…”

“…In addition, LINE‐1 nucleic acid can induce type I interferon (IFN), a key pathogenic mediator in SLE . In that regard, the data from Carter and colleagues’ study support the notion of a relationship between high levels of IgG anti‐p40 and a high type I IFN score . The RNP particles that contain LINE‐1 p40, associated LINE‐1 RNA, and DNA, as well as a multitude of proteins that have been implicated as autoantigens in systemic autoimmune diseases , should be priority targets for detailed study of the mechanisms through which the viral remnants in our genomes might act as initiators of autoimmunity.…”

Implications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus

“…Essentially all patients with SLE have IgG autoantibodies against ORF1p [ 107 , 108 ], which correlate with disease activity measured by the SLE disease activity index (SLEDAI), the presence of lupus nephritis, complement consumption, increased anti-dsDNA, and higher type I IFN activity [ 107 ]. Importantly, there anti-ORF1p autoantibodies do not represent anti-DNA reactivity, as free dsDNA did not compete (while free ORF1p did), DNase treatment did not affect them (while it eliminated anti-dsDNA reactivity), and ORF1p was recognized even when mixed with whole cell lysates.…”

“…As we recently demonstrated, the titers of IgG autoantibodies against L1 ORF1p correlate significantly with disease phenotypes, SLEDAI, markers of disease activity, and IFN score [ 107 ]. These autoantibodies could conceivably aid in the diagnosis and prognosis of the disease, perhaps guiding which endotype of SLE an individual patient has and, hence, which treatment regimen might be most effective.…”

A potential new mechanism for pregnancy loss: considering the role of LINE-1 retrotransposons in early spontaneous miscarriage

“…Various assays have been established to detect RT activity in cells, whether deriving from L1 ORF2p or HERV pol genes [175][176][177]. Using RT-qPCR to assay changes in expression of interferon-stimulated genes may also reveal autoinflammatory effects of retrotransposon misregulation, as described above for AGS and some other autoimmune conditions [137,[178][179][180].…”