Coordination of retrotransposons and type I interferon with distinct interferon pathways in dermatomyositis, systemic lupus erythematosus and autoimmune blistering disease

Abstract

Type I interferon (IFN) plays a crucial role in innate and adaptive immunity, and aberrant IFN responses are involved in systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and dermatomyositis (DM). Type I IFNs can be induced by transcribed retrotransposons. The regulation of retrotransposons and type I IFN and the downstream IFN pathways in SLE, DM, and autoimmune blistering disease (AIBD) were investigated. The gene expression levels of retrotransposons, including LINE-1, type I-III IFNs, and IFN-stimulated genes (ISGs) in peripheral blood cells from patients with DM (n = 24), SLE (n = 19), AIBD (n = 14) and healthy controls (HCs, n = 10) were assessed by quantitative polymerase chain reaction. Upregulation of retrotransposons and IFNs was detected in DM patient samples, as is characteristic, compared to HCs; however, ISGs were not uniformly upregulated. In contrast, retrotransposons and IFNs, except for type II IFN, such as IFN-γ, were not upregulated in SLE. In AIBD, only some retrotransposons and type I interferons were upregulated. The DM, SLE, and AIBD samples showed coordinated expression of retrotransposons and type I IFNs and distinct spectra of IFN signaling. A positive correlation between LINE-1 and IFN-β1 was also detected in human cell lines. These factors may participate in the development of these autoimmune diseases.

Endogenous retroelement activation is implicated in IFN-α production and anti-CCP autoantibody generation in early RA

“…An association between IFNA transcript and whole blood retrotransposon activity has recently been reported in other autoimmune diseases (45) but our demonstration of an association with IFN-α protein reinforces potential biological relevance in RA. Similar to other autoimmune diseases (45), we did not find a significant association between retrotransposon activity and downstream IFN-I signalling, although we noted a trend towards an inverse association with the IGS. This may be because many IRGs are potent LINE1 negative regulators (46) and thus examining protein levels, where possible, may be optimal.…”

“…We did not see any link between SAMHD1 expression and synovial ERE expression, and other retrotransposon regulatory mechanisms may be more relevant here, such as epigenetic silencing (21, 56), promoter methylation having been shown to affect LINE1 activity in autoimmune diseases (21, 45). Although we did not explore these mechanisms in detail, we did not see any difference between retrotransposon activity and DNMT1, DNMT3A or DNMT3B expression, known epigenetic modifiers of ERE activity (45). This may reflect sample size but may also suggest other mechanisms are dominant, such as SAMHD1 in B cells, or even differential expression in the recently described HUSH complex, a known gatekeeper of ERE induced IFN-I expression (56).…”

Amyopathic dermatomyositis may be on the spectrum of autoinflammatory disease: A clinical review

“…Retrotransposons and IFNs are upregulated in DM patient samples different from SLE, as a characteristic, compared to healthy controls. [ 42 ] Type I IFN responses are significantly enhanced in cells from juvenile DM. [ 43 ] These data also support the similarities between SAIDs and DM.…”

Involvement of retroelements in the autoimmune response in humans

“…High titers of anti-La/SSB and anti-Ro/SSA antibodies were detected in the sera of SLE patients [22]. Additionally, expression of type I IFNs and retrotransposons, such as IFN-β1 and L1, was found to be coordinated in SLE [23].…”