Interferon signature gene expression is correlated with autoantibody profiles in patients with incomplete lupus syndromes

Abstract

SummaryInterferon (IFN) signature genes have been shown to be expressed highly in peripheral blood of patients with systemic lupus erythematosus (SLE), especially in the presence of active disease. However, the expression of this gene signature in individuals with incomplete forms of lupus and the pathogenic relationship between IFN signature genes and autoantibody production have not been explored fully. In the present study, we examined the gene expression and autoantibody profiles of patients diagnosed with incomplete lupus erythematosus (ILE) to determine correlations of the gene expression signature with autoantibody production. Gene expression analysis was carried out on the 24K Illumina Human Refseq-8 arrays using blood samples from 84 subjects, including patients with SLE (n = 27) or ILE (n = 24), first-degree relatives (FDR) of these patients (n = 22) and non-autoimmune control (NC) individuals (n = 11). Autoantibody expression was measured using standard immunoassays and autoantigen proteomic arrays. Up-regulation of a set of 63 IFN signature genes was seen in 83% of SLE patients and 50% of ILE patients. High levels of IFN gene expression in ILE and SLE showed significant correlations with the expression of a subset of IgG autoantibodies, including chromatin, dsDNA, dsRNA, U1snRNP, Ro/SSA, La/SSB, topoisomerase I and Scl 70, while low IFN levels were correlated with immunoglobulin (Ig)M autoreactivity. These studies suggest that in patients with ILE the IFN gene expression signature may identify a subset of these individuals who are at risk for disease progression. Furthermore, high levels of alpha IFN may promote autoantibody class-switch from IgM to the more pathogenic IgG class.

Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification

“…Indeed, in our investigation, the number of positive autoantibodies was the most significant (p<0.001) predictor of increased IFN-α activity in cases. A recent study demonstrated IFN-α activity associated with autoantibody positivity, a small study (n=24) showed exacerbated type I IFN signatures in incomplete lupus erythematosus patients whose autoantibody specificities had already class-switched to the pathogenic IgG isotype23 and a number of studies have noted the ability of autoantibody-containing immune complexes to drive type I IFN activation 24–27. While IFN-α activity is clearly important in the transition to classified SLE, it may not be a leading factor for the initial development of lupus-associated autoantibody specificities.…”

Systemic lupus erythematosus: An update for ophthalmologists

“…In general the presence of evolving autoantibody specificities, including antibodies to dsDNA, which have been observed to accrue prior to the onset of lupus, suggest the development of overt disease is likely 5,49,141 . A prominent interferon-induced gene signature and altered Th17/Treg ratios have been proposed as immunological markers of progression from incomplete lupus to systemic lupus erythematosus, but our understanding is limited 71,131 . Although not definitive, there is suggestive evidence that hydroxychloroquine can delay or prevent the development of fullblown lupus in patients presenting with an incomplete picture 62 .…”

Preclinical Systemic Lupus Erythematosus

“…Additional longitudinal evaluation of ILE patients, both in the interferon-high and interferon-low groups, are necessary to see if ILE patients with elevated interferon signatures are at higher risk of transition to SLE. (38) …”