Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Abstract

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment

“…This notwithstanding, a common set of 36 type I IFN inducible transcripts was identified among the most overexpressed in the whole blood of 262 patients with SLE, RA, SSc, and myositis in contrast to 26 healthy controls (Higgs et al, 2011). Along the same line of evidence, when unsupervised clustering of integrated whole blood transcriptome and methylome was performed with data of 263 healthy controls and 918 patients with seven SADs (SLE, RA, SS, SSc, MCTD, antiphospholipid syndrome, and UCTD), among the four identified clusters, the "interferon" cluster was grouping individuals with all seven distinct SADs (Barturen et al, 2020). Thus, an IFN signature is common to all SADs, which associated with the genetic polymorphisms of IFN-related genes shared between SADs, may account for part of the "heritability" of systemic autoimmunity (Niewold et al, 2007;Kariuki et al, 2010).…”

“…However, an IFN signature is found in only 50-80% of SLE patients (Baechler et al, 2003;Bennett et al, 2003;Crow and Wohlgemuth, 2003) and the IFN-induced gene signature assessed in longitudinal studies may not correlate with disease activity (Landolt-Marticorena et al, 2009;Petri et al, 2009). Indeed, in addition to IFN modules, other gene modules have been variably reported to associate with SLE clinical features (Banchereau et al, 2016;Rai et al, 2016;Lu et al, 2019;Barturen et al, 2020;Guthridge et al, 2020). These data indicate that IFN does not account for all pathological and clinical aspects of SLE, which may be further explained by heterogeneity in the IFN-I pathway activation and genetic makeup (Kariuki et al, 2015).…”

“…RA is mainly characterized by erosive symmetrical arthritis, but systemic manifestations may involve the lung, the skin, and other organs. While the IFN-I signature is less conspicuous in RA than other SADs including SLE (Higgs et al, 2011;Barturen et al, 2020), an IFN-I signature precedes overt clinical manifestations and its presence increases the risk of developing the disease (Lübbers et al, 2013). The presence of pDCs and the expression of ISGs, IFN-alpha, and IFN-beta have been documented in the synovium of patients with RA (Lande et al, 2004;van Holten et al, 2005).…”

“…Thereafter, increased levels of IFN biological activity were documented in the serum of individuals suffering from various systemic autoimmune diseases (SADs) including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), and Sjogren's syndrome (SS) (Skurkovich et al, 1977;Hooks et al, 1979;Ytterberg and Schnitzer, 1982). In the following 40 years, it has been solidly established that systemic autoimmunity beyond SLE, RA, SSc, and SS to include myositis, mixed connective tissue disease (MCTD), and undifferentiated connective tissue disease (UCTD) is associated with conspicuous IFN biological activities (Higgs et al, 2011;Ekholm et al, 2016;Barturen et al, 2020). Further interest in IFN and SADs has spurred form the recent identification of monogenic disorders named interferonopathies characterized by high IFN production and clinical manifestations partly resembling those of SADs (Crow and Manel, 2015).…”

“…While IFNs are associated with SADs, the presence of high levels of IFNs is detectable in some but not all individuals suffering of SADs with frequencies of individuals with high IFN varying across the various SADs (Barturen et al, 2020). In the perspective of precision medicine, the identification of FIGURE 1 | Schematic model of the cascade of events characterizing the IFN response in SADs.…”