Background/Purpose: By using integrative transcriptomic and protein analyses, this study aimed at identifying and characterize distinctive molecular signatures between childhood-onset (cSLE) and adult-onset Lupus (aSLE) patients, along with their involvement in immunological and clinical features, and to analyze the relevance of the sustained positivity for anti-dsDNA antibodies.

Methods: Ninety-four subjects were enrolled, comprising two main combined study groups: 1) eleven consecutive children with pediatric-onset SLE (cSLE) and 11 age and sex matched healthy children (cHD); 2) sixty aSLE patients and 20 healthy adults (aHD). Total RNA was extracted from purified monocytes and pools from 5 subjects of each study group were obtained. Then, a nanostring autoimmune profiling array was used for mRNA expression data generation.

Results: Gene expression array identified 279 altered genes in monocytes from cSLE vs cHD. Comparatively, less than a half of genes (130) were found altered in monocytes from aSLE vs aHD. The analysis of common altered genes between the two study groups revealed 19 genes as upregulated in both patients’ cohorts. Interestingly, Gene Ontology enrichment analysis identified as main biological processes integrated by these genes the interferon signature (IFNs). Moreover, cSLE displayed at least a double fold change in the levels of these genes vs cHD than aSLE vs aHD.

Correlation and association studies demonstrated that in the cSLE cohort the altered expression of a number of genes integrating the IFNs was linked to several clinical features. Specifically, increased levels of IFI27 were associated to the occurrence of lupus nephropathy (LN) and positivity for anti-dsDNA, and correlated positively with the activity of the disease (SLEDAI), CV-risk factors (atherogenic index and ApoB/ApoA ratio) and plasma levels of proteins of the IFN family such as IP-10.

Accordingly, in aSLE, altered expression of IFNs was associated to the presence of LN and low levels of complement factors C3 and C4, as well as to increased plasma levels of IFNγ. Interestingly, most of them were further associated with the positivity for anti-dsDNA. A deeper study in this cohort demonstrated that a third of the aSLE patients’ displayed a sustained positivity for anti-dsDNA for more than 7 years. Moreover, these patients showed altered expression of several IFN genes, and presented LN along with a pathologic increase in the Carotid Intimae Media Thickness, and impaired microvascular endothelial function, thus supporting the potential role of the IFNs in the severity of the disease and the development of cardiovascular disease.

Conclusion: 1. Gene expression profile allowed the identification of distinctive molecular pathways among monocytes of cSLE and aSLE 2. An interferon signature, more strongly  deranged in cSLE than in aSLE patients, is closely related to the activity of the disease and the renal involvement. 3. The sustained positivity for anti-dsDNA in aSLE, further linked to that deranged IFNs and to the development of lupus nephritis, might fosters the establishment of an atherothrombotic status in these autoimmune patients.

Supported by ISCIII (PI18/0837 and RIER RD16/0012/0015), Co-funded with FEDER.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinctive-molecular-signatures-among-monocytes-from-childhood-and-adult-onset-systemic-lupus-erythematosus-clinical-involvement-and-relevance-of-sustained-anti-dsdna-positivity/