Background/Purpose:

Gene expression profiling experiments using peripheral blood mononuclear cells (PBMCs) revealed a crucial role of type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE). However, it is almost unknown how particular leukocyte subsets contribute to the overall type I IFN signature described for PBMCs. Furthermore, a detailed analysis of how IFN signatures differ in autoimmune disease from that observed after viral infection is missing so far. Therefore, we compared expression levels of 2442 IFN signature genes in peripheral CD4+ T helper cells, CD16-negative inflammatory and CD16-positive resident monocytes (Mo) isolated from patients with SLE, healthy donors (ND) and ND vaccinated against yellow fever by global gene expression profiling.

Methods:

Peripheral blood from 6 patients with SLE and 4 ND for CD4+ T cells, 4 patients with SLE and 4 ND for CD16-negative Mo, and 4 patients with SLE and 3 ND for CD16-positive Mo were recruited. Same ND were examined before and after immunization by yellow fever vaccine. After sorting cells, isolated RNA were applied to Affymetrix Human Genome U133 Plus 2.0 Array. Data analysis was done using BioRetis database, Genesis Software and Ingenuity Pathway Analysis (IPA). A reference list of 2442 IFN-related genes was obtained from recent publications and used to estimate IFN imprints.

Results:

When compared total significantly differentially expressed probe sets, 9 / 3 / 2 (CD4+ T cells/CD16-negative Mo/CD16-positive Mo, respectively) times more number of probes were detected in patients with SLE compared to immunized ND. The contribution of IFN signature to total gene signature was 20.7 / 23.3 / 23.3 % in patients with SLE, whereas 48.6 / 35.2 / 30.5 % in immunized ND. 98 / 165 / 173 probe sets (fold change>=2, <=-2) were detected as a “common” IFN signature observed both in autoimmunity and in immunized ND. 111 / 164 / 120 probe sets were detected as an “autoimmune-specific” IFN signature, whereas only 0 / 8 / 5 probe sets were detected to be specific for the “virus-induced” IFN signature. Expression pattern of these IFN signature genes clearly distinguished patients with SLE from immunized ND by hierarchical cluster analysis. Although major IFN signature genes were commonly expressed in CD4+ T cells and Mo of patients with SLE and immunized ND, expression magnitudes of them were higher in patients with SLE compared to immunized ND. In SLE, in addition to the typical “viral-induced” IFN signature, genes that are involved in apoptosis signaling, antiviral PKR signaling, Fcγ receptor-mediated phagocytosis and IL-10-/ IL-9-/ IL-15-mediated JAK/Stat signaling pathways were identified by IPA.

Conclusion:

This study demonstrated that IFN signature in autoimmunity and that in viral infection are quite different in the number of IFN-related genes activated and their expression magnitudes. Autoimmunity is characterized by a much stronger expression of IFN signature genes and is obviously modulated by a separate set of co-regulated genes defining the “autoimmune-specific” IFN signature. “Common” and “autoimmune-specific” IFN signature genes can be applied as a clinical biomarker to diagnose SLE flare discriminating from viral infection.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cell-type-specific-type-i-interferon-signatures-in-systemic-lupus-erythematosus-and-viral-infection-what-makes-the-difference/