Type I Interferon in the Pathogenesis of Lupus

Abstract

Investigations of patients with systemic lupus erythematosus (SLE) have applied insights from studies of the innate immune response to define type I interferon (IFN-I), with IFN-α the dominant mediator, as central to the pathogenesis of this prototype systemic autoimmune disease. Genetic association data identify regulators of nucleic acid degradation and components of TLR-independent, endosomal TLR-dependent, and IFN-I signaling pathways as contributors to lupus disease susceptibility. Together with a gene expression signature characterized by IFNI-induced gene transcripts in lupus blood and tissue, those data support the conclusion that many of the immunologic and pathologic features of this disease are a consequence of a persistent self-directed immune reaction driven by IFN-I and mimicking a sustained anti-virus response. This expanding knowledge of the role of IFN-I and the innate immune response suggests candidate therapeutic targets that are being tested in lupus patients.

Disruption of Type I-IFN Signaling Decreases Autoimmune Development and Kidney Damage, But Not Anxiety-Like Behaviors in Lupus NZB Mice

“…Serologic analysis revealed a decrease in serum ANA level by 26% in NZB/IFNARKO mice compared to NZB control mice (p = 0.07) ( Figure 3C). Together, the results confirmed an importance of type I-IFN signaling in the development of autoimmunity and kidney damage [3,6].…”

“…Significant attenuation of the autoimmune response and tissue inflammation in NZB/IFNARKO mice is detected by amelioration of glomerulonephritis, blockade of splenomegaly and decreased levels of serum ANA. Such observation provides further support for the importance of type I-IFN in the pathogenesis of autoimmune development and kidney injury [3]. Nevertheless, despite the reports of type I interferon for autoimmune-induced psychiatric abnormality developed in SLE patients [20] and lupus-prone mice [10], inhibition of type I-IFN signaling by knocking out its receptor does not change the performance of these mice on elevated-plus maze.…”

“…However, the etiology and pathogenesis of SLE remains largely unknown. Nevertheless, a role of type I interferon (IFN) has been suggested in the pathogenesis of SLE by studies both from humans and animal models [3]. For example, gene chip analyses reveal a significantly enhanced transcriptional profile in the cells prepared from SLE patients in response to IFN-α (a major form of type I IFN) [4,5].…”

FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression

“…Atorvastatin reversed MR signaling abnormalities in SLE T-cells (65). Fc␥R engagement by ICs in many cell types drive IFN production (66). The CD4…”

Type I interferon–mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy

“…Although pDCs are the main source of IFN-I, other cells such as epithelial cells or fibroblasts can secrete these cytokines (23). IFN production by neutrophils may be important in autoimmunity (24).…”