Type I Interferon Gene Response Is Increased in Early and Established Rheumatoid Arthritis and Correlates with Autoantibody Production

Abstract

BackgroundRheumatoid arthritis (RA) is an inflammatory debilitating disease that affects the joints in the early and productive phases of an individual’s life. Several cytokines have been linked to the disease pathogenesis and are known to contribute to the inflammatory state characteristic of RA. The participation of type I interferon (IFN) in the pathogenesis of the disease has been already described as well as the identity of the genes that are regulated by this molecule, which are collectively known as the type I IFN signature. These genes have several functions associated with apoptosis, transcriptional regulation, protein degradation, Th2 cell induction, B cell proliferation, etc. This article evaluated the expression of several genes of the IFN signature in different stages of disease and their correlation with the levels of anticitrullinated protein antibodies (ACPA) anticarbamylated protein (Anti-CarP) antibodies.MethodsSamples from individuals with early and established RA, high-risk individuals (ACPA+ and ACPA−), and healthy controls were recruited at “Unidad de Artritis y Rheumatismo” (Rheumatism and Arthritis Unit) in Guadalajara Jalisco Mexico. Determinations of ACPA were made with Eurodiagnostica ACPA plus kit. Anti-CarP determinations were made according to previously described protocols. RNA was isolated, and purity and integrity were determined according to RNA integrity number >6. Gene expression analysis was made by RT-qPCR using specific primers for mRNAs of the type I IFN signature. Relative gene expression was calculated according to Livak and Schmitgen.ResultsSignificant differences in gene expression were identified when comparing the different groups for MXA and MXB (P < 0.05), also when comparing established RA and ACPA− in both IFIT 1 and G15. An increased expression of ISG15 was identified (P < 0.05), and a clear tendency toward increase was identified for HERC5. EPSTRI1, IFI6, and IFI35 were found to be elevated in the chronic/established RA and early RA (P < 0.05). Significant correlations were identified for the IFN signature genes with the levels of ACPA and anti-CarP (P < 0.05).ConclusionOur data confirm previous observations in the role of IFN signature and the pathogenesis of RA. Also, we provide evidence of an association between several genes of the IFN signature (that regulate Th2 cells and B cell proliferation) with the levels of anti-CarP antibodies and ACPA.

The Interactions Between Cancer Stem Cells and the Innate Interferon Signaling Pathway

“…IFNs are fundamental players in the modulation of both innate and adaptive immune responses. Although they were first identified as molecules with a strong capability of inducing viral resistance in cells, many other activities have been discovered for this family of cytokines over the years, including their involvement in pathologies such as autoimmune diseases [e.g., systemic lupus erythematosus (6)(7)(8)(9) and rheumatoid arthritis (8,10,11)] and cancer (discussed below). IFNs, regardless of the specific receptor they activate, are able to exert pleiotropic effects, suggesting a rich signaling network coupled to IFN stimulation and undoubtedly adds complexity to understanding its effects on cell function and its contributions to immune response regulation.…”

Biological links in periodontitis and rheumatoid arthritis: Discovery via text‐mining PubMed abstracts

“…P. gingivalis produces a ubiquitin‐ligase Smurf‐1 dependent degradation of MyD88, an upstream regulator NF‐κB in neutrophils, and results in elevated type‐1 interferon . Type‐1 interferon is increased in RA and correlated to ACPA production and drug response . MyD88 is also implicated in neutrophil recruitment in hypersensitivity …”

Dysregulation of Innate Lymphoid Cells in Common Variable Immunodeficiency

“…Moreover, how does the observed IFN signature gene dysregulation relate to the profound B cell dysfunction characterizing CVID? IFN has been shown to delete B cells in the setting of viral infection but has also been linked to the development of autoantibodies, so clearer delineation of the impact of IFN, and perhaps IFN-γ specifically, upon B cells remains to be defined [109, 110]. While early reports have hinted at the importance of IFN and ILC expansion for emergence of non-infectious complications in CVID, the area remains in need of greater research efforts in order to progress toward impactful clinical intervention.…”