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CORRELATION BETWEEN TYPE I INTERFERON GENE RESPONSES AND AUTOANTIBODY PRODUCTION IN PRECLINICAL AND EARLY STAGE RHEUMATOID ARTHRITIS

JOSE ANTONIO ENCISO-MORENO1, Julio E. Castañeda Delgado1, 2, Noe Macias-Segura1, David Santiago-Algarra1, Jose D. Castillo-Delgado3, Ana L. Aleman-Navarro1, Pedro Martinez-Tejada4, Yolanda García De Lira1, Diana Olguin-Calderon1, Leonor Enciso-Moreno1, Yadira Bastian-Hernandez1, 2 and Cesar Ramos-Remus3*
  • 1 Unidad de Investigación Biomédica de Zacatecas, IMSS, Mexico
  • 2 Catedras-CONACyT at UIBMZ-Mexican Institute for Social Security, Mexico
  • 3 Unidad de investigación en enfermedades crónico-degenerativas, Mexico
  • 4 Hospital Dr. Emilio Varela-Luján, IMSS., Mexico

Rheumatoid arthritis (RA) is an autoimmune disease that shows a prevalence of approximately 1% worldwide. It is characterized by joint destruction and severe inflammation that ultimately results in deterioration of the quality of life and productivity loss. Although several of the immune mediated phenomena that have been associated with bone destruction and joint inflammation have been extensively described, the underlying causes of the autoimmune response and tolerance loss have not been identified. Recently, it was described in systemic lupus erythematosus as well as in rheumatoid arthritis, that increased expression of type I interferon genes are associated with onset of the disease. Given that several genes of the interferon signature are associated with immune regulation and immune response to viral pathogens (and in consequence with maintenance of auto tolerance), we wondered whether gene expression correlated with autoantibody production due to its participation in the pathogenesis of the disease. The aim of the present work was to evaluate the relative gene expression of the genes RSAD2, MXB, HERC5, IFIT2, EPSTRI1, IFI35, ISG15, IFI44L, IFIT1, IFI6, MXA, Ly6E in blood samples isolated from patients with RA and first degree relatives and evaluate their correlation with anticitrullinated and anticarbamilated antibodies in clinical and preclinical stages of the disease. For this purpose, blood samples were drawn from: First-degree relatives of patients with RA stratified in positive (ACCP+; n=20) or negative (ACCP-; n=20) to ACCP; patients with early RA (less than 2 years of diagnosis, eRA; n=10) and patients with established RA with more than 2 years with the disease (cRA). All patients with cRA were under treatment with disease modifying anti rheumatic drugs (DMARDs). A group of healthy controls without a family history of autoimmune diseases (assessed by COPCORD questionnaire) was also included, (HC; n=20). Antibody determinations were carried out in serum using a second generation ACCP ELISA (EuroDiagnostica, Sweden) and a in house validated assay for CarP antibodies. RNA was isolated and integrity verified by means of capillary electrophoresis (Bioanalyzer, Life Technologies). cDNA synthesis was carried out by a superscript II reverse transcription system (Invitrogen), with 2.5 ug total RNA for the reverse transcription reaction. qPCR assays were run in a Lightcycler 480 (Roche diagnostics). Normalization of gene expression data was made using the HPRT gene. The DDCt method was used for relative gene expression analysis. Normality of data was verified by a KS normality test. Multiple comparisons tests (Kruskal-Wallis or one way ANOVA) were done to identify differences in gene expression between groups. Spearman or Pearson correlation analysis was performed to identify associations between variables. Differences between the chronic arthritis group and the healthy controls were identified for IFIT1, IFIT2, IFI35, ISG15, Ly6E, HERC5, RSAD2, EPSTRI1 and MXA (p<0.05) confirming previous reports in our population. However, differences among the healthy controls or the ACPA- individuals and the eRA cases were also identified for the genes IFI 5, MXA and MXB (P<0.05) that have implicated in the early response to viral infections and suggesting that in individuals with early manifestations of the disease an infection might trigger it. A significant correlation was found for several genes in the signalling cascade such as IFIT1, EPSTRI1, IFI35, LY6E, HERC5 and MXA with autoantibody levels (both ACCP and carP, P<0.05). These data suggest that the signalling pathways responsible for autoantibody generation are being induced and the cascades that regulate the type I interferon gene response might contribute to the development of the disease and to the autoimmune reaction. Given the study design it is difficult to establish a causality relationship between autoantibody genesis and interferon gene responses, but further prospective designs might solve this issue. The use of these markers to further advance the classification of arthritis and early RA needs to be further explored.

Keywords: Rheumatoid arthritis, interferon signature, carbamylated, citrulinated, tolerance mechanisms

Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.

Presentation Type: Poster Presentation

Topic: Autoimmunity

Citation: ENCISO-MORENO J, Castañeda Delgado JE, Macias-Segura N, Santiago-Algarra D, Castillo-Delgado JD, Aleman-Navarro AL, Martinez-Tejada P, García De Lira Y, Olguin-Calderon D, Enciso-Moreno L, Bastian-Hernandez Y and Ramos-Remus C (2015). CORRELATION BETWEEN TYPE I INTERFERON GENE RESPONSES AND AUTOANTIBODY PRODUCTION IN PRECLINICAL AND EARLY STAGE RHEUMATOID ARTHRITIS. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00197

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Received: 15 May 2015; Published Online: 14 Sep 2015.

* Correspondence: MD. Cesar Ramos-Remus, Unidad de investigación en enfermedades crónico-degenerativas, Guadalajara, Jalisco, Mexico, r_ramos@prodigy.net.mx