Abstract
Background: Hashimoto’s thyroiditis and Graves’ disease are autoimmune thyroid disorders (AITD) of unknown origin. Enterovirus (EV) infection of thyroid cells has been implicated as a possible initiator of cell damage and of organ-specific autoimmunity. We asked whether persistent infection of human epithelial cells with EV strains obtained from thyroid tissue of AITD patients could be associated with transcriptional changes capable of fostering immunopathology. Methods: EV isolates obtained from thyroid tissue of AITD cases were used to infect the AV3 epithelial cell line. AV3 cells incubated with a virus-free medium from thyroid tissue of subjects without evidence of thyroid autoimmunity were used as uninfected controls. Transcripts of immune-related genes were compared in infected vs. uninfected cells. Results: The EV genome and antigens were detected only in the cells exposed to AITD-derived virus isolates, not in control cells. Persistent EV infection, while suppressing transcription of several type I IFN and cytokine determinants, was associated with enhanced transcription of NFKB1/RELA, IFNAR1, JAK1/STAT1, i.e., the determinants that play key immunologic roles. Infection also led to upregulation of the CCL2 chemokine and the IL-18 pro-inflammatory interleukin. Conclusion: As in the case of EV strains obtained from autoimmune diabetes, results show that the EV strains that are present in the thyroid of AITD cases do repress IFN and cytokine pathways. JAK1/STAT1 upregulation supports activation of TLR pathways and aberrant T cell signaling. In the early phases of AITD, our results highlight the potential benefit of interventions aimed at blocking the viral infection and easing the inflammatory response.
Highlights
IntroductionGraves’ disease (GD) is common and causes hyperthyroidism due to excessive production of thyroid hormones via stimulatory autoantibodies directed to the thyrotropin receptor [2]
Graves’ disease (GD) cases were characterized by low TSH levels and somewhat enhanced FT3 or FT4 levels together with positivity for thyroid receptor-stimulating autoantibodies (TR-Ab), reduced levels of serum TSH and possible positivity for other thyroid autoantibodies
In the context of autoimmune diabetes, pancreatic islets infected in vitro with echovirus strains isolated in the course of Cuba epidemics showed upregulated transcription of TLR3 and IFN-beta genes [28]
Summary
Graves’ disease (GD) is common and causes hyperthyroidism due to excessive production of thyroid hormones via stimulatory autoantibodies directed to the thyrotropin receptor [2]. In both cases, undetermined stimuli are deemed to break immune tolerance and promote organ-specific autoimmunity [3]. We asked whether persistent infection of human epithelial cells with EV strains obtained from thyroid tissue of AITD patients could be associated with transcriptional changes capable of fostering immunopathology. Methods: EV isolates obtained from thyroid tissue of AITD cases were used to infect the AV3 epithelial cell line. Conclusion: As in the case of EV strains obtained from autoimmune diabetes, results show that the EV strains that are present in the thyroid of AITD cases do repress
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