INTERFERON-ALPHA MEDIATES THE DEVELOPMENT OF AUTOIMMUNITY BOTH BY DIRECT TISSUE TOXICITY AND THROUGH IMMUNE-CELL RECRUITMENT MECHANISMS

• Published in: The Journal of immunology (1950) 2011-03, Vol.186 (8), p.4693-4706
• Main Authors: Akeno, Nagako, Smith, Eric P., Stefan, Mihaela, Huber, Amanda K., Zhang, Weijia, Keddache, Mehdi, Tomer, Yaron
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1002631

Interferon alpha (IFNα) is known to play a key role in autoimmunity, but the mechanisms are uncertain. Although the induction of autoimmunity by IFNα is consistent with primarily immuno-modulatory effects, the high frequency of non-autoimmune inflammation suggests other mechanisms. We used thyroiditis as a model to dissect these possibilities. IFNα treatment of cultured thyrocytes increased expression of thyroid differentiation markers, thyroglobulin (Tg), thyroid stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), and sodium iodide transporter (NIS). RNAseq analysis demonstrated that pathways of antigen presentation, pattern recognition receptors, and cytokines/chemokines were also stimulated. These changes were associated with markedly increased non-apoptotic thyroid cell death suggesting direct toxicity. To corroborate these in vitro findings we created transgenic mice with thyroid specific overexpression of IFNα under control of the Tg promoter. Transgenic mice developed marked inflammatory thyroid destruction associated with immune cell infiltration of thyroid and surrounding tissues leading to profound hypothyroidism, findings consistent with our in vitro results. In addition, transgenic mice thyroids showed upregulation of pathways similar to those observed in cultured thryocytes. In particular, expression of granzyme B, CXCL10, a subset of the TRIM (tripartite motif containing) family and other genes involved in recruitment of bystander cytotoxic immune responses were increased. Pathways associated with apoptosis and autophagy were not induced. Taken together, our data demonstrate that the induction of tissue inflammation and autoimmunity by IFNα involves direct tissue toxic effects as well as provocation of destructive bystander immune responses.