Nucleic acid accumulation in repeat expansion disease poses multiple challenges to cellular integrity. Myotonic dystrophy type 2 (DM2) results from large CCTG repeats in the CNBP gene leading to myopathy and an increased prevalence of autoimmunity. Here, we observed that DM2 patients exhibited a type-I interferon signature in blood and cultured fibroblasts. RNA repeat accumulation was prevalent in the cytosol of DM2 patient fibroblasts, facilitating repeat-associated non-AUG translation. The ensuing chronic endoplasmic reticulum (ER) stress response led to an ATF6-controlled induction of type-I IFN dependent on the cGAS/STING pathway. Recapitulating chronic ER stress in the monocytic THP-1 cell line revealed its dependence on mitochondrial DNA (mtDNA). Correspondingly, mitochondrial stress and cytosolic leakage of mtDNA was observed in DM2 patient fibroblasts. Altogether, our study demonstrates a novel mechanism by which large repeat expansions cause chronic ER and mitochondrial stress and induce a type-I interferon response that predisposes to autoimmunity. Keywords: ER stress, ATF6, Autoimmunity, type I IFN, repeat expansions