This invention relates to methods and compositions for treating or preventing disease comprising the administration of immune modulatory nucleic acids having one or more immune modulatory sequences (IMSs). The invention further relates to the means and methods for the identification of the IMSs for preventing or treating disease, more particularly the treatment and prevention of autoimmune or inflammatory diseases. The invention also relates to the treatment or prevention of disease comprising the administration of the immune modulatory nucleic acids alone or in combination with a polynucleotide encoding self-antigen(s), -proteins(s), -polypeptide(s) or -peptide(s). The present invention also relates to methods and compositions for treating diseases in a subject associated with one or more self-antigen(s), self-proteins(s), -polypeptide(s) or -peptide(s) that are present in the subject and involved in a non-physiological state.