Dendritic cells (DCs) are professional antigen-presenting cells and trigger downstream immune responses to antigen while integrating cellular pathogen and damage-associated molecular pattern (PAMP and DAMP) or immunomodulatory signals. In healthy individuals, resting and tolerogenic DCs draining skin and intestine facilitate expansion of regulatory T cells (Treg) to maintain peripheral antigen-specific immune tolerance. In patients with rheumatic diseases, however, DCs activated by PAMPs and DAMPs expand self-reactive effector T cells, including follicular helper T cells that promote the expansion of activated autoreactive B cells, chronic inflammation and end-organ damage. With the development of cellular and nanoparticle (NP)-based self-antigen-specific immunotherapies we here consider the new opportunities and the challenges for restoring immunoregulation in the treatment and prevention of autoimmune inflammatory rheumatic conditions through DCs.