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New developments in vaccine design shift towards safe, though sometimes less immunogenic, subunit and synthetic antigens. Therefore, the majority of current vaccines require adjuvants to increase immunogenicity. Most adjuvants available were developed empirically and their mode of action is only partly elucidated. Earlier work shows that adjuvants exert their effect mainly on the innate immune system. To improve vaccines, more knowledge on adjuvants’ modes of action and their effect on innate immune responses at the site of application are required. Furthermore, immune responses that take place after vaccination are sometimes linked with the development or exacerbation of autoimmune diseases (AID). It is highly debated íf vaccines indeed induce or aggravate AID and in particular adjuvants are mentioned as potential cause. Since vaccines are given on a large scale, more research is warranted. The aim of this thesis was to study working mechanisms of vaccines and adjuvants locally (innate immune system) as well as systemically (adaptive immune system) to identify possible risks on severe side effects of vaccination and potentially improve vaccine effectiveness. A panel of human and experimental adjuvants was tested in mice for their local effects and ability to initiate adaptive responses. Rapid but transient immune-stimulatory environments were induced by most adjuvants. Antigen-uptake and -presentation by APC and maturation of APC were differentially affected by distinct adjuvants. The choice of adjuvant determined the outcome of the initiated adaptive immune response and we showed that the route of administration of vaccines (intranasal or intradermal) also influences the response induced. Two potential mechanisms on how AID could result from vaccination were explored; (1) bystander activation and (2) disturbances in regulatory T cells (Treg). During bystander activation, T cells unrelated to the antigen presented can be activated without (strong) T cell