Vaccination in autoimmunity can have beneficial, but also detrimental effects. In this thesis, we tried to identify factors that contribute to a favourable or an unfavourable outcome of vaccination in Juvenile Idiopathic Arthritis (JIA) and experimental arthritis. In the first part, we focused on the potential unwanted effects of vaccination against Meningitis type C in two studies in JIA patients receiving the Meningococcal C vaccine. In chapter 2 we describe that no clinical disease aggravation was detected after MenC vaccination in a large cohort of JIA patients. Although geometric mean titers of anti-MenC antibodies were lower in treatment groups receiving immune suppressive medication, functional MenC bactericidal capacity of these antibodies was adequate in all patients. These were encouraging results, supporting the positive advice of administration of vaccines to children with JIA. However, the results of chapter 3 raise a concern for JIA patients with non-remitting disease. The increased pro-inflammatory cytokine profile raised by vaccine specific T cells after vaccination in these patients in combination with an aberrant FOXP3+ regulatory T cell (Treg) response theoretically could hold a risk for aggravating autoimmunity, although this potential clinical effect was not observed in our study. For the second part of this thesis, we studied the potential protective effects of nasal peptide vaccination against rat adjuvant induced arthritis. First, we hypothesized that mucosal vaccination with a bystander antigen like heat shock protein (HSP) (peptide immunotherapy) may be able to protect against autoimmune arthritis (reviewed in chapter 4). In chapter 5 we show that mucosal administration of such a bystander peptide derived from bacterial HSP60 protects against experimental arthritis, and that this protection was transferable by CD4+ T cells. Skewing of the peptide-specific immune response towards a regulatory phenotype might have played a role, as peptide treatment was associated with a reduction of peptide specific tumour necrosis factor α (TNFα) production by CD4+Tcells and the presence of suppressive CD4+FoxP3+ Treg cells. Addition of a mucosal adjuvant (CpG) to peptide specific immunotherapy clearly enhanced clinical efficacy in experimental arthritis (chapter 6). Co-treatment of p1 with CpG increased both the number and activation status of plasmacytoid DC in draining MLN, which was accompanied by augmented p1-specific T cell proliferation and IL-10 production. After arthritis induction, p1- and p1/CpG-treated rats showed increased amounts of CD4+FoxP3+ Tregs in the joint draining lymph nodes, which correlated with lower arthritis scores. The data in chapter 7 show an improvement in the clinical and immunological effect of nasal HSP peptide immunotherapy in a therapeutic (instead of preventive) setting. Peptide immunotherapy with a bacterial HSP60 peptide after initiation of adjuvant arthritis was most effective when combined with low dose TNFα receptor blockade (Etanercept), reaching the same level of protection as full dose Etanercept treatment. Combination treatment led to an increase in peptide specific IL-10 production by CD4+ T cells and an upregulation of FoxP3 gene expression in CD4+CD25+ Treg cells. These new approaches for more effective peptide immunotherapy could pave the way for a promising future of peptide specific immunotherapy in autoimmune disease.