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Objective: Several hypotheses have been proposed to explain the strong association between HLA-B27 and ankylosing spondylitis (AS). Among these, the arthritogenic peptide theory proposes that certain B27 subtype alleles bind specific arthritogenic peptide(s) due to their unique amino acid anchor residues. Cartilage antigens have been discussed as candidate targets for the immune response in AS. The recognition of HLA-B27-peptide complexes by self-reactive CD8+ T cells might contribute to joint-specific tissue damage. Therefore, we investigated the presence of autoreactive CD8+ T cells specific for cartilage-derived peptides in patients with AS., Methods: An HLA-B27-binding prediction program and a proteasome-cutting prediction program for the human 20S proteasome were used to screen 18 human cartilage proteins for potentially immunogenic nonamer peptides. The peptides identified were used to stimulate peripheral blood mononuclear cells from 20 HLA-B27-positive patients with AS and synovial fluid (SF) mononuclear cells from 7 HLA-B27-positive patients with AS. Activation of T cells was measured by antigen-specific intracellular cytokine staining and quantified by flow cytometry., Results: From the screening analysis, we identified 121 nonamer peptides. Of these, 1 peptide derived from type II collagen and 1 from type VI collagen were stimulatory for peripheral blood CD8+ T cells in only 1 of 20 patients. However, in 4 of 7 SF samples the same type VI collagen-derived nonamer peptide stimulated SF CD8+ T cells, but none of the other peptides was stimulatory. This CD8+ T cell response could be blocked by an anti-HLA-B27 antibody, confirming an HLA-B27-restricted immune response., Conclusion: Our findings suggest that cartilage-directed cellular autoimmunity might play an important role in joint-specific tissue damage in patients with AS. Future research is necessary to determine whether the identified peptide is of pathogenetic relevance.